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    You are here : Home » MS Research News » New Discoveries » Nerve and Brain Cell Research

    Nerve and Brain Cell Research

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    Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation

    Brain CellsMultiple sclerosis involves demyelination and axonal degeneration of the central nervous system. The molecular mechanisms of axonal degeneration are relatively unexplored in both multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis.

    We previously reported that targeting the axonal growth inhibitor, Nogo-A, may protect against neurodegeneration in experimental autoimmune encephalomyelitis; however, the mechanism by which this occurs is unclear.

    We now show that the collapsin response mediator protein 2 (CRMP-2), an important tubulin-associated protein that regulates axonal growth, is phosphorylated and hence inhibited during the progression of experimental autoimmune encephalomyelitis in degenerating axons.

    The phosphorylated form of CRMP-2 (pThr555CRMP-2) is localized to spinal cord neurons and axons in chronic-active multiple sclerosis lesions. Specifically, pThr555CRMP-2 is implicated to be Nogo-66 receptor 1 (NgR1)-dependent, since myelin oligodendrocyte glycoprotein (MOG)35–55-induced NgR1 knock-out (ngr1−/−) mice display a reduced experimental autoimmune encephalomyelitis disease progression, without a deregulation of ngr1−/− MOG35–55-reactive lymphocytes and monocytes.

    The limitation of axonal degeneration/loss in experimental autoimmune encephalomyelitis-induced ngr1−/− mice is associated with lower levels of pThr555CRMP-2 in the spinal cord and optic nerve during experimental autoimmune encephalomyelitis.

    Furthermore, transduction of retinal ganglion cells with an adeno-associated viral vector encoding a site-specific mutant T555ACRMP-2 construct, limits optic nerve axonal degeneration occurring at peak stage of experimental autoimmune encephalomyelitis.

    Therapeutic administration of the anti-Nogo(623–640) antibody during the course of experimental autoimmune encephalomyelitis, associated with an improved clinical outcome, is demonstrated to abrogate the protein levels of pThr555CRMP-2 in the spinal cord and improve pathological outcome.

    We conclude that phosphorylation of CRMP-2 may be downstream of NgR1 activation and play a role in axonal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Blockade of Nogo-A/NgR1 interaction may serve as a viable therapeutic target in multiple sclerosis.

    Full text

    Steven Petratos, Ezgi Ozturk, Michael F. Azari, Rachel Kenny, Jae Young Lee, Kylie A. Magee, Alan R. Harvey, Courtney McDonald, Kasra Taghian, Leon Moussa, Pei Mun Aui, Christopher Siatskas, Sara Litwak, Michael G. Fehlings, Stephen M. Strittmatter and Claude C. A. Bernard

    Source: Brain Copyright © 2012 Guarantors of Brain (08/05/12)

    Neuroscientists discover key protein responsible for controlling nerve cell protection

    Nerve Cells A key protein, which may be activated to protect nerve cells from damage during heart failure or epileptic seizure, has been found to regulate the transfer of information between nerve cells in the brain. The discovery, made by neuroscientists at the University of Bristol and published in Nature Neuroscience and PNAS, could lead to novel new therapies for stroke and epilepsy.

    The research team, led by Professor Jeremy Henley and Dr Jack Mellor from Bristols Medical School, has identified a protein, known as SUMO, responsible for controlling the chemical processes which reduce or enhance protection mechanisms for nerve cells in the brain.

    These key proteins produce subtle responses to the brains activity levels to regulate the amount of information transmitted by kainate receptors - responsible for communication between nerve cells and whose activation can lead to epileptic seizures and nerve cell death.

    Protein function is controlled by altering their structure in processes that can be independent or inter-related including phosphorylation, ubiquitination and SUMOylation. In the present work it is shown that phosphorylation of kainate receptors on its own promotes their activity. However, phosphorylation also facilitates SUMOylation of kainate receptors that reduces their activity. Thus there is a dynamic and delicate interplay between phosphorylation and SUMOylation that regulates kainate receptor function.

    This fine balance between phosphorylation and SUMOylation is dependent on brain activity levels where damaging activity that occurs during stroke or epilepsy will enhance SUMOylation and therefore reduce kainate receptor function to protect nerve cells.

    Dr Mellor, Senior Lecturer from the Universitys School of Physiology and Pharmacology, said: Kainate receptors are a somewhat mysterious but clearly very important group of proteins that are known to be involved in a number of diseases including epilepsy. However, we currently know little about what makes kainate receptors so important. Likewise, we also know that SUMO proteins play an important role in neuroprotection. These findings provide a link between SUMO and kainate receptors that increases our understanding of the processes that nerve cells use to protect themselves from excessive and abnormal activity.

    Professor Henley added: This work is important because it gives a new perspective and a deeper understanding of how the flow of information between cells in the brain is regulated. The team has found that by increasing the amount of SUMO attached to kainate receptors which would reduce communication between the cells could be a way to treat epilepsy by preventing over-excitation of the brains nerve cells.

    The research follows on from previous findings published in Nature that discovered SUMO proteins target the brains kainate receptors altering their cellular location.

    The research teams comprised academics from the University of Bristols MRC Centre for Synaptic Plasticity and the Division of Neuroscience in the School of Physiology & Pharmacology and the School of Biochemistry. This work was supported by the Wellcome Trust, Biotechnology and Biological Sciences Research Council (BBSRC), European Research Council (ERC), Medical Research Council (MRC) and EMBO.

    Source: Scientist Live ©2012 Setform Limited (27/04/12)

    Breakthrough in nerve mapping gives hope for neurologists

    NeuronsA breakthrough in the mapping of monkey nerve fibers might lead to early diagnosis and improved treatment for neurological diseases in humans, according to Taiwanese research published Friday.

    "The structure of nerve fibers, we have found, follows a checker-board pattern," said Tseng Wen-yih, a biomedical expert from National Taiwan University, at a press conference held to announce the publication of the findings in a peer-reviewed journal.

    Neurological disorders such as schizophrenia, hyperactive disorder, autism, dementia and epilepsy can be triggered when a deviation occurs in the brain's "wiring system," he said.

    Unlike the common portrayal of brain nerve fibers as branches of a tree that spread in every direction, Tseng said his team found that fiber bundles constitute an orderly three-dimensional grid that more resembles intricately woven cloth.

    "The findings took us by surprise," Tseng told reporters. "We have uncovered a clear blueprint of brain fibers."

    Tseng and a group of scientists from around the world, including some from Harvard University, have been working together for years to uncover fiber trajectories, and their latest findings were published in the journal Science on March 30.

    The study was based on the brains of monkeys from six different species, but current magnetic resonance imaging (MRI) technology needs improvement to fully sketch out the fiber pathways of living humans, Tseng said.

    Nevertheless, the discovery could yield many applications, including the understanding and prevention of neurological disorders in humans.

    Taking autism as an example, Tseng said that the fiber bundles in sufferers in areas of cognition and language processing seem abnormal.

    If a more sophisticated MRI machine could be designed, doctors would be able to diagnose patients more quickly and precisely, he added.

    The blueprint could also serve as a guideline for the assessment of drug efficiency on patients, he added.

    Tseng said he is in negotiations with local hospitals to take his findings to the stage of clinical trials.

    Describing the discovery as "revolutionary," Yang Pan-chyr, dean of National Taiwan University's College of Medicine, said scientists could work on the findings and further explain how the brain works.

    Source: Focus Taiwan (30/03/12)

    Neuron transplants can repair brain circuits

    NeuronsA new study by Harvard University neuroscientist Jeffrey Macklis and colleagues suggests it is possible to transplant fetal neurons into a part of the mouse brain that does not normally generate new brain cells, and they will repair abnormal circuits. In this case, the researchers repaired a genetic defect that causes obesity, but that was not the goal of their work which was to establish proof of principle that transplanted neurons can integrate into existing faulty brain circuits and restore them.

    The study, published online in the journal Science on 25 November, challenges the idea that you can't repair key parts of the mammalian brain.

    The researchers, from Harvard University, Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) used mutant mice that had been genetically engineered to lack the receptor for leptin, a hormone that acts on brain cells in the hypothalamus to regulate metabolism and control body weight. Without this receptor, mice become morbidly obese and diabetic.

    This type of genetically modified mouse is commonly used as an animal model for researching obesity, diabetes, and dyslipidemia, and is known as the "db/db mouse".

    The researchers took normal hypothalamus neurons, selected at a particular stage development, from the brains of fetal mice that did not lack the leptin receptor, and transplanted them into the hypothalamus of the mutant mice. To put the transplanted cells exactly in the right place, in a microscopically small region of the hypothalamus, they used a method known as "high-resolution ultrasound microscopy".

    The transplanted neurons repaired the defective brain circuits, so the mutant mice could respond to leptin, with the result that they gained substantially less weight.

    The mice that received the transplanted cells still grew to be fatter than normal mice, but they were not as fat as morbidly obese-prone mice that did not receive the transplants, and they did not become diabetic. The transplant recipients weighed about 40 to 45 grams a few days after birth, compared with 25 grams for normal mice and 55 to 60 grams for obese-prone mice that underwent a placebo-like operation without receiving any new neurons.

    Macklis and colleagues also investigated what happened in the brains of the mice after they received the transplants. They used several markers, including the fact that another gene in the transplanted neurons causes a protein to fluoresce green in a given light, to follow the path the cells took. They found that the transplanted neurons had specialized into several different types normally found in the hypothalamus. Not only this, but they had also formed synapses with other neurons: synaptic connections are essential for brain cells to communicate with each other.

    The researchers write in their paper:

    "Donor neurons differentiated and integrated as four distinct hypothalamic neuron subtypes, formed functional excitatory and inhibitory synapses, partially restored leptin responsiveness, and ameliorated hyperglycemia and obesity in db/db mice."

    They also showed that the new hypothalamic neurons had the same pattern of electrical activity as normal neurons in response to leptin, and were communicating with the native neurons.

    Macklis told Science NOW that the new neurons were behaving like "antennas" for leptin, and sending those signals into the brain. He and his colleagues write in their conclusion:

    "These experiments serve as a proof of concept that transplanted neurons can functionally reconstitute complex neuronal circuitry in the mammalian brain."

    They hope the ability to repair brain circuits in this way will open the door to treating a range of of higher level conditions, including spinal cord injury, autism, epilepsy, Huntington's disease, Parkinson's disease, Multiple Sclerosis and ALS (Lou Gehrig's disease).

    However, the path to such new avenues is likely to bring challenges as well as promises. Within the last month we have had the news that Geron, the Californian biotech company, has pulled out of its trial on using stem cells to repair spinal injury, and it seems lack of funding is why it is withdrawing from stem cell work altogether. And studies testing fetal cell transplants for treating Parkinson's disease have also not yielded the anticipated promises.

    But Macklis and colleagues appear more optimistic, pointing to new lessons learned in their study, such as the importance of harvesting the fetal neurons at precisely the point when they are about to differentiate into different types of hypothalamic neurons. Previous experiments may have failed because the scientists did not realize the importance of this timing. It could be, for instance, that there is a need to match the signals in the new environment to the readiness of the transplanted cells to receive them.

    They call their study a "proof of concept" for the broader idea that new neurons can integrate into and modify defective complex circuits in the brains of mammals.

    They are now moving onto what they call "controlled neurogenesis", where scientists direct the growth of new brain cells from inside the brain, thus opening a new route to regenerative therapies.

    Macklis told Harvard Gazette:

    "The next step for us is to ask parallel questions of other parts of the brain and spinal cord, those involved in ALS and with spinal cord injuries."

    "In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can," he added.

    Funds from the National Institutes of Health, the Jane and Lee Seidman Fund for Central Nervous System Research, the Emily and Robert Pearlstein Fund for Nervous System Repair, the Picower Foundation, the National Institute of Neurological Disorders and Stroke, Autism Speaks, and the Nancy Lurie Marks Family Foundation, paid for the study.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011 (28/11/11)

    Persian spice saffron may hold potential treatment for MS

    SaffronAn active ingredient in the Persian spice saffron may be used to treat diseases involving neuroinflammation, such as multiple sclerosis, according to Medical researchers at the University of Alberta.

    "We found there is a compound in saffron, known as crocin, that exerts a protective effect in brain cell cultures and other models of MS. It prevented damage to cells that make myelin in the brain," said researcher Chris Power of the University.

    "Myelin is insulation around nerves. MS is characterized by inflamed brain cells that have lost this protective insulation, which ultimately leads to neurodegeneration," he explained.

    Power noted they are not close to a clinical trial stage yet, but the finding is still exciting.

    It has been known in the research community for years that crocin protected neurons in certain situations, but Power and his team wanted to delve further into this area.

    His team discovered that inflammation and a specific type of cell stress are closely linked and lead to neurodegeneration and inflammation, which cause cells to lose their protective coating - a process known as demyelination.

    In experiments conducted by Power and his colleagues, the use of crocin suppressed both inflammation and this specific type of cell stress, resulting in decreased neurological impairment in lab models and cell cultures with MS.

    "There are still many questions to be answered about how crocin exerts these neuroprotective effects, but this research highlights a potential treatment role for crocin in diseases involving chronic neuroinflammation - something that had not been recognized until now," noted Power.

    The findings have been recently published in the peer-reviewed publication, The Journal of Immunology.

    Neuroinflammation and endoplasmic reticulum stress are coregulated by crocin to prevent demyelination and neurodegeneration.


    Endoplasmic reticulum (ER) stress is a homeostatic mechanism, which is used by cells to adapt to intercellular and intracellular changes. Moreover, ER stress is closely linked to inflammatory pathways. We hypothesized that ER stress is an integral component of neuroinflammation and contributes to the development of neurological diseases.

    In autopsied brain specimens from multiple sclerosis (MS) and non-MS patients, XBP-1 spliced variant (XBP-1/s) was increased in MS brains (p < 0.05) and was correlated with the expression of the human endogenous retrovirus-W envelope transcript, which encodes the glycoprotein, Syncytin-1 (p < 0.05).

    In primary human fetal astrocytes transfected with a Syncytin-1-expressing plasmid, XBP-1/s, BiP, and NOS2 were induced, which was suppressed by crocin treatment (p < 0.05).

    Crocin also protected oligodendrocytes exposed to cytotoxic supernatants derived from Syncytin-1-expressing astrocytes (p < 0.05) and NO-mediated oligodendrocytotoxicity (p < 0.05).

    During experimental autoimmune encephalomyelitis (EAE), the transcript levels of the ER stress genes XBP-1/s, BiP, PERK, and CHOP were increased in diseased spinal cords compared with healthy littermates (p < 0.05), although CHOP expression was not involved in the EAE disease phenotype.

    Daily treatment with crocin starting on day 7 post-EAE induction suppressed ER stress and inflammatory gene expression in spinal cords (p < 0.05), which was accompanied by preserved myelination and axonal density, together with reduced T cell infiltration and macrophage activation. EAE-associated neurobehavioral deficits were also ameliorated by crocin treatment (p < 0.05).

    These findings underscored the convergent roles of pathogenic ER stress and immune pathways in neuroinflammatory disease and point to potential therapeutic applications for crocin.

    Source: J Immunol. 2011 Nov 1;187(9):4788-99. & Pubmed PMID: 21964030 & So Yahoo News Copyright © 2011 Yahoo India Pvt. Ltd. (07/11/11)

    Researchers possibly solve multiple sclerosis brain-cell mystery

    Brain CellsResearchers at UC Davis have discovered the source of cells involved in a phenomenon called reactive astrogliosis, characterized by a large number of enlarged star-shaped cells in the brains and spinal cords of people with multiple sclerosis, Alzheimer's disease and multiple episodes of minor head trauma. In multiple sclerosis, these abnormal cells are found in plaques that damage the myelin sheath that surrounds neurons, impairing their signaling function.

    The study is lead by David Pleasure, director of UC Davis' Institute for Pediatric Regenerative Medicine, and offers the first firm evidence to date that, at least in the case of multiple sclerosis, the cells are descendant from normal astrocytes.

    "This may not hold true for all diseases, but, in the case of MS, we have a very robust model," said Pleasure, who also is a professor in the Department of Neurology. The study used a widely used mouse-model of MS.

    The findings, published in the Aug. 17 issue of the Journal of Neuroscience, used genetic fate-mapping techniques in a mouse model to show that reactive astroglial cells in the MS model were derived from normal astrocytes that had increased in size and number.

    The findings are significant because the neurological diseases and injuries in which reactive astrogliosis occurs are also ones for which there are no effective cures. Knowing the origin of the cells, scientists can now compare normal astrocytes with the ones associated with disease and try to figure out what has gone awry.

    In multiple sclerosis, these abnormal cells are found in and around plaques in the brain and spinal cord, where there is evidence of damage to myelin sheaths and axons. In patients with Alzheimer's disease or after recurrent head trauma, these abnormal cells are scattered throughout the brain.

    "Some say these cells are 'bad guys' that contribute to the pathology of diseases. Some say they are 'good guys' trying to support the neurons under adverse conditions."

    The current study does not settle that controversy, but it is an important step in that direction and in the search for cures, Pleasure said.

    MS is an autoimmune disease in which a person's own disease-fighting mechanisms attack neurons in the central nervous system, destroying the myelin and, to some degree, the axon — the long, slender projection of the nerve cell. The disease is characterized initially by episodes of reversible neurologic deficits. In most patients, these episodes are followed by progressive neurologic deterioration over time. The cause of the disease is unknown.

    Normal astrocytes, collectively called astroglia, are the "helper cells" of the central nervous system, offering biochemical support and providing nutrients to neurons found in the brain and spinal cord. Until now, scientists did not know whether the cells found in demyelinating plaques came from other neurological cell types, as at least one study had suggested, or from normal astrocytes.

    Fuzheng Guo, the study's first author and a postdoctoral fellow in Pleasure's lab, led the team that conducted the experiments for the current study. The team used genetically engineered mice whose astrocytes express enhanced yellow fluorescent protein when injected with tamoxifen, a synthetic form of the hormone estrogen.

    Researchers injected these 2- to 5-month-old mice with tamoxifen and, 30 to 40 days later, injected them with a protein that causes experimental autoimmune encephalomyelitis, a widely used model for MS. Control mice received sham injections. At regular intervals, the team scored the severity of the multiple sclerosis-like symptoms, such as limping.

    The idea was to determine what happened to the normal astrocytes — as well as any cells that might descend from them via cell division — as the animals developed the disease.

    At the end of the experiment, the team counted and measured astroglial cells in both diseased and control mice. They found, in the gray matter of the brain and spinal cord, only an increase in cell size. In the white matter, they found both an increase in size and number of astrocytes.

    The team also conducted similar experiments tracking the fate of other neurological cell types, including oligodendrocyte progentior cells (which give rise to oligodendrocytes that insulate axons) and ependymal cells (which line the cerebral ventricles).

    According to Pleasure, the current study will help to guide the search for a cure for MS and other diseases involving demyelination. His lab and others are now repeating these experiments using models of other diseases. They also are taking a closer look at the potential role of astrocytes in those diseases.

    "Now, we can, among other things, carefully compare normal and reactive astrocytes to understand what specific changes are happening and then get an idea if those changes are likely to be detrimental or supportive to neurons."

    Other authors of the study include, from UC Davis, Chengji Zhou, assistant professor of cell biology and human anatomy; postdoctoral fellows Jiho Sohn and Yazhou Wang; graduate students Yoshiko Maeda, Monica Delgado and Emily Mills and Joyce Ma, a medical student; research associates Laird Miers and Jie Xu; and associate project scientist Peter Bannerman, as well as Hirohide Takebayashi of Japan's Kumamoto University.

    The research was supported by grants from the National Institutes of Health, the National Multiple Sclerosis Society, Shriners Hospitals for Children and the California Institute for Regenerative Medicine.

    Source: University Of California © 2011 Regents of the University of California (31/08/11)

    Researchers discover target molecule to repair injured nerve cells

    Brain CellsA team of investigators at UC Davis and Shriners Hospital have discovered that a factor in the embryonic development of brain cells is an important target for developing new drugs and stem cell therapies to treat patients who have lost function from multiple sclerosis, cerebral palsy, stroke and other “demyelinating” diseases and injuries.

    The study, which was conducted in mice, appears online today in Scientific Reports, a new primary research, open-access journal from the publishers of Nature.

    “We have discovered that enhancing a factor important in early brain development could play a powerful role in healing,” said Wenbin Deng, principal investigator of the study and leader of a team of researchers at the Institute of Pediatric Regenerative Medicine at Shriners Hospital for Children, Northern California. “This information can be very important for harnessing the regenerative capacity of the brain through drugs or stem cell therapy.”

    The study focused on cells in the brain called oligodendrocytes, which surround nerve fibers and provide them with a protective myelin sheath. Myelin increases the speed at which nerve impulses propagate, similar to the role of insulation around an electric wire, and is essential for the proper functioning of the nervous system. Diseases that injure oligodendrocytes include multiple sclerosis, cerebral palsy and leukodystrophies. Traumatic brain injuries can also cause demyelination, as can strokes.

    Deng’s team studied a factor that has been found only in oligodendrocytes. Although researchers knew the factor, called Zfp488, is required for oligodendrocytes to mature during embryonic development, they were surprised to find it also plays a role in adult brain cells.

    For the study, the investigators induced demyelination in mice by feeding them a diet containing cuprizone, a chemical that specifically damages mature oligodendrocytes. After two weeks, one group of mice was injected with a retrovirus that contained the genetic code for Zfp488, causing these mice to express this factor in their cells. After three more weeks on the diet, these mice developed new oligodendrocytes from precursor cells in much greater numbers than occurred in control mice, which were also on the cuprizone diet but were not provided with Zfp488.

    The researchers found not only oligodendrocyte recovery, but important differences in motor function between the two groups. Three days after the diet was stopped, mice provided with Zfp488 performed significantly better on a test of running time than did the controls, and performed as well as mice that never received the demyelinating diet. This is especially important, according to Deng, because people with a demyelinating disease have poor motor control as a major symptom.

    “The fact that Zfp488 not only induced remyelination but also led to restoration of function is very exciting,” said Deng, who is also an assistant professor in the UC Davis Department of Cell Biology and Human Anatomy. “This is a step toward our most important goal of finding a therapy for functional recovery for patients with a demyelinating disorder or injury.”

    According to Deng, the study findings could lead to identifying a drug that specifically enhances the activity of Zfp488. Another potential avenue of therapy could be to implant precursor cells of oligodendrocytes to promote regeneration.

    “Until this study, we had no clear idea of a target to promote remyelination in demyelinating diseases and injuries,” said David E. Pleasure, the director of research at the Institute for Pediatric Regenerative Medicine, one of the authors of the study, and a professor in the departments of neurology and pediatrics at UC Davis School of Medicine. “This knowledge opens up exciting new avenues of research.”

    The article is titled, “Zfp488 promotes oligodendrocyte differentiation of neural progenitor cells in adult mice after demyelination.” The lead author is Mangala M. Soundarapandian of the UC Davis Department of Cell Biology and Human Anatomy. Other authors are U-Ging Lo, also of the Department of cell Biology and Human Anatomy; Mari S. Golub of the UC Davis Murine Behavioral Assessment Laboratory; Daniel H. Feldman of the Institute for Pediatric Regenerative Medicine; and Vimal Selvaraj, previously at UC Davis and currently at Cornell University.

    The Institute for Pediatric Regenerative Medicine is a joint initiative between the UC Davis School of Medicine and Shriners Hospital for Children, Northern California, to carry out basic and translational stem cell research with the aim of helping children with brain and spinal cord dysfunction, orthopaedic disorders and burns. It occupies more than 22,000 square feet of laboratory research space inside Shriners Hospital in Sacramento, across the street from UC Davis Medical Center.

    Source: Media Newswire (c) (21/06/11)

    Estrogen receptors play anti-inflammatory role in the brain

    Estrogen ReceptorsResearchers have uncovered an unexpected role for estrogen receptors in the brain in keeping inflammation under control. The findings reported in the May 13 issue of the Cell Press journal Cell may have important implications for the treatment of multiple sclerosis (MS) and many other neurodegenerative diseases. They might also help to explain why women are three times more susceptible to developing MS than men are, researchers say.

    "We've really discovered an alternative pathway for estrogen receptors in the brain," said Christopher Glass of the University of California, San Diego.

    Estrogen receptors are primarily known to activate programs of gene expression, he explained. In this case, however, estrogen receptors are critical for turning off genes that would otherwise lead to chronic inflammation.

    The estrogen receptor (ER) in question is not the classical ERα ones responsible for the sex-specific effects of estrogen. Rather, they are related receptors known as ERβ found in cells of the brain known as microglia and astrocytes. Microglia serve as sentinels of infection and injury in the brain. Upon detection of microbial invasion or evidence of tissue damage, microglia rapidly initiate an inflammatory response that serves to recruit the immune system and tissue repair processes. Among other roles, astrocytes also sense infection and injury, and amplify the immune reaction initiated by microglia.

    Both ERα and ERβ respond to the hormone estradiol, the major form of estrogen in humans. Glass and study first author Kaoru Saijo now show that ERβ also responds to a second hormone called ADIOL as well. That ADIOL is converted by special enzymes from its precursor DHEA in microglia.

    When levels of either ADIOL or ERβ were experimentally reduced, cells and animals showed an exaggerated inflammatory response. On the other hand, treatment with either ADIOL or synthetic molecules designed to specifically target ERβ prevented inflammation and its effects in mice with experimental autoimmune encephalomyelitis, a condition that closely mimics MS in humans.

    Although MS is a very complicated disease, the findings suggest drugs targeted at the ERβ receptors might effectively shut down the inflammation that goes along with the disease, Saijo said. The same principle might also work in the treatment of other neurodegenerative conditions associated with inflammation, including Parkinson's, Alzheimer's and HIV-associated dementia.

    The findings might also help to explain the strong sex bias in MS, which disproportionately affects relatively young women. "When ERβ receptors see estradiol, they may kick ADIOL out leaving the brain more susceptible to inflammation," Saijo said. In other words, estradiol and ADIOL compete for ERβ and in that competition estradiol will generally win.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011  (16/05/11)

    A possible new target for treatment of multiple sclerosis

    Axons and NeuronsDamage to susceptible nerve cells can be reversed

    The immune system recognizes and neutralizes or destroys toxins and foreign pathogens that have gained access to the body. Autoimmune diseases result when the system attacks the body's own tissues instead.

    One of the most common examples is multiple sclerosis (MS). MS is a serious condition in which nerve-cell projections, or axons, in the brain and the spinal cord are destroyed as a result of misdirected inflammatory reactions. It is often characterized by an unpredictable course, with periods of remission being interrupted by episodes of relapse.

    A team of researchers led by LMU Munich Professor Martin Kerschensteiner of the Medical Center of the University of Munich and Professor Thomas Misgeld from the Technical University of Munich has now been able to explain how the damage is inflicted.

    Their results reveal that the inflammatory reaction can induce a previously unknown type of axonal degeneration, which they call "focal axonal degeneration" (FAD). In an animal model of MS, this process is reversible if it is recognized and treated early, so the researchers believe that it could serve as a potential target for therapeutic intervention. "Development of an effective treatment will be a long-term project," cautions Kerschensteiner. "As yet, we only have a superficial understanding of the underlying molecular mechanisms and, of course, finding effective therapies will require time-consuming screens and extensive trials of drug candidates." (Nature Medicine online, 27 March 2011)

    Multiple sclerosis is a common and, in many cases seriously disabling, autoimmune disease that can lead to the disturbance or loss of sensory function, voluntary movement, vision and bladder control. Commonly, it is thought that the primary target of MS is the myelin sheath, an insulating membrane that enwraps axons, and increases the speed of signal transmission. However, damage to nerve fibers is also a central process, as whether autoimmune pathology ultimately leads to permanent disability depends largely on how many nerve fibers are damaged over the course of time.

    The team led by Kerschensteiner and Misgeld set out to define precisely how the damage to the nerve axons occurs. As Misgeld explains, "We used an animal model in which a subset of axons is genetically marked with a fluorescent protein, allowing us to observe them directly by fluorescence microscopy." After inoculation with myelin, these mice begin to show MS-like symptoms. But the researchers found that many axons showing early signs of damage were still surrounded by an intact myelin sheath, suggesting that loss of myelin is not a prerequisite for axonal damage.

    Instead a previously unrecognized mechanism, termed focal axonal degeneration (FAD), is responsible for the primary damage. FAD can damage axons that are still wrapped in their protective myelin sheath. This process could also help explain some of the spontaneous remissions of symptoms that are characteristic of MS. "In its early stages, axonal damage is spontaneously reversible," says Kerschensteiner. "This finding gives us a better understanding of the disease, but it may also point to a new route to therapy, as processes that are in principle reversible should be more susceptible to treatment."

    However, one must remember that it takes years to transform novel findings in basic research into effective therapies. First the process that leads to disease symptoms must be elucidated in molecular detail. In the case of MS it has already been suggested that reactive oxygen and nitrogen radicals play a significant role in facilitating the destruction of axons. These aggressive chemicals are produced by immune cells, and they disrupt and may ultimately destroy the mitochondria. Mitochondria are the cell's powerhouses, because they synthesize ATP, the universal energy source needed for the build-up and maintenance of cell structure and function.

    "In our animal model, at least, we can neutralize these radicals and this allows acutely damaged axons to recover," says Kerschensteiner. The results of further studies on human tissues, carried out in collaboration with specialists based at the Universities of Göttingen and Geneva, are encouraging. The characteristic signs of the newly discovered process of degeneration can also be identified in brain tissue from patients with MS, suggesting that the basic principle of treatment used in the mouse model might also be effective in humans.

    Even if this turns out to be the case, it would not mean that a new therapy would soon be at hand. The chemical agents used in the mouse experiments are not specific enough and not tolerated well enough to be of clinical use. "Before appropriate therapeutic strategies can be developed, we need to clarify exactly how the damage arises at the molecular level," says Kerschensteiner. "We also want to investigate whether similar mechanisms play a role in later chronic stages of multiple sclerosis ."

    The work received generous support from the Deutsche Forschungsgemeinschaft (DFG), in the context of Sonderforschungsbereich 571 (Autoimmune disease: From symptoms via mechanism to therapy) and the Emmy Noether Program. The Hertie Foundation and the Alexander von Humboldt Foundation also contributed significantly to financing the project. The study was performed within the framework of the Center for Integrated Protein Science Munich (CIPSM) – a Cluster of Excellence – and the Multiple Sclerosis Competence Network set up by the Federal Ministry for Research and Technology.


    "A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis",
    Ivana Nikiæ, Doron Merkler, Catherine Sorbara, Mary Brinkoetter, Mario Kreutzfeldt, Florence M Bareyre, Wolfgang Brück, Derron Bishop, Thomas Misgeld & Martin Kerschensteiner
    Nature Medicine online, 27 March, 6 p.m. London time / 1 p.m. US Eastern time doi: 10.1038/nm.2324

    Source: Eureka Alert (28/03/11)

    Neuro signals study gives new insight into brain disorders

    NeuronsResearch into how the brain transmits messages to other parts of the body could improve understanding of disorders such as epilepsy, dementia, multiple sclerosis and stroke.

    Scientists at the University of Edinburgh have identified a protein crucial for maintaining the health and function of the segment of nerve fibres that controls transmission of messages within the brain.

    The study, published in the journal Neuron, could help direct research into neurodegenerative disorders, in which electrical impulses from the brain are disrupted. This can lead to inability to control movement, causing muscles to waste away.

    Professor Peter Brophy, Director of the University of Edinburgh's Centre for Neuroregeneration, said: "Knowing more about how signals in the brain work will help us better understand neurodegenerative disorders and why, when these illnesses strike, the brain can no longer send signals to parts of the body."

    The brain works like an electrical circuit, sending impulses along nerve fibres in the same way that current is sent through wires.

    These fibres can measure up to a metre, but the area covered by the segment of nerve that controls transmission of messages is no bigger than the width of a human hair.

    Dr Matthew Nolan, of the University's Centre for Integrative Physiology, said: "At any moment tens of thousands of electrical impulses are transmitting messages between nerve cells in our brains. Identifying proteins that are critical for the precise initiation of these impulses will help unravel the complexities of how brains work and may lead to new insights into how brains evolved."

    The research is funded by the Wellcome Trust and the Medical Research Council.

    Source: Medical News Today © 2011 MediLexicon International Ltd (14/03/11)

    Researchers find reduced levels of an important neurotransmitter in MS

    NeuronsThe pathological processes in MS are not well understood, but an important contributor to its progression is the infiltration of white blood cells involved in immune defense through the blood-brain barrier.

    Douglas Feinstein, research professor in anesthesiology at the UIC College of Medicine, and his colleagues previously showed that the neurotransmitter noradrenaline plays an important role as an immunosuppressant in the brain, preventing inflammation and stress to neurons. Noradrenaline is also known to help to preserve the integrity of the blood-brain barrier.

    Because the major source of noradrenaline is neurons in an area of the brain called the locus coeruleus, the UIC researchers hypothesized that damage to the LC was responsible for lowered levels of noradrenaline in the brains of MS patients.

    "There’s a lot of evidence of damage to the LC in Alzheimer’s and Parkinson’s disease, but this is the first time that it has been demonstrated that there is stress involved to the neurons in the LC of MS patients, and that there is a reduction in brain noradrenaline levels," said Paul Polak, research specialist in the health sciences in anesthesiology and first author on the paper.

    For the last 15 years, Feinstein and his colleagues have been studying the importance of noradrenaline to inflammatory processes in the brain.
    "We have all the models for studying this problem, so in some ways it was a small step to look at this question in MS," said Polak.

    The researchers found that LC damage and reduced levels of noradrenaline occur in a mouse model of MS and that similar changes could be found in the brains of MS patients.

    The findings suggest that LC damage, accompanied by reduction in noradrenaline levels in the brain, may be a common feature of neurologic diseases, Polak said.

    "There are a number of FDA-approved drugs that have been shown to raise levels of noradrenaline in the brain, and we believe that this type of therapeutic intervention could benefit patients with MS and other neurodegenerative diseases, and should be investigated," he said.

    Source: © 2003-2011 (11/02/11)

    Membrane molecule keeps nerve impulses hopping

    NervesNew research from the University of North Carolina at Chapel Hill School of Medicine describes a key molecular mechanism in nerve fibers that ensures the rapid conductance of nervous system impulses. The findings appear online Jan. 27, 2011 in the journal Neuron.

    Our hard-wired nerve fibres or axons rely on an insulating membrane sheath, the myelin, made up of fatty white matter to accelerate the rate of transmission of electrical impulses from the brain to other parts of the body.

    Myelin thus acts to prevent electrical current from leaking or prematurely leaving the axon. However, the myelin surrounding the axon isn’t continuous; there are regularly spaced unmyelinated gaps about 1 micrometer wide along the axon. These unmyelinated regions named as nodes of Ranvier are where electrical impulses hop from one node to the next along the axon, at rates as fast as 160 metres per second (360 mph).

    “Determining exactly how the nodes of Ranvier function and how they are assembled, has fired the interest of neuroscientists for more than a century,” said UNC neuroscientist Manzoor Bhat, PhD, Professor of Cell and Molecular Physiology in the UNC Neuroscience Research Center. “The answers may also provide important clues to the development of targeted treatments for multiple sclerosis and other disorders involving demyelination and/or disorganization of nodes of Ranvier.”

    Bhat and colleagues focused on a protein called Neurofascin 186, which accumulates in the membranes of axons at the nodes of Ranvier. Together with proteins Ankyrin-G and sodium channels, these molecules form a complex that facilitates passage of sodium ions through the channels in axons, thus making them paramount for the propagation of nerve impulses along myelinated nerve fibres.

    Bhat’s team had previously identified a homolog of Neurofascin in laboratory studies of Drosophila nerve fibers, and because its in vivo function had not been clearly defined in a mammalian system, they decided to study the function of this protein in laboratory mice.

    Using targeted gene deletion methods, the UNC scientists genetically engineered mice lacking Neurofascin 186 in their neurons. “This caused the failure of sodium channels and Ankyrin-G to accumulate at the nodes of Ranvier. The result was paralysis, as there was no nerve impulse conductance,” Bhat said.

    According to Bhat, Neurofascin is an adhesion molecule that serves as the nodal organizer. “Its job is to cluster at the nodes of Ranvier. In doing so, it brings together sodium channels and Ankyrin-G where they interact to form the nodal complex.  And if you don’t have this protein, the node is compromised and there is no impulse propagation along the axon.”

    In further analysis, the researchers identified another important function of the nodes of Ranvier in myelinated nerve cells: to act as barriers to prevent the invasion of the nodal gap by neighbouring paranodal molecular complexes. “So this tells us that sodium channels, Neurofascin 186, and Ankyrin-G must always remain in the node to have functional organization. If they don’t, the flanking paranodes will move in and occupy the nodal gap and block nerve conduction,” Bhat said.

    The UNC neuroscientists see clinical implications for human disease. “In MS, for example, the proteins that make up the nodal complex start diffusing out from their normal location once you start losing the myelin sheath. If we can restore the nodal complex in nerve fibres, we may be able to restore some nerve conduction and function in affected axons.”  Their future studies are aimed at understanding whether the nodal complex could be reorganized and nerve conduction restored in genetically modified mutant mice.

    “The discovery of an essential gap protein is exciting because it opens up the possibility that tweaking the protein could restore normal gap function in people with multiple sclerosis and other diseases in which the myelin sheaths and gaps deteriorate over time,”  said Laurie Tompkins, PhD, who oversees Manzoor Bhat’s and other neurogenetics grants at the National Institutes of Health.

    Support for the research came from the National Institute of General Medical Sciences, the National Institute of Neurological Disorders & Stroke of the National Institutes of Health and the National Multiple Sclerosis Society.

    UNC co-authors are postdoctoral fellow Courtney Thaxton, PhD; research specialist, Anilkumar Pillai; and graduate student, Alaine Pribisco. Dr. Jeffrey Dupree, assistant professor at Virginia Commonwealth University, collaborated in these studies.

    Source: (27/01/11)

    Mitochondrial DNA deletions and neurodegeneration in MS

    OBJECTIVE: Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system. We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.

    METHODS: Ninety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity.

    RESULTS: The density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls. The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions. Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS. The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level. Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons.

    INTERPRETATION: These findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation. We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.

    Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM, Mahad DJ.

    Institute of Ageing and Health, Mitochondrial Research Group, Newcastle University, Newcastle upon Tyne, UK

    Source: Ann Neurol. 2010 Nov 8. & Pubmed PMID: 21061391 (15/11/10)

    Fruit fly study sheds light on brain development and diseases

    NeuronsScientists have identified a new genetic marker that makes fruit fly a better model for brain development and diseases.

    The human brain is composed of 100 billion individual nerve cells which communicate with each other via a complex network of connections. Errors in communications of these cells are often at the basis of brain and nerve diseases such as Alzheimer's and multiple sclerosis.

    In the search for possible solutions to these diseases, one important aspect is to understand how the connections between nerve cells develop.

    The fruit fly, Drosophila melanogaster, is an important, low-cost model organism with 60 percent genetic similarity with humans.

    The fruit fly plays a significant role in clarifying various neurological processes such as the way our memory works and our sense of smell and in studying particular neurodegenerative diseases.

    The team headed by Bassem Hassan uses the fruit fly as a model to study brain development.

    Though Drosophila has long been used to study the connections between nerve cells, one specific marker was still missing.

    To understand the whole circuit between nerve cells, markers are needed for the different compartments of nerve cells (presynaptic or output cells and postsynaptic or input cells).

    Under the direction of Bassem Hassan and in collaboration with Wim Annaert, Laura Nicola, Ariane Ramaekers and their colleagues have identified the missing marker, DenMark (Dendritic Marker), a hybrid of a mouse protein and a fluorescent protein.

    The high specificity of such a marker for the input compartment of the nerve cells in Drosophila gives rise to hope that it can also be used in other model organisms.

    Nerve cells communicate via a synapse. A synapse is a space in the connection between nerve cells, more specifically the space between the presynaptic membrane (of an axon) and the postsynaptic membrane (of a dendrite).Axons conduct away from the cell, dendrites (usually) to it.The "message is transmitted" via the synapse by neurotransmitters.

    Source: SiFi News Copyright © Sify Technologies Ltd, 1998-2010. (15/11/10)

    Salk scientists discover new target for MS

    AxonsScientists are closer to solving one of the many mysteries of multiple sclerosis and other demyelinating diseases, thanks to a recent study conducted at the Salk Institute for Biological Studies.

    The research revealed a previously unknown connection between two ion channels, which, when misaligned, can cause the many bizarre symptoms that characterize the condition.

    The findings, reported in this week's online edition of the Proceedings of the National Academy of Sciences (PNAS), provide fresh insights into the mechanisms underlying MS and suggest a novel target for therapeutic intervention.

    "Our findings offer an avenue of hope for the many millions of MS patients," explains Howard Hughes Medical Institute investigator Terrence J. Sejnowski, professor and head of the Salk Institute's Computational Neurobiology Laboratory, who led the study. "We've discovered a new target that could be efficacious. This particular pathway or ion channel is a key player in this disease, and we think that manipulating it could have a huge benefit for people suffering from MS."

    Multiple sclerosis affects an estimated 400,000 Americans and more than 2.5 million people worldwide. A chronic, often disabling disease that attacks the central nervous system, it is responsible for a baffling range of neurological symptoms, including numbness, tingling, muscle weakness, paralysis, and vision loss.

    It is thought to result when the immune system attacks the myelin sheath that insulates axons, the nerve fibers that conduct electrical impulses to and from the brain and between neurons within the brain. Ordinarily, the myelin speeds up the signals the axons transmit, called action potentials.

    When axons lose their insulation, however, either signal conduction fails because the demyelinated axons are unable to generate an impulse, resulting in a loss of sensation, weakness, or blindness, or the axons become hyperexcitable and overcompensate by firing even in the absence of an input, causing twitching.

    The first computer model of axonal transmission, developed in the 1950s for the giant axon of the squid, which lacks myelin, tracked positively charged sodium and potassium ions, whose movements across the neuronal membrane generate the necessary electrical signals. Building on that model, Sejnowski and his team included myelin in their own model, then demyelinated one of the sections and incorporated all the changes known to take place as a result.

    "It's been known for a long time that the two most important ions in the axon are sodium and potassium," says Sejnowski. "What we did was use a program that can model every part of the axon by breaking it into little segments so we could we keep track of the ions going in and out of each segment. And what we found really surprised us."

    The vast majority of prior clinical studies had focused on the sodium channel, which is responsible for initiating the action potential, and many of the targets for MS drugs likewise focus on the sodium channel. While enhancing the sodium current did boost the signal in Sejnowki's model, to everyone's amazement, it was the ratio of densities between the sodium channel and a previously ignored but ubiquitous voltage-insensitive potassium current called the leak current, which sets the ground state of the neuron, that determines whether neurons can fire properly.

    If the sodium level drops, an accompanying drop in the leak current will maintain the signal, whereas if the sodium drops but the leak current doesn't, signal transmission may fail. Conversely, if the sodium level is too high and the leak current doesn't increase, a patient may experience twitching. The "safe" zone lies between the two limits.

    "Trying to influence the balance between the two ion channels is a completely new approach, and drugs that target leak currents could be as important as those targeting the sodium current," adds Sejnowski. "I think we have a good chance at some point to help MS patients. The first step is to understand what's going on."

    "Our model offers a novel explanation for many of the peculiar and intermittent symptoms that MS patients experience," says first author Jay S. Coggan, who had studied leak channels in previous work. "The injured axon is continually struggling to maintain order within a functional range. There is danger to the right and left. A variety of perturbations can nudge the axon one way or the other. It makes sense that leak channels might participate in these changes."

    In some instances, for example, their symptoms worsen if they are too warm, but improve if they are cooled off-a phenomenon that correlates to the fact that these channels are temperature-dependent. "If a patient is near one of the boundaries and only marginally 'safe,' heating up could cause him or her to cross into the failure zone," Coggan adds. Temperature, therefore, hints at which boundary the patient is approaching.

    Beyond MS and demyelinating diseases, insights into the sodium/leak current have applications to intractable pain-a field that Sejnowski's group will be investigating next.

    In addition to Sejnowski, Coggan and Thomas Bartol of the Salk Institute, Steve Prescott, an assistant professor in the Department of Neurology at the University of Pittsburgh contributed to the study.

    The work was funded by the Howard Hughes Medical Institute.

    Source: Newswise © 2010 Newswise, Inc (26/10/10)

    Spinal cord regeneration success in mice

    Nerve CellsUS researchers have for the first time encouraged substantial regrowth in nerves controlling voluntary movement after spinal cord injury.

    By manipulating an enzyme involved in cell growth, researchers were able to regenerate spinal cord nerves in mice, Nature Neuroscience reports.

    It follows similar work on repairing the optic nerve to restore sight.

    UK experts said the next challenge would be to turn the findings into a treatment suitable for humans.

    The ability to grow new nerve cells is present at birth but then diminishes with age.

    It means that after injury or illness to the spine such cells, known as axons, cannot regenerate.

    In the latest study the researchers attempted to switch back on the signalling pathway that encourages this new growth in young mammals.

    They did it by knocking out a gene called PTEN in mice which in normal circumstances puts a halt on new nerve growth.

    The team, from Harvard Medical School and the University of California, Irvine, reported substantial regrowth in severed spinal cords in the animals.

    They are now working on tests to see if the technique can actually restore spinal cord function.

    Potential treatment
    Study author Professor Oswald Steward said: "Until now, such robust nerve regeneration has been impossible in the spinal cord.

    "Paralysis and loss of function from spinal cord injury has been considered untreatable, but our discovery points the way toward a potential therapy to induce regeneration of nerve connections following spinal cord injury in people."

    Professor James Fawcett, head of clinical neuroscience at Cambridge University, said there was an awful lot of work going on in this area and the results were exciting.

    But he pointed out: "It seems to work in young mice but we need to see what happens in older mice.

    "We need to make it clear that this is not ready for human patients."

    Dr Michael Coleman, from The Babraham Institute in Cambridge added that the challenge would be taking the results and turning them into a treatment that could be used in humans.

    "Finding drugs to block the same pathway would be one approach as even gene therapy, which is highly experimental, could not easily 'remove' a gene as they have done so here."

    Source: BBC News © British Broadcasting Corporation 2010 (09/08/10)

    Wallerian Degeneration: A Major Component of Early Axonal Pathology in MS


    Axonal loss is a major component of the pathology of multiple sclerosis (MS) and the morphological basis of permanent clinical disability. It occurs in demyelinating plaques but also in the so-called normal-appearing white matter (NAWM).

    However, the contribution of Wallerian degeneration to axonal pathology is not known.

    Here, we analyzed the extent of Wallerian degeneration and axonal pathology in periplaque white matter (PPWM) and lesions in early multiple sclerosis biopsy tissue from 63 MS patients.

    Wallerian degeneration was visualized using an antibody against the neuropeptide Y receptor Y1 (NPY-Y1R).

    The number of SMI-32-positive axons with non-phosphorylated neurofilaments was significantly higher in both PPWM and plaques compared to control white matter.

    APP-positive, acutely damaged axons were found in significantly higher numbers in plaques compared to PPWM. Strikingly, the number of NPY-Y1R-positive axons undergoing Wallerian degeneration was significantly higher in PPWM and plaques than in control WM. NPY-Y1R-positive axons in PPWM were strongly correlated to those in the lesions.

    Our results show that Wallerian degeneration is a major component of axonal pathology in the periplaque white matter in early MS. It may contribute to radiological changes observed in early MS and most likely plays a major role in the development of disability.

    Dziedzic T, Metz I, Dallenga T, König FB, Müller S, Stadelmann C, Brück W.

    Department of Neuropathology, University Medical Center, Georg August University, Göttingen, Germany.

    Source: Pubmed PMID: 20477831 (28/05/10)

    Glial cells can cross from the central to the peripheral nervous system
    Glial CellsGlial cells, which help neurons communicate with each other, can leave the central nervous system and cross into the peripheral nervous system to compensate for missing cells, according to new research in the Dec. 2 issue of The Journal of Neuroscience. The animal study contributes to researchers' basic understanding of how the two nervous systems develop and are maintained, which is essential for the effective treatment of diseases such as multiple sclerosis.

    The nervous system is divided into the central nervous system (the brain and spinal cord) and the peripheral nervous system (sensory organs, muscles, and glands). A major difference between the systems is that each has its own type of glial cells. In a healthy body, glial cells are tightly segregated and aren't known to travel between the two systems. The peripheral nervous system also regenerates more than the central nervous system, due in part to its glial cells -- a characteristic that, if better understood, might be used to improve the regenerative capabilities of the central nervous system.

    Glial cells serve nerve cells by insulating them with layers of fats and proteins called myelin. Myelin coatings are necessary for nerve signals to be transmitted normally; when the sheaths are lost, disorders involving impairment in sensation, movement and cognition such as multiple sclerosis or amyotrophic lateral sclerosis develop. Glial cells named oligodendrocytes produce myelin around nerves of the central nervous system, while those named Schwann cells make myelin that insulates peripheral nerves.

    This study shows that in the absence of Schwann cells, oligodendrocytes migrate from the central nervous system along motor nerves and form myelin on peripheral nerves, indicating that glial cell movement across the border is controlled by a self-policing mechanism.

    "Past studies have hinted that Schwann cells can cross into the central nervous system after peripheral nerves near the border are damaged, or after central nerves lose their myelin sheath," said Bruce Appel, PhD, of the University of Colorado Denver Anschutz Medical Campus, one of the study's authors. "However, migration across the border has never been observed directly, nor was there any evidence that oligodendrocytes can move in the opposite direction."

    The authors used time-lapse video of mutant zebrafish to study the glial cell movement. Movies of translucent live zebrafish that lacked Schwann cells showed that oligodendrocytes left the central nervous system to wrap peripheral nerves with myelin -- effectively attempting to compensate for the missing Schwann cells.

    "This new observation is not only relevant to normal nerve function, but also to potential causes of disease in the peripheral nervous system. We're still unsure as to exactly how foreign glial cells interact with the other system. Do they help heal or do they act as a toxin?" said Bruce Trapp, PhD, at the Cleveland Clinic, who is unaffiliated with the study. "Knowing the mechanisms that anatomically restrict peripheral and central nervous system glia could help develop therapies that treat or prevent certain nervous system diseases."

    Appel and his colleagues said that future investigations are needed to determine how different glial cells communicate to restrict their movements between nervous systems, and whether oligodendrocyte myelin can fully substitute for Schwann cell myelin on motor nerves.

    The research was supported by the National Institute of Neurological Disorders and Stroke and a zebrafish initiative funded by the Vanderbilt University Academic Venture Capital Fund.

    Source: ScienceDaily © 1995-2009 ScienceDaily LLC (02/12/09)

    Drug studied as possible treatment for spinal injuries might also treat Multiple Sclerosis
    Nerve AxonsResearchers have shown how an experimental drug might restore the function of nerves damaged in spinal cord injuries by preventing short circuits caused when tiny "potassium channels" in the fibers are exposed.

    The chemical compound also might be developed as a treatment for multiple sclerosis.

    Because nerves usually are not severed in a common type of spinal cord trauma, called "compression" injuries, the drug offers hope as a possible treatment, said Riyi Shi, a professor in Purdue University's Department of Basic Medical Sciences, School of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.

    "Compression is responsible for most spinal cord injuries, including many resulting in paralysis," Shi said. "Since the nerves are not severed, this type of drug represents a potential golden opportunity to treat spinal cord injuries."

    The experimental compound, 4-aminopyridine-3-methyl hydroxide, has been shown to restore function to damaged axons, slender fibers that extend from nerve cells and transmit electrical impulses in the spinal cord.

    Findings, based on experiments with guinea pig spinal cord tissue, appeared online in the Journal of Neurophysiology. The work was led by Department of Basic Medical Sciences doctoral student Wenjing Sun.

    Shi said the findings were made possible by the interdisciplinary nature of the work, which also involves researchers Richard Borgens, director of Purdue's Center for Paralysis Research and the Mari Hulman George Professor of Neurology in the School of Veterinary Medicine; Stephen Byrn, the Charles B. Jordan Professor of Medicinal Chemistry, and Daniel Smith, a research assistant professor, both in the Department of Industrial and Physical Pharmacy; and Ji-Xin Cheng, an associate professor in the Weldon School of Biomedical Engineering and Department of Chemistry.

    K+ Channel Blocking

    Researchers have shown how an experimental drug might restore the function of nerves damaged in spinal cord injuries by preventing short circuits caused when tiny "potassium channels" in the fibers are exposed by trauma. The compound also might be developed as a treatment for multiple sclerosis. This diagram illustrates how the drug functions as a "channel blocker," meaning it permits the conduction of signals even though the protective myelin insulation has been damaged.

    (Photo Credit: Purdue University, Department of Basic Medical Sciences)

    The researchers subjected spinal cord tissue to stresses that mimic what happens in a compression injury, which stretches nerves. Then they treated the damaged axons with 4-aminopyridine-3-methyl hydroxide.

    The compound is a derivative of the drug 4-aminopyridine, used primarily as a research tool and also to manage symptoms of multiple sclerosis.

    The axons of each nerve are sheathed in a thick insulating lipid layer, called myelin, which enables the transmission of signals without short circuiting, much like the insulation surrounding electrical wires. Spinal cord trauma damages the myelin sheath, exposing "fast potassium channels" that are embedded in the axons and are critical for transmitting nerve impulses.

    The researchers confirmed previous circumstantial evidence suggesting injury causes the myelin insulation to recede, exposing the channels and impairing signal transmission. Laboratory and imaging techniques revealed the exposed channels in damaged axons.
    The researchers also discovered that 4-aminopyridine-3-methyl hydroxide is a "potassium channel blocker," using a sophistic laboratory technique called "patch clamp" to measure signal conduction. Findings confirmed that the compound prevents the exposed channels from leaking electrical current and enhances nerve conduction in segments of the damaged spinal cord.

    The compound could make it possible to sidestep spinal cord damage by enabling axons to transmit signals as though they were still sheathed in myelin, Shi said.

    Nerves transmit signals through a series of rapid electrical pulses, or "action potentials." For proper nerve function, the time gap between pulses must be as brief as possible. However, 4-aminopyridine has been shown to lengthen the gap, or "refractory period," between pulses. The researchers found that 4-aminopyridine-3-methyl hydroxide restores function without affecting the refractory period. As a result, the damaged nerves perform more like healthy nerves than those treated with other drugs, he said.

    Another key advantage of the new compound is that it's about 10 times more potent than 4-aminopyridine, meaning lower doses can be used to reduce the likelihood of serious side effects.

    Because myelin also is damaged in multiple sclerosis, the same drug might be used to restore nerve function in people stricken with the disease, Shi said. Since the newer drug can be used in lower doses, it might be more effective than 4-aminopyridine in treating multiple sclerosis, which affects more than 350,000 people in the United States and 2.5 million worldwide, he said.

    Source: Science Codex (20/11/09)

    Team solves structure of NMDA receptor unit that could be drug target for neurological diseases

    NMDA ReceptorsA team of scientists at Cold Spring Harbor Laboratory (CSHL) reports their success in solving the molecular structure of a key portion of a cellular receptor implicated in Alzheimer’s, Multiple Sclerosis, and other serious illnesses.

    Assistant Professor Hiro Furukawa, Ph.D., and colleagues at CSHL, in cooperation with the National Synchrotron Light Source at Brookhaven National Laboratory, obtained crystal structures for one of several “subunits” of the NMDA receptor. This receptor, formally called the N-methyl-D-aspartate receptor, belongs to a family of cellular receptors that mediate excitatory nerve transmission in the brain.

    Excitatory signals represent the majority of nerve signals in most regions of the human brain. One theory of causation in Alzheimer’s, Parkinson’s and multiple sclerosis posits that excessive amounts of the excitatory neurotransmitter, glutamate, can cause an overstimulation of glutamate receptors, including the NMDA receptor. Such excitotoxicity, the theory holds, can cause nerve-cell death and subsequent neurological dysfunction.

    A class of inhibitors of the NMDA receptor under the generic name Memantine has been approved by the U.S. Food and Drug Administration for use in moderate and severe cases of Alzheimer’s. Memantine is a non-specific inhibitor of the NMDA receptor and is neither a cure nor an agent that can halt progression of the disease. The search is well under way for molecules that can shut down the NMDA receptor with much greater specificity. The CSHL team’s work pertains directly to that effort.

    The NMDA receptor is modular, composed of multiple domains with distinct functional roles. Part of the receptor is lodged in the membrane of nerve cells and part juts out from the membrane. Furukawa’s CSHL team focused on a portion of the so-called extracellular domain of the receptor, a subunit called NR2B, which includes a domain of particular interest called the ATD (the amino terminal domain).

    “This part is of great interest to us because it has very little in common with ATDs in other kinds of glutamate receptors involved in nerve transmission,” says Furukawa. Its uniqueness makes it a potentially interesting target for future drugs. “Our interest is even keener because we already know there are a rich spectrum of small molecules that can bind the ATD of NMDA receptors.”

    Without a highly detailed molecular picture of the ATD, however, efforts to rationally design inhibitors cannot proceed. Hence the importance of Furukawa’s achievement: a crystal structure revealed by the powerful light source at Brookhaven National Laboratory, that shows the ATD to have a “clamshell”-like appearance that is important for its function. The results are published in a paper appearing online ahead of print in The EMBO Journal, the publication of the European Molecular Biology Organization.

    The team obtained structures of the ATD domain with and without zinc binding to it. Zinc is a natural ligand that docks at a spot within the “clamshell” in routine functioning of the NMDA receptor. Of much greater interest is the location and nature of a suspected binding site of a small molecule type that is known to bind the ATD and inhibit the action of the NMDA receptor.

    These inhibitor molecules are members of a class of compounds called phenylethanolamines which “have high efficacy and specificity and show some promise as neuroprotective agents without side effects seen in compounds that bind at the extracellular domain of other receptors,” Furukawa explains. Now that his team has solved the structure of the ATD domain of the NR2B subunit, it becomes possible to proceed with rational design of a phenylethanolamine-like compound that can precisely bind the ATD within what Furukawa and colleagues call its “clamshell cleft,” based on the crystal structure they have obtained.

    “Structure of the Zinc-bound Amino-terminal Domain of the NMDA receptor NR2B subunit” will be published online ahead of print November 12 in The EMBO Journal. The authors are: Erkan Karakas, Noriko Simorowski, and Hiro Furukawa

    Source: BreakThrough Medical News Digest © 2009 BreakThrough Medical News Digest (13/11/09)

    Juggling may help fight Multiple Sclerosis
    Juggling BallsComplex tasks like juggling produce significant changes to the structure of the brain, according to scientists at Oxford University.

    In the journal, Nature Neuroscience, the scientists say they saw a 5% increase in white matter - the cabling network of the brain.

    The people who took part in the study were trained for six weeks and had brain scans before and after.

    Long term it could aid treatments for diseases like multiple sclerosis.

    Diffusion MRI

    The team at Oxford's Department of Clinical Neurology used a diffusion MRI which is able to measure the movement of water molecules in the tissues of the brain.

    The signal changes according to how many bundles of nerve fibres there are and how tightly packed they are.

    Changes in grey matter, where the processing and computation in the brain happens, have been shown before, but enhancements in the white matter have not previously been demonstrated.

    Three ball cascade

    The scientists studied a group of 24 healthy young adults, none of whom could juggle.

    They divided them into two groups.

    One of the groups was given weekly training sessions in juggling for six weeks and was asked to practice 30 minutes every day the other 12 continued as normal.

    After training, the 12 jugglers could perform at least two continuous cycles of the classic three ball cascade.

    Both groups were scanned using diffusion MRI before and after the training.

    At the six week point, a 5% increase in white matter was shown in a rear section of the brain called the intraparietal sulcus for the jugglers.

    This area has been shown to contain nerves that react to us reaching and grasping for objects in our peripheral vision.

    There was a great variation in the ability of the volunteers to juggle but all of them showed changes in white matter.

    The Oxford team said this must be down to the time spent training and practising rather than the level of skill attained.

    Dr Heidi Johansen-Berg, who led the team, said: "MRI is an indirect way to measure brain structure and so we cannot be sure exactly what is changing when these people learn.

    "Future work should test whether these results reflect changes in the shape or number of nerve fibres, or growth of the insulating myelin sheath surrounding the fibres.

    "Of course, this doesn't mean that everyone should go out and start juggling to improve their brains.

    "We chose juggling purely as a complex new skill for people to learn."

    Clinical Applications

    Dr Johansen-Berg said there were clinical applications for this work but there were a long way off.

    She said: "Knowing that pathways in the brain can be enhanced may be significant in the long run in coming up with new treatments for neurological diseases, such as multiple sclerosis, where these pathways become degraded."

    Professor Cathy Price, of the Wellcome Trust Centre for Neuroimaging, said: "It's extremely exciting to see evidence that training changes human white matter connections.

    "This compliments other work showing grey matter changes with training and motivates further work to understand the cellular mechanisms underlying these effects."

    Source: BBC News © British Broadcasting Corporation 2009

    Hopes raised for possible Multiple Sclerosis treatment
    Neural Nerve Cells

    Scientists in Bristol claim results from a research project into multiple sclerosis (MS) could lead to treatment to reduce the severity of the disease.

    The team carried out tests on mice and then on human brain tissue and found galanin, a protein within brain nerve cells, was resistant to MS.

    Professor David Wraith at the University of Bristol said the results were "extremely promising".

    The team said it could be at least 10 years before a drug is developed.

    Professor David Wynick, who works on the function of galanin, set up the project with a group of other scientists working on the development of a vaccine for the treatment of multiple sclerosis.

    He said: "It has been known for some time that galanin plays a protective role in both the central and peripheral nerve systems - when a nerve is injured levels of galanin increase dramatically in an attempt to limit cell death."

    The team discovered that mice with high levels of galanin were completely resistant to the MS-like disease, experimental autoimmune encephalomyelitis (EAE). Transgenic mice that contained no galanin at all developed a more severe form of the disease.

    MS is a neurological condition that affects the transfer of messages from the central nervous system to the rest of the body.

    It is the most common neurological disorder among young adults, affecting around 100,000 people in the UK with 2,500 newly diagnosed each year.

    There is no cure for MS, but drugs can be used to reduce the number and severity of relapses, and to reduce the number of new attacks.

    Source BBC News © British Broadcasting Corporation 2009 (25/08/09)

    Advances in lab-grown motor nerves could help further understand Multiple Sclerosis and related conditions
    MS Brain
    In the July issue of Biomaterials, published by Elsevier, researchers from the University of Central Florida (UCF) report on the first lab-grown motor nerves that are insulated and organized just like they are in the human body. The model system will drastically improve understanding of the causes of myelin-related conditions, such as diabetic neuropathy and later, possibly multiple sclerosis (MS). In addition, the model system will enable the discovery and testing of new drug therapies for these conditions.

    MS, diabetic neuropathy, and many conditions that are caused by a loss of myelin, which forms protective insulation around our nerves, can be debilitating and even deadly. Adequate treatments do not yet exist. Researchers at the UCF have identified this to be a result of a deficiency in model research systems.

    James Hickman, a bioengineer at UCF and the lead researcher on this project explained: "The nodes of Ranvier act like power station relays along the myelin sheath. They chemically boost signals, allowing them to get across breaks in myelin, or from node to node, at the electrically charged nodes of Ranvier. Nerve malfunctions, called neuropathies, involve a breakdown in the way the brain sends and receives electric signals along nerve cells, leading to malfunctions at the nodes of Ranvier, along with demyelination". Hickman's team has now achieved the first successful model nodes of Ranvier formation on motor nerves in a defined serum-free culture system.

    Researchers have long recognized the need for lab-grown motor nerve cells that myelinate and form nodes of Ranvier in order to use controlled lab conditions to zero in on the causes of demyelination. Yet, due to the complexity of the nervous system, it has been a challenge to study demyelinating neuropathies, and researchers have been confined to using animal models.

    The main difference with this research was that Hickman's group began with a model that was serum-free. They had already developed techniques for growing various nervous system cells in serum-free media, including motoneurons, and here they attempted myelination using the growth medium they have worked with for many years.

    In the body, nerve cells grow in two distinct environments: In the peripheral nervous system (PNS), cells are exposed to blood and other fluids that contain high concentrations of protein, among various other constituents, depending on where the cells are located in the body. In the central nervous system (CNS), the spinal cord and brain are surrounded by cerebrospinal fluid that contains only trace amounts of protein. This system now allows for both the PNS and CNS to be studied in the same defined system.

    The UCF team plans to use their new model system to explore the origins of diabetic neuropathy. Once the causes of myelin degradation are identified, targets for new drug therapies can be tested with the model. Other planned experiments will focus on how electrical signals travel through myelinated and unmyelinated nerves to reveal how nerves malfunction as well as for spinal cord injury studies. "Being able to study these fully developed structures means we can really start looking at these things in a way that just wasn't possible before," commented Hickman.

    The full article is "Node of Ranvier formation on motoneurons in vitro" by John W. Rumsey, Mainak Das, Maria Stancescu, Marga Bott, Cristina Fernandez-Valle, James J. Hickman. It appears in Biomaterials, Volume 30, Issue 21, July 2009, Pages 3567-3572, published by Elsevier.

    Source: Medical News Today © 2009 MediLexicon International Ltd (26/07/09)

    Glutamate identified as predictor of disease progression in multiple sclerosis

    MS Brain MRI

    UCSF researchers have identified a correlation between higher levels of glutamate, which occurs naturally in the brain as a byproduct of metabolism, and greater disease burden in multiple sclerosis patients. The study is the first to measure glutamate toxicity in the brain over time and suggests an improved method for tracking the disease and predicting its course.

    The research team employed a novel technique, developed by Radhika Srinivasan, PhD, study author and assistant researcher in the UCSF Department of Radiology and Biomedical Imaging, to measure glutamate levels in clinical trial patients. The technique was based on a sophisticated form of imaging known as proton MR spectroscopy, which uses simple radio-frequency pulses targeting specific brain chemicals.

    Study findings were presented during the American Academy of Neurology annual scientific meeting in Seattle.

    Glutamate, a neurotransmitter, in normal levels performs fundamental processes like memory and sensory perception. In excess, it triggers a cascade of negative reactions in the brain leading to many of the complications associated with neurologic diseases such as MS, Parkinson's disease, stroke, ALS (amyotrophic lateral sclerosis or Lou Gehrig's disease) and Alzheimer's disease by destroying nerve cells and causing seizures, injury after stroke, and the perception of pain, among other problems.

    Already a target for therapeutic drug development, the identification of the glutamate pathway for MS suggests a new way for clinicians to monitor treatment of these drugs.

    "This is the first time that we have had the ability to measure glutamate toxicity in the brain in real time, which gives us a marker for monitoring disease progression as well as our treatment of the disease," said Daniel Pelletier, MD, study author, associate professor of neurology and a member of the Multiple Sclerosis Research Group at the University of California, San Francisco.

    "For instance, we already have anti-glutamate drugs, so now we can assess, with imaging, the impact of the therapy and the progression of the disease," he said.

    Elevated levels of glutamate in the brain are understood clinically as a cause of cell injury and death. Injury to neuro-axons, which are the long fibers that extend from the cell body of a neuron cell toward other nerve cells, is partly responsible for disability progression in MS. In a previous study using proton MR spectroscopic imaging, the research team reported that MS brains have significant elevation of glutamate concentrations. For this study, researchers looked for levels of glutamate and levels of NAA (n-acteylaspartate), a marker of axonal integrity in mature brains, to see if a relationship existed.

    The team scanned 265 MS patients annually and followed them for an average of 1.8 years. Accounting for disease duration and age of onset, researchers found that significant annual loss of NAA, which is a measure of neurodegeneration, was associated with concentration of glutamate. This finding indicated that the higher the level of glutamate, the greater the expected neuro-axonal loss over time.

    According to the authors, the study is the largest clinical analysis to date of metabolism byproducts in the brain, and the results strongly support the link between the excess of glutamate and decline of neuro-axonal integrity in MS.

    The finding, Pelletier says, goes beyond MS. "Now that we have those markers, we can quantify levels of glutamate for other neurologic diseases, which could be another way to track disease progression and therapeutic intervention."

    The UCSF study, known as the EPIC MRI Study, aims to develop reliable genetic biomarkers that correlate with quantitative Magnetic Resonance Imaging (MRI) measures of disease burden and severity. Participants are involved for at least two years and receive an annual brain MRI.

    Additional UCSF authors are Sarah J. Nelson, PhD, chair, Division of Bioengineering; John Kornak, PhD, assistant adjunct professor of Radiology; Darin T. Okuda, MD, assistant clinical professor in Neurology; and Bill Chu, specialist in Radiology.

    The study was funded in part by the National MS Society.

    Source: EurekaAlert! (30/04/09)

    Reserve neuronal cells in the brain can be activated

    Brain Axons

    Scientists at Karolinska Institutet have found a way of activating the neuronal reserves in the brains of mice by switching off the signal that inhibits the formation of new nerve cells. The study is presented in the online edition of the scientific journal Nature Neuroscience.

    "So far, this is just basic research of no immediate practical significance, but the results are very exciting nonetheless," says Professor Jonas Frisén at the Department of Cell and Molecular Biology, who led the study.

    New nerve cells are formed from stem cells in specific areas of the human brain. This process increases after a stroke, something that might explain the recovery that is often observed in patients, particularly in the first year following the onset of illness. In the present study, the scientists have demonstrated how a type of cell that does not give rise to new cells in the healthy brain is activated after a stroke in laboratory animals.

    In addition to the stem cells that are normally active, there is therefore also a kind of reserve stock of cells the can be activated when demand increases. The team have identified the molecular mechanisms that control the activation of these cells, and shown that it is possible to increase the formation of new nerve cells in healthy mice by switching off the so-called Notch signalling pathway, which inhibits the creation of new nerve cells.

    Source: Insciences Organisation (23/02/09)

    Worm gene provides possible hope for restoring nerves damaged by MS
    Worm Gene and Nerve regrowth

    University of Utah scientists identified a worm gene that is essential for damaged nerve cells to regenerate, and showed they could speed nerve regeneration by over-activating the gene – a step toward new treatments for nerves injured by trauma or disease. Oddly, the gene and a related "pathway" – a chain of molecular events – is not required for normal nerve development in embryos, the researchers report in the Jan. 22 issue of Science Express, the online edition of the journal Science.

    "We discovered a molecular target for a future drug that could vastly improve the ability of a neuron to regenerate after injury," either from trauma or disease, says biology Professor Michael Bastiani, leader of the research team and a member of the Brain Institute at the University of Utah.

    Study coauthor and biology Professor Erik Jorgensen – the Brain Institute's scientific director – says: "In the future, we would like to develop drugs that could activate this chain of molecular events in nerve cells and stimulate regeneration of diseased and injured nerve cells. At this point, we can't do that. But this study gives us hope that in the future, we will have a rational approach for stimulating regeneration."

    "Eventually, this may be a way to treat spinal cord injuries," adds study coauthor Paola Nix, a biology research associate.

    Bastiani says an ability to stimulate nerve regeneration one day also may help treat multiple sclerosis, in which nerves are damaged by loss of their myelin coating.

    He says the study used nematode worms, which "have the same molecules performing similar functions in humans. We found a pathway that not only regenerates nerves in the worm but also exists in humans, and we think it serves the same purpose."

    Nix adds: "The next thing to do would be to test this gene in [other] animals and eventually humans to see if it plays the same role."

    The core of the molecular chain of events involves four genes. The most important is dlk-1¸ which is known as a "MAP kinase kinase kinase" or MAPKKK. When the Utah scientists "overexpressed" the dlk-1 gene in worms – making it more active than normal – broken nerves in the worms regenerated much more quickly than expected. When dlk-1 was blocked, regeneration did not occur.

    The study's other authors were Marc Hammarlund, a former University of Utah postdoctoral researcher now at Yale University, and lab technician Linda Hauth.

    The research was funded initially by the Craig H. Neilsen Foundation, and the scientists dedicated it to Neilsen, a Utah native and chairman of Ameristar Casinos. Neilsen was paralyzed by a spinal cord injury during a 1985 car wreck. He funded the project in hope of finding a cure. He died in 2006, while the study was underway.

    Searching for Nerve Regeneration Genes

    Nerve cells have the ability to regenerate in the embryo, but lose the ability as an organism ages. Most adult nerve cells "regenerate poorly or not al all," the researchers write, although peripheral nerve cells – like those in the arms and legs – regenerate better than central nervous system neurons in the brain and spinal cord. No one knows why.

    The new study focused on regeneration of motor neuron axons – the wiry part of every nerve cell that transmits signals to other nerve cells or to cells such as muscle.

    The research team developed a "genetic screen" to look for genes involved in nerve regeneration. They mutated a worm gene that produces a protein named beta spectrin, which helps keep nerve cells flexible. Mutant worms lacked beta spectrin, so their nerves broke as they crawled around a culture dish.

    Te scientists used a method named RNA interference to suppress the functioning of 5,000 of the 20,000 worm genes – one at a time. People also have those 5,000 genes.

    Each gene was "knocked down one by one, and we looked for the loss of the ability to regenerate," Nix says.

    The researchers were able to watch nerves regenerate – or not – because they had placed a jellyfish gene in the worms, which made the worms' nerve cells glow fluorescent green – easy to see when observed under a microscope.

    They found the dlk-1 gene was crucial for regeneration because every time the scientists blocked it, nerve regeneration was halted.

    More than One Way to Regenerate a Neuron

    After identifying dlk-1, the biologists determined the effects of other genes on regeneration, allowing them to "map" genes and proteins involved in the regeneration pathway. The "core" of this pathway – including dlk-1 and three other genes – "activates this entire program of regeneration," Bastiani says.

    "One of the coolest things is we can improve regeneration," Nix says. "We originally looked at loss of this gene, dlk-1. The loss blocks regeneration. We can cut the nerve in these mutants and they don't regenerate. So we see worms with nerve stumps that don't do anything. But when we overproduce dlk-1 – make an excess amount of it – then we see an improvement in regeneration."

    Jorgensen – an investigator with the Howard Hughes Medical Institute – says that "normally, young worms regenerate really well; old worms don't regenerate at all. What we can do by overexpressing dlk-1 is make old worms regenerate like young worms."

    The chain of events the researchers identified as playing an essential role in nerve regeneration is known as a "MAP kinase pathway." Various MAP kinases play roles in cell division, response to stress, and cell specialization, Jorgensen says.

    The pathway discovered in the new study "is unique in that it is not used by the nervous system during normal embryo development, yet it is absolutely required for regeneration," Bastiani says. "Most of us believed that virtually everything we found in regeneration also would be involved in development. So it is surprising."

    He says while the dlk-1 gene is the most obvious target for new drugs to stimulate nerve regeneration, other genes in the pathway also could be potential targets.

    Caution Urged as Hopes Have Been Dashed Before

    Bastiani and Jorgensen say the new findings are particularly promising because another approach to spurring regeneration has failed to yield fruit.

    About two decades ago, other researchers discovered that molecules in glial cells – which physically support nerve cells in the brain – inhibit regeneration of nerve cells in adult organisms.

    Scientists "have hoped for many years that by being able to eliminate these molecules that inhibit regrowth, that we would be able to stimulate nerve regeneration," Jorgensen says. Mice treated with that approach so far have showed only mild improvement in nerve regeneration, says Bastiani.

    Yet, the study found possible impediments to the new approach. To trigger regeneration, the DLK-1 protein (produced under orders from the dlk-1 gene) "has to act around the time of injury," Bastiani says. "This might be a real problem because, as a drug target, there might be a time window in which you have to activate this pathway to stimulate regeneration after a spinal cord injury."

    If worms and other animals have genes like dlk-1 that can enhance nerve regeneration, why are those genes normally inactive or only somewhat active?

    "You might argue there is a tradeoff between regeneration ability and maintenance and stability," Bastiani says. "The tradeoff for you and me is we want memories that last a lifetime," so stability of the nerve in our brain is desirable – not a lot of nerve turnover and regeneration. "The tradeoff is you lose the ability to regenerate robustly."

    Source: e! Science News © 2009 Eureka! Science News (23/01/09)

    Neurons Can Regrow!

    There’s evidence that the adult human brain has the ability to grow new neurons, say researchers at the Cleveland Clinic Lerner Research Institute.

    The study included nine people with multiple sclerosis (MS) and a control group of four healthy people. In MS, the immune system destroys the myelin sheaths that surround and protect nerves. When the myelin is destroyed, the nerves misfire, and nerve impulses can be slowed or disrupted.

    The researchers analyzed neurons in normal subcortical white matter and acute and chronic demyelinated brain lesions, and found that neurons which occupy white matter are also destroyed during the demyelination process.

    However, the team also found that in a small percentage of old MS lesions, white matter neurons were increased by 72 percent compared to normal brain regions. In addition, these interneurons appeared to be fully developed.

    “Our study suggests that demyelinated tissues produce signals that can enhance the generation of new neurons in damaged areas of the brain. Based on our findings, there is enough evidence to support the idea that new neurons can re-grow in multiple sclerosis lesions,” research leader Bruce Trapp, neurosciences chair at Lerner, said in a Cleveland Clinic news release.

    It’s not clear how much function the new neurons have, but Trapp and his colleagues plan further research into that question.

    “The basic science discovery may provide the basis for the development for new therapies for MS and other neurodegenerative diseases,” Trapp said.

    Source: Copyright © 2008 ScoutNews, LLC. (26/10/08)

    Brain cells may regenerate after damage from multiple sclerosis
    Brian cells in areas targeted by multiple sclerosis may regenerate - often years after the initial injury, according to research by a team of Cleveland Clinic neuroscientists.

    The finding, published online today, lends further support for the concept of adult neurogenesis -- that the human brain can regenerate itself, and in the case of MS, is working to repair itself.

    Multiple sclerosis is a chronic disease in which the immune system begins to attack the fatty protective barrier around nerve fibers in the central nervous system. When that area, known as the myelin, is destroyed, the impulses traveling along those pathways from the brain or spinal cord can be slowed, distorted, or cut off completely if the nerve itself is injured.

    The researchers examined the brains of nine multiple sclerosis patients who donated their organs after death in the hopes of furthering research on the disease,

    "The brain is continuously trying to replace what has been destroyed -- not just myelin, but also neurons," said Bruce Trapp, one of the lead authors on the paper and chair of neurosciences at the Lerner Research Institute.

    Trapp think the biggest impact of the paper will be just that -- that there is evidence of the neurogenesis in this area of the brain. Many scientists have resisted the increasing amount of evidence that shows regeneration of neurons in other areas of the brain, like the hippocampus, because of a long-held belief that the brain cannot regenerate. In short, you're stuck with what you've got.

    "It's a controversial area, and it's something that's very difficult to prove," said Trapp.

    Trapp and his team went looking for old MS lesions in the brains they examined, and wanted to know what happened to the neurons in those areas. They weren't surprised that many of them were destroyed, probably as "bystanders" when the myelin was attacked.

    "But then we were shocked when we saw areas of old lesions, and these lesions can be decades old, that had very high concentrations of neurons," Trapp said. In one quarter of the lesions they looked at, there was a 72 percent increase in density of interneurons, which are the neurons that communicate locally.

    The question of whether a motor neuron, which communicates over a long distance, could regenerate is still an unanswered question.

    Trapp's team was able to count the neurons because the white matter is relatively neuron-poor compared to the rest of the brain. They were also able to show that the neurons had made connections to each other through synapses.

    But, Trapp doesn't know if the neurons he saw were capable of communicating with one another or were functional.

    Source: ©2008 (25/07/08)

    Mitochondrial defects in acute multiple sclerosis lesions

    Multiple sclerosis is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the CNS.

    The structural and immunopathological patterns of demyelination suggest that different immune mechanisms may be involved in tissue damage.

    In a subtype of lesions, which are mainly found in patients with acute fulminant multiple sclerosis with Balo's type concentric sclerosis and in a subset of early relapsing remitting multiple sclerosis, the initial myelin changes closely resemble those seen in white matter stroke (WMS), suggesting a hypoxia-like tissue injury.

    Since mitochondrial injury may be involved in the pathogenesis of such lesions, we analysed a number of mitochondrial respiratory chain proteins in active lesions from acute multiple sclerosis and from WMS using immunohistochemistry.

    Functionally important defects of mitochondrial respiratory chain complex IV [cytochrome c oxidase (COX)] including its catalytic component (COX-I) are present in Pattern III but not in Pattern II multiple sclerosis lesions. The lack of immunohistochemically detected COX-I is apparent in oligodendrocytes, hypertrophied astrocytes and axons, but not in microglia.

    The profile of immunohistochemically detected mitochondrial respiratory chain complex subunits differs between multiple sclerosis and WMS. The findings suggest that hypoxia-like tissue injury in Pattern III multiple sclerosis lesions may be due to mitochondrial impairment.

    Don Mahad1, Iryna Ziabreva1, Hans Lassmann2 and Douglas Turnbull1

    1The Mitochondrial Research Group, University of Newcastle upon Tyne, UK and 2Centre for Brain Research, Medical University of Vienna, Austria Correspondence to: Prof. Dr Hans Lassmann, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Wien Austria

    Source: Brain 2008 131(7):1722-1735; doi:10.1093/brain/awn105 (02/07/08)

    Neuroscience researcher working toward a cure for Multiple Sclerosis
    If finding a way to restore nerve cells’ protective coating were the only challenge, multiple sclerosis would be a more manageable disease.

    But researchers at the UConn Health Center say MS also takes it toll on axons, the nerve cell extensions that carry nerve impulses.

    The devastation hinders the ability of neurons to communicate with each other, resulting in debilitating neurodegenerative disease.

    “The long-term disability of MS is caused by degeneration of axons that have lost their myelin sheath – their protective coating,” says Rashmi Bansal, an associate professor of neuroscience.

    Bansal recently won a grant from the National Multiple Sclerosis Society for her research focusing on a specific protein and its role in MS.

    In MS patients and mouse models, this protein, called fibroblast growth factor, increases in areas of the nervous system where the myelin is missing.

    “There’s got to be an important connection of this observation with the disease scenario,” Bansal says.

    Signals from these growth factors regulate the biology of cells called oligodendrocytes, which produce myelin in the central nervous system.

    Fibroblast growth factors bind and signal to oligodendrocytes through three different receptors, which are the docking sites for these growth factors. Bansal’s previous research found this interaction varied depending on the receptor involved.

    “Stimulation of one receptor versus the other led to different responses,” Bansal says. “And interestingly, we found that in oligodendrocytes, while one response was positive, the other was a negative pathological one.

    So that raises the question of what the fibroblast growth factor is doing. Is it good or bad to have a lot of it in MS lesions?”

    Bansal’s grant, more than $600,000 over three years, is for the next step. She and her research team, including postdoctoral fellow Miki Furusho, are working with mice that are missing the gene for one or more of the fibroblast growth factor receptors.

    “We want to know, what’s the outcome of getting rid of this gene? It would give us a handle on what each receptor is doing for normal myelination in the animal,” Bansal says.

    “But what would be really interesting and important for MS research will be to know the function of these receptors in myelin disease and recovery.”

    Bansal says initial studies with these mice have given indications of defects in oligodendrocyte development and myelination, “but how it’s going to play out in the disease scenario, we don’t know yet. In this grant we have proposed experiments that will allow us to address these questions.”

    In addition to her own research projects, Bansal is committed to carrying on the work of professor of neuroscience Steven Pfeiffer, a colleague who died last year.

    During his 38 years at the Health Center, Pfeiffer developed an international reputation as a biomedical scientist working toward a cure for MS.

    “He and I worked together on various aspects of MS research ever since I joined the University,” Bansal says.

    Bansal says MS research at UConn is embracing modern scientific advances such as proteomic analysis, an approach aimed at discovering new proteins.

    Bansal and her team, including postdoctoral fellow Akahiro Ishii, will continue the pursuit of the proteins in human myelin, which was a major focus of Pfeiffer’s research.

    “Myelin composition is well known to have some major proteins,” Bansal says.

    “This proteomic analysis allows us to determine the minor components – and minor doesn’t mean unimportant: the smallest components could be the ones that are the most important. This study will provide us with several novel targets to go after and will form a valuable foundation for understanding the molecular mechanism of myelination and the pathogenesis of human myelin disease such as MS.”

    The MS Society also awarded Bansal two other grants since 1999, and she has won funding from the National Institutes of Health over that same period.

    “Our goal – like many researchers – is that somehow in our lifetime we’ll be able to see our research from the bench get into the clinics and help the people with multiple sclerosis,” Bansal says.

    “That’s the main ambition and dream for us.”

    Source: University of Connecticut © University of Connecticut (25/04/08)

    Neublastin Virtually Restores Complete Long Term Sensory Motor Function In Preclinical Studies
    Biogen Idec in collaboration with scientists at the University of Arizona and Tufts University reported in the April issue of the journal Nature Neuroscience that in preclinical studies, injections of the protein neublastin promoted the regeneration of damaged sensory nerve cells and produced virtually complete, long-term restoration of sensory and motor function. These studies suggest neublastin has potential for further development as a treatment for traumatic nerve injury.

    Neublastin, also known as artemin, belongs to a family of proteins, called glial-derived neurotrophic factors (GDNF), which promote nerve cell survival. The protein is unique because it acts selectively on sensory neurons. In previous preclinical studies, neublastin reversed a number of features of chronic pain associated with peripheral nerve injury.

    Specifically in the studies, six neublastin injections were administered over 11 days following injury to the dorsal root, a bundle of peripheral nerve fibers adjacent to the spinal cord that transmit sensory information to the central nervous system. The injections promoted nerve growth into the spinal cord and restored the ability to respond normally to a variety of sensory stimuli and perform complex motor activities such as grasping an object on contact. The functional recovery occurred even after a two-day delay in administering neublastin and lasted for more than six months.

    “Sensory nerves entering the spinal cord have minimal capacity to regenerate and severe injury often results in permanent loss of sensory functions,” said Frank Porreca, PhD, Professor of Pharmacology at the University of Arizona, the study’s senior author. “The results of our preclinical studies, showing dramatic, long-term recovery of pain sensation and complex motor skills after neublastin injections, represent an important and novel advance in research efforts in the area of traumatic nerve injury.”

    In a series of biochemical, molecular and electrophysiology studies, the researchers also demonstrated that neublastin promoted the regeneration of multiple classes of nerve cells back into the spinal cord and the re-establishment of functional connections with their spinal targets.

    “These exciting results support further research, as the data suggest that neublastin may have the potential to promote sensory neuronal regeneration and functional recovery following injury,” said Ken Rhodes, PhD, Vice President, Discovery Neurobiology, Biogen Idec. “The neublastin program is part of Biogen Idec’s commitment to innovative neurological science and discovery.”

    Biogen Idec is developing neublastin for use in treating peripheral nervous system diseases under an exclusive license from NsGene. Scientists at NsGene discovered neublastin in 1998.

    Source: Biogen Idec (07/04/08)

    Brain drug target discovery in Multiple Sclerosis
    US researchers have found two potential targets for treating multiple sclerosis after an extensive trawl through proteins in the brain.

    Comparison of 2,538 proteins from MS patients with those from healthy brains showed damage in two proteins not before linked to the disease.

    In mice blocking the effects of the proteins led to reversal of symptoms, the study in Nature reported.

    There are about 100,000 people with MS in the UK.

    The condition is caused by a defect in the body's immune system, which turns in on itself, attacking the fatty myelin sheath which coats the nerves, leading to symptoms including blurred vision, loss of balance and, in some cases, paralysis.

    Study leader Professor Lawrence Steinman said this was the first large-scale study to search for defective proteins in MS lesions in the brain.

    They found a few proteins peculiar to MS brain lesions.

    But two in particular - tissue factor and protein C inhibitor - showed signs of damage during the chronic active stage of the disease.

    These normally participate in the control of blood clotting and in anti-inflammatory pathways. The researchers guessed that the damaged proteins might be helping the progression of MS and, by using inhibitors of the proteins found they could successfully ameliorate the disease in mice.


    Professor Steinman, from Stanford University School of Medicine in California, said the finding opened up the way for new treatments.

    However, using existing drugs which interfere with the control of blood clotting would be dangerous because of an increased risk of bleeding.

    Professor Neil Scolding, from the University of Bristol Institute of Clinical Neurosciences, said: "From the scientific perspective, the exciting thing is that it's pretty much the first time that proteomics has directly yielded a candidate molecule that is both unexpected and novel on the one hand and has therapeutic potential.

    "From the clinical perspective, showing that treatment approaches predicted by this proteomic interrogation of MS tissue do have a clear impact in experimental models of MS is extremely promising.

    "This points the way to a new area of MS research of considerable interest, and which could well lead in the future to new lines of treatment."

    Dr Laura Bell, Research Communications Officer at the MS Society, said she looked forward to seeing how the research progressed.

    "This is early research but provides an interesting insight into some of the potential players that cause different types of damage to the central nervous system in people with MS.

    "Understanding how MS develops is vital to target therapies for the condition."

    Source: BBC News © BBC 2008 (17/02/08)

    Spinal cord research moving forward in 2008
    Since its co-founding in 1985 by Dr. Barth A. Green and three families affected by spinal-cord injuries, The Miami Project to Cure Paralysis at the Miller School of Medicine has enjoyed a legacy of scientific and social developments.

    In 2004, the Miami Project published a breakthrough article regarding dramatic improvement in animal models of spinal-cord injury, utilizing a combination of cells and drugs.

    Now, they are trying to bring a treatment using Schwann cells, or cells particular to the peripheral nervous system that separate and insulate nerve cells, to clinical trial. This requires an FDA application and extensive process for approval, but could be a major advancement in spinal-cord injury research.

    Scientific Director for The Miami Project Dr. W. Dalton Dietrich is working to coordinate faculty members with consultants from the FDA.

    "Approval is being sought, and hopefully will be attained, from the FDA to begin phase one of trials and to begin clinical transformation," says Maria Amador, director of education for The Miami Project. "The hope is to get approval by the end of 2008."

    One of the project's major goals is to use neurobiological science on a fundamental level and to apply these findings on a clinical level. While the project is focused on spinal-cord injury, its developments can also carry over to other neurological disorders.

    For example, the study of remyelination of cells can potentially impact multiple sclerosis research. Multiple sclerosis is a neurodegenerative disease that affects muscle movements, coordination and balance, and has numerous symptoms including spasms, problems in speech and vision problems.

    Nationwide, several other medical facilities are initiating their own spinal-cord research using The Miami Project as a guide.

    Dietrich said that research centers at the University of Louisville, University of Kentucky, The Ohio State University and the University of California, Irvine, are developing large SCI research centers.

    "Some of these new centers have used the organizational framework of The Miami Project," Dietrich said. "We are also very involved with training the next generation of scientists to continue this important work. These are truly exciting times."

    Source: The Miami Hurricane © 2008 The Miami Hurricane. (24/01/08)

    Understanding The Nervous System To Improve Treatment For Multiple Sclerosis
    Uncover the neural communication links involved in myelination, the process of protecting a nerve’s axon, and it may become possible to reverse the breakdown of the nervous system’s electrical transmissions in such disorders as multiple sclerosis, spinal cord injuries, diabetes and cancers of the nervous system.

    With $697,065 in grants from the New Jersey Commission on Spinal Cord Injury and the New Jersey Commission on Brain Injury Research, Haesun Kim of Teaneck, NJ, assistant professor of biological sciences at Rutgers University in Newark, is working on gaining a better understanding of those links.

    Specifically, her work focuses on Schwann cells within the peripheral nervous system and their communication links with the axons they myelinate by enwrapping them in myelin. Axons are the long fibrous part of neurons that carry the nerve’s electrical signals. A fatty substance, myelin covers those axons both to protect them and to provide a conduit for the fast conduction of electrical signals within the nervous system. Once that myelin is lost,the electrical signal breaks down and eventually the neuron dies – like a cell phone that loses its signal.

    Determining how Schwann cells and axons communicate with one another could lead to an understanding of how to promote remyelination, the rebuilding of myelin, and restoration of that signal. One unique aspect of the communication link between Schwann cells and axons is that they are mutually dependent upon that connection for their existence.

    “When Schwann cells are generated during development, axons send out signals to the Schwann cells and tell them, ‘You are going to become myelin cells and you are going to myelinate me,’” explains Kim. “The Schwann cells in turn guide the axons to where they need to go and direct the axons to grow.”

    By pinpointing the sequence and nuances of the communication links involved in myelination, targeted genetic and pharmacological interventions possibly could be developed to restore the loss of myelin. Such an understanding additionally may allow for the effective transplanting of Schwann cells in the central nervous system to promote remyelination and the correction of neurological disorders at that level.

    The New Jersey Commission on Spinal Cord Injury has provided $397,066 and the New Jersey Commission on Brain Injury Research $299,999 to support Kim’s research.

    Kim received her M.S. in biology from the University of Toledo, her Ph.D. in cell biology, neurobiology and anatomy from the University of Cincinnati, and performed her post-doctoral work at the Dana-Farber Cancer Institute at Harvard Medical School. She joined the Rutgers-Newark faculty in 2004.

    Source: Rutgers State University (09/11/07)

    Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients.

    Neuronal and axonal degeneration results in irreversible neurological disability in multiple sclerosis (MS) patients.

    A number of adaptive or neuroprotective mechanisms are thought to repress neurodegeneration and neurological disability in MS patients.

    To investigate possible neuroprotective pathways in the cerebral cortex of MS patients, we compared gene transcripts in cortices of six control and six MS patients.

    Out of 67 transcripts increased in MS cortex nine were related to the signalling mediated by the neurotrophin ciliary neurotrophic factor (CNTF). Therefore, we quantified and localized transcriptional (RT-PCR, in situ hybridization) and translational (western, immunohistochemistry) products of CNTF-related genes. CNTF-receptor complex members, CNTFRalpha, LIFRbeta and GP130, were increased in MS cortical neurons. CNTF was increased and also expressed by neurons. Phosphorylated STAT3 and the anti-apoptotic molecule, Bcl2, known down stream products of CNTF signalling were also increased in MS cortical neurons.

    We hypothesize that in response to the chronic insults or stress of the pathogenesis of multiple sclerosis, cortical neurons up regulate a CNTF-mediated neuroprotective signalling pathway.

    Induction of CNTF signalling and the anti-apoptotic molecule, Bcl2, thus represents a compensatory response to disease pathogenesis and a potential therapeutic target in MS patients.

    Dutta R, McDonough J, Chang A, Swamy L, Siu A, Kidd GJ, Rudick R, Mirnics K, Trapp BD. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

    Source: Brain. October 2007 (03/10/07)

    Specialised brain cells survive, function
    A U.S. study shows specialised neurons thought to die after directing the connections of other neurons can survive birth and remain functional.

    Michael Friedlander and colleagues at the Baylor College of Medicine and the University of Alabama at Birmingham found about 10 percent of such specialised neurons remain active in the adult brain.

    The scientists said their finding -- which challenges accepted ideas about the brain's embryonic development -- might lead to new methods of facilitating the restoration of brain functions lost due to accident or disease.

    "Since those cells are critical elements that guided the wiring of the brain's cerebral cortex in the first place, maybe we could tap into that ability later on," said Friedlander, chairman of the school's department of neuroscience and the study's senior author.

    The finding by Friedlander and Dr. Juan Torres-Reveron at Yale University is reported in the Journal of Neuroscience.

    Source: Science Daily Copyright 2007 by United Press International. All Rights Reserved.(14/09/07)

    New insight into the mechanism by which glial cells recognise and myelinate axons
    In a host of neurological diseases, including multiple sclerosis (MS) and several neuropathies, the protective covering surrounding the nerves - an insulating material called myelin - is damaged.

    Scientists at the Weizmann Institute of Science have now discovered an important new line of communication between nervous system cells that is crucial to the development of myelinated nerves - a discovery that may aid in restoring the normal function of the affected nerve fibres.

    Nerve cells (neurons) have long, thin extensions called axons that can reach up to a meter and or more in length. Often, these extensions are covered by myelin, which is formed by a group of specialised cells called glia. Glial cells revolve around the axon, laying down the myelin sheath in segments, leaving small nodes of exposed nerve in between.

    More than just protection for the delicate axons, the myelin covering allows nerve signals to jump instantaneously between nodes, making the transfer of these signals quick and efficient. When myelin is missing or damaged, the nerve signals can't skip properly down the axons, leading to abnormal function of the affected nerve and often to its degeneration.

    In research published recently in Nature Neuroscience, Weizmann Institute scientists Prof. Elior Peles, graduate student Ivo Spiegel, and their colleagues in the Molecular Cell Biology Department and in the United States, have now provided a vital insight into the mechanism by which glial cells recognise and myelinate axons.

    How do the glial cells and the axon coordinate this process. The Weizmann Institute team found a pair of proteins that pass messages from axons to glial cells. These proteins, called Necl1 and Necl4, belong to a larger family of cell adhesion molecules, so called because they sit on the outer membranes of cells and help them to stick together. Peles and his team discovered that even when removed from their cells, Necl1, normally found on the axon surface, and Necl4, which is found on the glial cell membrane, adhere tightly together. When these molecules are in their natural places, they not only create physical contact between axon and glial cell, but also serve to transfer signals to the cell interior, initiating changes needed to undertake myelination.

    The scientists found that production of Necl4 in the glial cells rises when they come into close contact with an unmyelinated axon, and as the process of myelination begins. They observed that if Necl4 is absent in the glial cells, or if they blocked the attachment of Necl4 to Necl1, the axons that were contacted by glial cells did not myelinate. In the same time period, myelin wrapping was already well underway around most of the axons in the control group.

    "What we've discovered is a completely new means of communication between these nervous system cells," says Peles. "The drugs now used to treat MS and other degenerative diseases in which myelin is affected can only slow the disease, but not stop or cure it. Today, we can't reverse the nerve damage caused by these disorders. But if we can understand the mechanisms that control the process of wrapping the axons by their protective sheath, we might be able to recreate that process in patients."

    Prof. Elior Peles's research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Nella and Leon Benoziyo Center for Neurological Diseases; the Kekst Family Center for Medical Genetics; The David and Fela Shapell Family Center for Genetic Disorders; the Wolgin Prize for Scientific Excellence; the National Institutes of Health (NIH); the National Multiple Sclerosis Society; the US-Israel Binational Science Foundation; and the Israel Science Foundation.

    The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,500 scientists, students, technicians, and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials, and developing new strategies for protecting the environment.

    Source: News-Medical.Net ©2007 News-Medical.Net (27/06/07)

    Schwann cell precursors: a favourable cell for myelin repair in the Central Nervous System
    Cell transplant therapies are currently under active consideration for a number of degenerative diseases. In the immune-mediated demyelinating-neurodegenerative disease multiple sclerosis (MS), only the myelin sheaths of the Central Nervous System(CNS) are lost, while Schwann cell myelin of the Peripheral Nervous System(PNS) remains normal.

    This, and the finding that Schwann cells can myelinate CNS axons, has focussed interest on Schwann cell transplants to repair myelin in MS.

    However, the experimental use of these cells for myelin repair in animal models has revealed a number of problems relating to the incompatibility between peripheral glial cells and the CNS glial environment.

    Here, we have tested whether these difficulties can be avoided by using an earlier stage of the Schwann cell lineage, the Schwann cell precursor (SCP). For direct comparison of these two cell types, we implanted Schwann cells from post-natal rat nerves and SCPs from embryo day 14 (E14) rat nerves into the CNS under various experimental conditions.

    Examination 1 and 2 months later showed that in the presence of naked CNS axons, both types of cell form myelin that antigenically and ultrastructurally resembles that formed by Schwann cells in peripheral nerves.In terms of every other parameter we studied, however, the cells in these two implants behaved remarkably differently.

    As expected from previous work, Schwann cell implants survive poorly unless the cells find axons to myelinate, the cells do not migrate significantly from the implantation site, fail to integrate with host oligodendrocytes and astrocytes, and form little myelin when challenged with astrocyte-rich environment in the retina.

    Following SCP implantation, on the other hand, the cells survive well, migrate through normal CNS tissue, interface smoothly and intimately with host glial cells and myelinate extensively among the astrocytes of the retina. Furthermore, when implanted at a distance from a demyelinated lesion, SCPs but not Schwann cells migrate through normal CNS tissue to reach the lesion and generate new myelin.

    These features of SCP implants are all likely to be helpful attributes for a myelin repair cell. Since these cells also form Schwann cell myelin that is arguably likely to be resistant to MS pathology, they share some of the main advantages of Schwann cells without suffering from the disadvantages that render Schwann cells less than ideal candidates for transplantation into MS lesions.

    Woodhoo A, Sahni V, Gilson J, Setzu A, Franklin RJ, Blakemore WF, Mirsky R, Jessen KR.

    Department of Anatomy and Developmental Biology, University College London, London and Cambridge Centre for Brain Repair and Department of Veterinary Medicine, University of Cambridge, UK.

    Source: Pubmed (13/06/07)

    New Neurons in Old Brains Exhibit Babylike Plasticity
    Study finds a window of adaptability in newly formed brain cells; may lead to stem cell therapies for neurodegenerative disorders.

    Researchers have identified a "critical period" during which new nerve cells in adult brains have the same capacity to learn as those in developing brains. The finding in mice, reported in this week's Neuron, provides the promise of therapies that may one day limit or perhaps even reverse the damage of neurodegenerative diseases such as multiple sclerosis and Parkinson's.

    Scientists first observed neurogenesis—the creation of new neurons in the adult brain—in animal brains in the 1960s but did not find evidence of it in humans until the late 1990s, says senior study author Hongjun Song, an assistant professor of neurology at the Johns Hopkins University School of Medicine in Baltimore.

    Song says he and his colleagues set out to determine whether the young cells differed from older ones—and, if so, how much and at what stage of development. Using a retrovirus that targets dividing, or reproducing, cells, the team tracked new neurons in the hippocampus (a midbrain structure involved with learning and memory) from their births to their deaths. The scientists could determine the behaviour of cells by measuring their electrophysiological activity during different phases. "In young animals, cells are very active, very plastic, and they can change their properties readily," he says. "This whole process [also] happens in the environment of adult circuitry."

    The team found that there is a two-week window, or critical period, about a month after these new cells hatch during which they act like the neurons of a newborn baby. The researchers cued the new cells with a pattern of electrical activation that mimics the sequence that takes place in the brain of a mouse as it learns about a special spot (such as a corner in its cage where it may receive food or a shock). During this time, the cell synapses (connections that allow neurons to communicate with each other) that are artificially stimulated become stronger.

    This strengthening, known as long-term potentiation, results in more efficient information transmission between cells, and is thought to prime them to learn. "For the young cells, it's much easier to be potentiated, but, also, once they are potentiated, the amount of potentiation is much bigger than with brand-new cells," Song says. "What this does is allow [these young cells] to fine-tune their connections."

    "From these data it seems that for high levels of plasticity what matters is the age of the single neuron and not the age of the brain in which the new neuron becomes incorporated," says Tommaso Pizzorusso, a neurobiologist at the Institute of Neuroscience of the National Research Council in Pisa, Italy. "Unfortunately, adult neurogenesis is limited to very specific structures of the brain and, therefore, the remainder of the brain is left with reduced levels of plasticity typical of 'old' cells."

    Song believes that the new findings may open the door to stem cell–based therapies for diseases like multiple sclerosis, Parkinson's and Alzheimer's in which "mature neurons have died and all those fine connections are gone." He says such treatments could involve injecting young nerve cells, in the regions where they are not already continuously being produced, to upgrade flawed existing neural circuitry. "Introducing young neurons," he says, "can make the older circuitry more plastic and adapt to new conditions."

    Source: Scientific © 1996-2007 Scientific American, Inc. All rights reserved. (24/05/07)

    Nerve Fibres are severed by inflammation in MS lesions, leading to permanent disabilities
    Bruce Trapp, PhD––Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio

    Multiple sclerosis (MS) is a chronic, disabling neurodegenerative disease. It strikes most often during early adulthood, and it affects about twice as many women as men. Many aspects of MS, including its cause, are not well understood. It is unknown whether MS represents a single disease, or if its symptoms are the result of different diseases that have the same neurodegenerative effects. There is, however, a growing understanding of how the permanent physical and mental disabilities caused by MS arise over time.

    MS is characterised by lesions in the central nervous system that interfere with nerve function. These lesions are inflammatory, meaning that immune cells that are normally restricted to the blood have migrated into the brain and the cellular partition between the brain and the blood stream (the blood-brain-barrier) has broken down. Local swelling occurs in the lesion site as cells and water move out of the blood stream into the nervous system tissue. This swelling causes problems with nerve function, because oedema and compression of the fibres can block electrical transmission along the nerve fibres. In addition, the immune cells in the lesion make chemicals that attack myelin, a fatty sheath made by support cells that surrounds nerve fibres (called axons). The myelin sheath supports the ability of neurons to transmit signals through the axon, and it provides special chemicals that neurons need to survive. When myelin is attacked and destroyed, the axon can compensate to some extent by rearranging signaling molecules in the denuded area, but the speed and strength of nerve signals traveling through the axon is impaired.

    Most of the time, in the early stages of MS, these inflammatory attacks occur over short intervals of acutely heightened disease activity. These episodes are followed by periods of recovery and remission. During the remission period, the local swelling in the nervous system lesion resolves, the immune cells become less active or inactive, and the myelin-producing cells remyelinate the axons. Nerve signaling improves, and the disability caused by the inflammation becomes less severe or goes away entirely. This phase of the disease is called relapsing-remitting MS(RRMS). The lesions do not all heal completely, though. Some remain as “chronic” lesions, which usually have a demyelinated core region which lacks immune cells. Over time, the cells in the center of such lesions mostly die, although inflammation often continues at their edges. People believed for many years that mainly the myelin was destroyed during the acute attacks and the axons were spared. Recent research has shown this is not the case. Even from the very beginning of MS onset, some of the nerve fibres that cross the lesion are damaged to the point that the axons are severed. This is fatal to the neuron. Broken axons in the brain cannot grow back. The axon eventually degenerates, and the cell body of the neuron may die.

    The brain can adapt well to the loss of some neurons, and permanent disability may not occur for many years. However, more than 50% of patients with MS eventually enter a stage of progressive deterioration, called secondary progressive MS (SPMS). In this stage, the disease no longer responds well to disease-modifying drugs, and patients’ disabilities steadily worsen. The destruction of neurons from early in the natural course of MS suggests that the progressive disabilities of SPMS might be the result of an accumulated neuronal loss that eventually overwhelms the brain’s compensatory abilities.

    To investigate this further, researchers have been looking into the permanent nervous-system damage caused by MS. They are finding that damage from lesions that are “clinically silent” (that is, those that don’t cause obvious symptoms), from lesions in the grey matter of the brain, and from the cumulative loss of axons (Figure 2) all underlie the permanent disability that most people with MS eventually experience.

    Current Research Findings
    Damage from clinically silent lesions is significant. Magnetic resonance imaging (MRI) has been extremely useful in extending researchers’ understanding of MS. MRI scans show that there are many more lesions in the nervous system of many people with MS than might be expected from their disabilities. This seems to be because most lesions occur in parts of the nervous system that are not immediately responsible for some sort of behavioural output, like walking or speaking, or for sensory perception. Therefore, even during the “remitting” phases of RRMS, there is generally ongoing damage from MS in these clinically silent lesions. Therefore, damage to the nervous system can be much more extensive than would be guessed by looking at a patient’s symptoms alone.

    To explore the extent of damage to axons in MS lesions, Trapp and colleagues (1998) examined brain specimens obtained at autopsy from patients with MS and from people who had had healthy brains. To count the damaged axons, they cut the brain tissue into thin slices, perpendicular to the axons, and looked for swellings in the oval shapes that represent axon cross sections (Figure 1). The swelling indicated severed, degenerating nerve fibres. They found that in new inflammatory lesions there were about 11,000 severed axons per cubic millimeter of brain tissue. In older, chronic lesions, where many cells had already died, there were about 3,000 severed axons per cubic millimeter at the lesion edges (where inflammation was most active), and about 900 in the lesion centres, where little myelin or inflammatory cells remained. In the normal-appearing tissue from the brains of control subjects, there was less than one severed axon per cubic millimeter. These observations showed that severe damage to axons was the norm in MS lesions, and that the greater the inflammation, the greater the number of severed axons. This meant that inflammation, which characterises early, active MS, effectively severs axons. The smaller number of severed axons in older lesions indicates that over time the severed axons also continue to degenerate, but at a slower rate.

    Lesions in the Grey Matter of the Cerebral Cortex.
    Traditionally, MS lesions have been thought of as a “white matter” disease. White matter is the axon-rich portions of the brain, where the abundant, fatty myelin makes the tissue look white. The “grey matter” contains neuron cell bodies, and their many thin fibres that handle nerve signals. This includes the dendrites, which are highly branched and detect and pass on signals coming from other neurons to the cell body. Each neuron also has an axon, which is the long thin process that carries information away from the cell body (i.e., to other neurons or to the muscles). Although they are in the “grey” matter, many of these axons are myelinated. They are not as densely packed as in the white matter, though, and therefore the myelin doesn’t affect the colour of the tissue as much.

    Although researchers have thought of MS lesions as primarily affecting the white matter, recent studies of the cerebral cortex from deceased patients with MS have contradicted this idea (see Trapp, 2007). The cerebral cortex is the thin sheet of gray matter at the surface of the brain that is responsible for most higher-order processes, like reasoning. What became clear from these studies was that the grey-matter lesions can be extensive in MS, although less obvious in the microscope because the lesions show many fewer signs of inflammation. They have been classified into three types. The first, type I, describes lesions located at the boundary between the grey and white matter that affect both kinds of nerve tissue. The second, type II, occurs in the grey matter close to blood vessels, and may not be specifically caused by MS, because similar lesions can also be found in brain tissue from people who did not have MS. The third, type III, can be extensive, spreading out over large areas of the cerebral cortex, and usually, though not always, affecting only the upper portion of the cortical grey matter.

    In one study, researchers examined the characteristics of grey-matter lesions in brain specimens from 20 people with MS and 7 without (Bo, Vedeler, Nyland, Trapp, & Mork, 2003). They found that within the lesions, axons and dendrites were severed and there was extensive neuron cell death. Furthermore, the total brain area taken up by the lesions in the grey matter of the 20 brains studied was much greater than the lesions in the white matter (26% vs. 6.5%). This finding shows that damage to the grey matter of the cerebral cortex may contribute significantly to the development of permanent physical disabilities and difficulties with higher, cognitive, functions such as memory and thinking seen in SPMS, and indeed may be the dominant location for lesions in MS.

    Unfortunately, there is no good noninvasive system for viewing cortical lesions. The inflammation and the contrast with nearby tissues that makes white-matter lesions relatively easy to see by MRI are lacking in the grey matter lesions, which is partly why these lesions were largely overlooked in the past. New imaging techniques that allow cortical lesions to be monitored in patients with MS are urgently needed.

    Future Research
    To understand how to stop the damage inflicted on the nervous system by inflammation, we need a better understanding of exactly how the damage occurs. At the moment, it is not completely clear how the axons in MS lesions are severed. It is likely that when the myelin has been stripped away by the immune attack, the axons are more vulnerable to chemicals made by the immune cells (e.g., enzymes that attack cellular components, like proteins). In addition, neurons rely on myelin-producing cells for factors that are essential for their survival. When the myelin has been repeatedly stripped from axons in chronic lesions, myelinproducing cells are lost and the neurons may die because they lack sufficient amounts of these survival molecules. Finally, many studies have shown that when neurons are significantly damaged, they are programmed to self-destruct. Therefore, it is possible that repeated or long-term damage could trigger neuronal suicide. A deeper understanding of the mechanisms underlying the damage may help in identifying specific targets for new therapies.

    One issue that remains mysterious is why patients experience the progressive disability that defines the SPMS phase of the disease. It makes sense that when enough axons are severed in inflammatory lesions, permanent damage to brain function would eventually result. By the time patients enter the SPMS phase, however, inflammation tends to be much less prominent, and, in fact, the disease responds poorly or not at all to anti-inflammatory medications. One study(Confavreux, Vukusic, Moreau, & Adeleine, 2000), showed that it took extremely variable lengths of time for a patient’s disability to reach a score of 4 on the Extended Disability Status Scale. However, the time required thereafter to reach a score of 7 was very similar from patient to patient. This is consistent with the idea that after some threshold of neural damaged is reached, the damage progresses regardless of continuing or abating inflammation.

    Why and how this progressive degeneration occurs needs to be understood, so that therapies can be developed to prevent it. Furthermore, if subsequent research proves that progressive neurodegeneration is set in motion when a threshold amount of neuron loss is crossed, it will be important to seek new therapies that can be taken over the long-term and can halt inflammation early in the disease, long before this critical threshold is reached.

    Finally, to follow the effectiveness of such therapies, new imaging techniques that permit physicians to follow the amount and rate of axon loss in individual patients will be invaluable. The development of such techniques is an important goal for the near future.

    Clinical Implications
    The studies described here support the idea that anti-inflammatory treatment of MS should begin as early in the course of the disease as possible. By extension, suspected MS should be verified as quickly as possible, because many patients have silent lesions for years before their first acute neurological episode, and it is important to minimise this early damage. Likewise, treatment should be continued between relapses, to prevent or minimise damage from clinically silent lesions.

    Further Reading
    Bo, L., Vedeler, C. A., Nyland, H. I., Trapp, B. D., & Mork, S. J. (2003). Subpial demyelination in the cerebral cortex of multiple sclerosis patients. Journal of Neuropathology and Experimental Neurology, 62, 723-732.

    Confavreux, C., Vukusic, S., Moreau, T., & Adeleine, P. (2000). Relapses and progression of disability in multiple sclerosis. The New England Journal of Medicine, 343, 1430-1438.

    Trapp, B. D. (2007). Pathogenesis of neurological disability in multiple sclerosis. International Journal of MS Care, Supplement, pp. 4-7.

    Trapp, B. D., Peterson, J., Ranshohoff, R. M., Rudick, R., Mork, S., & Lars, B. (1998). Axonal transection in the lesions of multiple sclerosis. The New England Journal of Medicine, 338, 278-285.

    Trapp, B. (2007). Nerve Fibers are Severed by Inflammation in MS Lesions, Leading to Permanent Disabilities. Multiple Sclerosis Quarterly Report, 26(2), 6-10. Copyright 2007 by United Spinal Association. Reprinted with permission.

    New Therapeutic Targets For Neurodegenerative Diseases
    The focus of work in the Neurosciences Department’s Neurobiology Laboratory at the University of the Basque Country’s Faculty of Medicine and Odontology is the investigation of the molecular and cellular bases of neurodegenerative illnesses – those that affect the brain and the spinal cord. Some of these neurodegenerative illnesses are well known and affect a significant part of the population, such as Alzheimer’s disease and multiple sclerosis.

    Researchers at the University of the Basque Country (UPV-EHU) are studying the signals in the central nervous system - the brain and the spinal cord - that do not function well, in particular, those signals that cause the death of nerve cells. There are basically two types of cells in the central nervous system: neurones and the glial cells. Both types are sensitive to these functioning errors and both can die. In the case of Alzheimer’s disease, it is the neurones, above all, that die. However, in the case of multiple sclerosis, it is a class of glial cells – known as oligodendrocytes – that perish.

    From in vitro cells to biological samples of human origin

    The researchers at the Neurobiology Laboratory are investigating cells  in cultures - neurones, oligodendrocytes or other cells of the nervous system -, and are trying to reproduce in vitro circumstances that are thought to be relevant in these ailments. That is to say, they are creating the conditions that cause the death of these cells, in order to determine what molecules intervene in the process – from the moment of the lethal signal to the point where the cells collapse. In this type of experimental work a series of molecules involved in the death process are identified, the aim being to come up with pharmaceutical medicines that will improve treatment.

    Apart from working with in vitro cells, they are also experimenting with animals that reproduce some of the elements involved in neurodegenerative illnesses under certain conditions, i.e. sensory symptoms, motor symptoms, etc. and that can be induced in these animals. And they are examining if these substances that have proved to be interesting with the in vitro cells are also efficacious in these experimental models of the diseases.

    Moreover, over the past few years they have had the opportunity to study samples of brains of patients who have died of some neurodegenerative illness, such as, for example, multiple sclerosis. The illnesses leaves a mark in these samples and, although the brain has been at a terminal stage of the illness, they can investigate to see if there are signs of alterations to the molecules similar to those observed in the experiments, both with cells and with the animals. In this way it can be determined if the molecular targets discovered experimentally are relevant or not to the neurodegenerative processes and, if they are, develop pharmaceutical medicines that can neutralise these processes or the elements that enable them to progress, the goal being to halt the process of death.

    In collaboration with neurologists they have also been able to access biological samples of patients who have given their consent and donated them to research. Biological samples such as, fundamentally, blood, given that changes in blood plasma that may indicate alterations at the brain level can be identified.

    In search of biological samples

    All this is a dynamic process that enables clues to be found and which are, in some cases, relevant for developing pharmaceutical drugs that can halt, or at least slow down, the course of a neurodegenerative illness. Apart from finding these molecules or targets that interact with pharmaceutical medicines, in order to stop the process of progressive deterioration, substances that favour the survival of the neurones and oligodendrocytes are also sought; substances such as, for example, antioxidants, given that, in many of the neurodegenerative illnesses the cells die because oxidative stress is produced. In recent years the Neurobiology Laboratory researchers have found a number of antioxidants that put a brake on the dying process and can act as a neuroprotector. Antioxidants of natural origin that are in our diet – fruit, vegetables, and so on – and which, in some way appear to alleviate the damage cause by these illnesses.

    In short, the goal is to gain more knowledge about the molecular bases of these pathologies, define therapeutic targets (molecules of the cell that recognise a pharmaceutical drug and thus respond to it) and, in the last analysis, to come up with pharmaceutical medicines that improve treatment.

    Research team: C. Matute, A. Palomino, S. Mato, O. Oyanguren, A. Gutierrez, A. Pérez and E. Alberdi.

    Source: ScienceDaily Copyright © 1995-2007 ScienceDaily LLC (10/05/07)

    Brain’s White Matter: More “Talkative” than Once Thought
    Johns Hopkins scientists have discovered to their surprise that nerves in the mammalian brain’s white matter do more than just ferry information between different brain regions, but in fact process information the way grey matter cells do.

    The discovery in mouse cells, outlined in the cover story of the March issue of Nature Neuroscience, shows that brain cells “talk” with each other in more ways than previously thought.

    “We were surprised to see these nerve axons talking to other cells in the white matter,” says Dwight Bergles, Ph.D., an associate professor of neuroscience at Hopkins.

    The discovery focuses on oligodendrocyte precursor cells (OPCs), whose main role when they mature into oligodendrocytes is to wrap themselves around and insulate nerves with a whitish coat of protective myelin. The immature cells simply hang around and divide very slowly, waiting to be spurred into action.

    To learn more about OPCs that reside in the brain’s white matter, the Johns Hopkins researchers measured activity from individual precursor cells in the corpus callosum, a region of white matter that connects the two brain hemispheres. To their surprise, OPCs were found to have electrical signals produced by the neurotransmitter glutamate, similar to the signals used as the principle means of cell-to-cell communication and information processing in the grey matter. The phenomenon was unlikely, they said, because in the mouse brain, OPCs in the myelin-rich white matter are far from synapses, the points of contact between nerves where glutamate is released.

    Theorising that OPCs might have experienced glutamate in some less obvious way in this area of the brain, Bergles and his team studied nearby nerve cells to figure out where the glutamate might be coming from.

    By forcing single nerve cells to become excited one at a time, they discovered that as electrical impulses are carried along the nerves, glutamate is released and causes electrical signals in the OPCs. A further microscopic hunt revealed that pools of glutamate were present in the nerve fibres wherever they touched OPCs. All of the nerve cells in the white matter that released glutamate within reach of OPCs, moreover, had something in common: no myelin insulation.

    Normally myelin speeds electrical impulses. Cells lacking the coating fire 20 to 90 times slower than cells coated with myelin. Myelin loss is well known to impair signaling and information processing, causing nerve cells to die and creating such neurodegenerative conditions as multiple sclerosis.

    Bergles speculates that this white matter activity his team discovered may help “naked” nerve cells signal nearby OPCs and say “cover me with myelin because we need to replace another cell that has been damaged.”

    The research was funded by the National Institutes of Health, the March of Dimes, NARSAD, the National Multiple Sclerosis Society and the Medical Scientist Training Program.

    Authors on the paper are Jennifer Ziskin and Bergles of Hopkins, Akiko Nishiyama and Maria Rubio of the University of Connecticut, and Masahiro Fukaya of Hokkaido University in Sapporo, Japan.

    Source: Newswise © 2007 Newswise. All Rights Reserved.(07/05/07)

    Deactivating protein may protect nerve fibres in MS
    OHSU findings could lead to first drug to treat progressive, disabling form of disease.

    Oregon Health & Science University neuroscientists are eyeing a protein as a potential therapeutic target for multiple sclerosis because de-activating it protects nerve fibers from damage.

    OHSU researchers, working with colleagues at the Portland Veterans Affairs Medical Center and the University of Padova in Italy, have shown that genetically inactivating a protein called cyclophilin D can protect nerve fibres in a mouse model of multiple sclerosis. Cyclophin D is a key regulator of molecular processes in the nerve cell's powerhouse, the mitochondrion, and can participate in nerve fibre death. Inactivating cyclophilin D strengthens the mitochondrion, helping to protect nerve fibres from injury. The findings are published today, 24/04/07, in Proceedings of the National Academy of Sciences.

    "We're extremely excited," said Michael Forte, Ph.D., senior scientist at the Vollum Institute at OHSU and the study's lead author. "While we can't genetically inactivate cyclophilin D in people, there are drugs out there that can block the protein. Our research predicts that drugs that block cyclophilin D should protect nerve fibres from damage in MS."

    Such a drug would be the first therapy specifically for secondary-progressive MS, one of the more debilitating forms of MS involving an initial period of relapsing and remitting, followed by a steady worsening of symptoms. It affects half of the estimated 2 million people with MS.

    The only available therapies for MS are anti-inflammatory drugs, which reduce the inflammation believed to spur certain T-cells in the body to attack myelin, the fatty sheath insulating nerve fibres in the brain and spinal cord. The fibres can't conduct impulses, leading to paralysis, memory loss, dizziness, fatigue, pain and imbalance. Over time, the nerve fibres themselves degenerate, leading to permanent functional deficits.

    "All MS drugs available right now are anti-inflammatory," said study co-author Dennis Bourdette, M.D., professor and chairman of neurology in the OHSU School of Medicine, and director of the OHSU MS Centre of Oregon. "What is desperately needed is a therapeutic that protects the nerve fibres from degeneration."

    In recent years, scientists have increasingly viewed MS as a neurodegenerative disorder rather than simply an inflammatory one. Loss of nerve cells, injury to nerve fibres and atrophy within the central nervous system occur progressively from the start of the disease, eventually leading to permanent disability, especially in patients who've had MS for many years.

    "What puts people in wheelchairs from MS is not an inflammatory attack on myelin of the central nervous system. It's the severing of the axons (nerve fibres), which is a permanent thing," Forte said.

    Inflammation triggers a chain of molecular events that leads to progressive nerve fibre deterioration in MS, including the development of free radicals such as reactive oxygen and nitrogen that slow the cell's energy generation capability. It also throws off mitochondrial function by causing calcium to build up in the cell, reducing levels of ATP that serves as the cell's fuel source.

    But scientists believe that cyclophilin D is responsible for causing the unregulated opening of a pore in the mitochondrion's membrane that allows the calcium overload. The OHSU team showed that mice lacking cyclophilin D still developed an MS-like disease, but unlike their counterparts possessing the protein, the mutant mice partially recovered. Scientists found their nerve fibres remained intact, and they resisted the free radicals and calcium overload.

    "What we've done is make it so the mitochondria can tolerate higher loads of calcium before they die," Forte said. "The mutant mice are protected from axonal damage associated with this MS-like disease in mice."

    The scientists are now testing drugs that could be used to shut down the cyclophilin D protein and the mitochondrion pore it activates. "If you basically inhibited that protein with a drug, you would see the same axonal preservation that you saw in the mutant mouse," Forte said.

    One class of compounds Forte and Bourdette are particularly interested in is non-immunosuppressive derivative of cyclosporin A (CsA). Some nonimmunsuppressive derivatives of cyclosporin A are in human trials for other conditions. Because these drugs are already being tested in humans, they could be rapidly tested in MS. Bourdette believes that a cyclophilin D antagonist could potentially become available as a treatment for MS within five years.

    "We don't have to invent the drugs to target this protein. They already exist," Bourdette said.

    Such a therapy can't come soon enough for 36-year-old West Linn, Ore. resident Laura Wieden, who has suffered since 1995 from relapsing-remitting MS that's caused weakness in both legs and forced her to ride a Segway personal transportation device or a wheelchair. "For me, it's fabulous," she said. "If you can prevent MS, that's great, but what about the millions of people who have it? They need something that keeps the cells from dying. This just holds so much promise."

    Wieden's father, Dan Wieden, co-founder of Portland-based Wieden + Kennedy advertising agency, set up a fund in his daughter's name – the Laura Fund for Innovation in Multiple Sclerosis Research – to support MS research that pushes traditional boundaries to discovery. The discovery by Forte, Bourdette and their team, which was funded in part by the foundation, fits the bill, he said.

    "It goes to prove that sometimes the big breakthroughs do not come from the more traditional lines of inquiry," he said. "What I appreciate about our relationship with OHSU is that there seems to be a sense of urgency about these projects. And it's been beneficial for us to develop a more personal relationship with the researchers. That way it becomes not just an academic exercise, but a very passionate inquiry on their part."

    Source: Oregon Health & Science University

    NIH Awards $7.39 million to Burnham Neurobiologists
    A team of researchers at the Burnham Institute for Medical Research (“Burnham”) has been awarded $7.39 million from the National Institute of Child Health and Human Development of the National Institutes of Health. The funding will support a five-year, multi-project study entitled “Neuron-Glia Communication in Development.”

    Glial cells are at the centre of most functions of the nervous system. They outnumber neurons (nerve cells) in the brain and spinal cord by a factor of 10:1 and provide physical and nutritional support for neurons. They are also believed to guide the migration of neurons during development and to regulate the chemical environment surrounding synapses in the adult brain. And yet, little is known about the molecular mechanisms by which glial cells communicate with neurons and how the failure of such communication leads to neurological diseases. New studies underway at Burnham are addressing this information gap.

    “The study of neuron-glia communication is a rapidly emerging field in basic neurobiology. It also has strong relevance to demyelinating diseases, such as multiple sclerosis and neuropathies,” said project director Yu Yamaguchi, M.D., Ph.D. Myelin is the protective sheath coating nerve fibres, and the damage or loss of myelin (demyelination) severely impairs the ability of nerve fibres to conduct electrical signals. Multiple sclerosis is the most well known of the so-called demyelinating diseases. “With this funding, we expect to resolve how glial cells function in the normal brain. But also, we hope to provide new insights into the mechanisms of demyelinating diseases,” said Yamaguchi.

    In this NIH-funded project, Dr. Yamaguchi, who is a Professor in Burnham’s Glycobiology Program, leads a team including four other faculty members at the Institute: Professor William Stallcup, Ph.D., Professor Elena Pasquale, Ph.D., Professor Barbara Ranscht, Ph.D., and Assistant Professor Dongxian Zhang, Ph.D. This is a mature collaboration: the members of this team have worked together for more than 10 years as a highly interactive group at Burnham. Their work has contributed key findings about the formation of nerve cell circuitry, synaptic functions, proliferation and migration of nerve cells, helping to advance medical researchers’ understanding of normal brain development as well as cancer and degenerative diseases of the brain.

    About Burnham Institute for Medical Research.

    Burnham Institute for Medical Research conducts world-class collaborative research dedicated to finding cures for human disease, improving quality of life, and thus creating a legacy for its employees, partners, donors, and community. The La Jolla, California campus was established as a nonprofit, public benefit corporation in 1976 and is now home to three major centers: a National Cancer Institute-designated Cancer Center, the Del E. Webb Center for Neurosciences and Aging, and the Infectious and Inflammatory Disease Center. Burnham today employs over 750 people and ranks consistently among the world’s top 20 research institutes. In 2006, Burnham established a presence at the University of California, Santa Barbara, led by Dr. Erkki Ruoslahti, Distinguished Professor. Burnham is also establishing a campus at Lake Nona in Orlando, Florida that will focus on diabetes and obesity research and will expand the Institute’s drug discovery capabilities.

    Source: Newswise © 2007 Newswise. All Rights Reserved.

    Calcium is spark of life, kiss of death for nerve cells
    Oregon Health & Science University research shows how calcium regulates the recharging of high-frequency auditory nerve cells after they've fired a burst of signals, and it may have implications for neurological disorders.

    The study by scientists at OHSU's Vollum Institute and the University of Arkansas for Medical Sciences, which appears in the current issue of the journal Nature Neuroscience, shows that calcium ions play a greater role in keeping in check the brain's most powerful circuits, such as those used for processing sound signals, than previously thought.

    A better understanding of that role could someday help prevent the death of neurons behind some diseases of the brain and spinal cord, such as stroke and multiple sclerosis, the scientists say.

    The research, led by postdoctoral fellow Jun Hee Kim, Ph.D., and her advisor, Henrique von Gersdorff, Ph.D., both scientists at the Vollum Institute, found that calcium tempers the activity of a high-throughput sodium pump, located in the plasma membrane covering nerve endings, that controls how quickly and accurately a nerve cell continues firing after an initial burst of spiking activity.

    "What's happening in the brain is you have all these action potentials (spikes) that are firing - the action potential is the way you transmit information quickly from neuron to neuron - and when you have an action potential, you have an explosive influx of sodium ions into the cell," von Gersdorff said. "As a result, the cell is depolarized and it needs to be quickly repolarised."

    To repolarise a cell so it can continue firing, and do so accurately and at high-input frequencies, the sodium pump ejects three positively charged sodium ions and imports two positively charged potassium ions. The net result is one positive charged is expelled from the cell, causing a hyperpolarisation of the cell's membrane potential.

    Quick repolarisation of the nerve cell is essential. Mature auditory nerve cells fire at frequencies that are 10 to 100 times higher than most high-frequency cells in the brain - 1 kiloHertz, or 1,000 Hertz. Most brain synapses, the space between nerve cells through which impulses are transmitted and received, begin failing beyond 10 Hertz.

    "In the last few years, we have been studying high-frequency firing cells in the auditory part of the brain. We found that these cells and nerve terminals are amazing because they can fire at 1,000 Hertz without failures and with high precision," von Gersdorff said. "That discovery in our lab prompted us to ask the question: How is it that these nerve cells can handle all this high-frequency firing?"

    Enter calcium, which, by inhibiting the activity of the sodium pump, regulates signal firing, and may conserve energy and keep the high-frequency cells from burning out. But calcium in high levels within a nerve cell can be toxic, so the researchers discovered another purpose for the sodium pump: powering a protein located on the nerve terminal membrane called the sodium-calcium exchanger, which removes the calcium and replaces it with sodium. That action, in turn, triggers the sodium pump, and so on.

    The sodium-calcium exchanger "can import high concentrations of sodium from outside the cell, and it uses the gradient of low internal sodium in the cell as a form of energy to get rid of calcium. That energy comes, ultimately, from the sodium pump and its use of ATP, the cells' major fuel," von Gersdorff explained. The pump is "always keeping sodium concentration in the neuron low and that allows the sodium-calcium exchanger protein to constantly exchange sodium for calcium." 

    Otherwise, if allowed to get too high within the cell, the calcium shuts down the sodium pumps, creating a "vicious loop," von Gersdorff said.

    "You then get a simultaneous build-up of calcium and sodium in the cell, and it's 'Goodbye to your neuron.' It goes at some point into an irreversible cycle of death," he said.

    One potential therapeutic approach to preventing cell death caused by increasing calcium levels is making the sodium pump more insensitive to calcium. A potential new drug, for example, could "help the neuron to keep extruding sodium so it can help the sodium-calcium exchanger get rid of calcium, thereby not allowing calcium to reach toxic levels," von Gersdorff said.

    For the time being, von Gersdorff's lab will continue studying how calcium regulates the sodium pump.

    "Our hope is that these basic, fundamental issues will eventually lead to therapeutic strategies that alleviate neuronal damage from ischemia and stroke," he said.

    Source: Oregon Health & Science University

    Cannabinoid CB1 and CB2 Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis
    Cristina Benito,1 Juan Pablo Romero,1,2 Rosa María Tolón,1 Diego Clemente,3 Fabián Docagne,3 Cecilia J. Hillard,4 Camen Guaza,3 and Julián Romero1,2

    1Laboratorio de Apoyo a la Investigación, Fundación Hospital Alcorcón, 28922 Madrid, Spain, 2Department of Biochemistry, Francisco de Vitoria University, Pozuelo de Alarcón, 28223 Madrid, Spain, 3Neuroimmunology Group, Neural Plasticity Department, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain, and 4Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

    Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS).

    However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patients. Areas of demyelination were identified and classified as active, chronic, and inactive plaques. CB1 and CB2 receptors and FAAH densities and cellular sites of expression were examined using immunohistochemistry and immunofluorescence.

    In MS samples, cannabinoid CB1 receptors were expressed by cortical neurons, oligodendrocytes, and also oligodendrocyte precursor cells, demonstrated using double immunofluorescence with antibodies against the CB1 receptor with antibodies against type 2 microtubule-associated protein, myelin basic protein, and the platelet-derived growth factor receptor-, respectively.

    CB1 receptors were also present in macrophages and infiltrated T-lymphocytes. Conversely, CB2 receptors were present in T-lymphocytes, astrocytes, and perivascular and reactive microglia (major histocompatibility complex class-II positive) in MS plaques.

     Specifically, CB2-positive microglial cells were evenly distributed within active plaques but were located in the periphery of chronic active plaques. FAAH expression was restricted to neurons and hypertrophic astrocytes. As seen for other neuroinflammatory conditions, selective glial expression of cannabinoid CB1 and CB2 receptors and FAAH enzyme is induced in MS, thus supporting a role for the endocannabinoid system in the pathogenesis and/or evolution of this disease.

    Source: The Journal of Neuroscience, February 28, 2007, 27(9):2396-2402; doi:10.1523/JNEUROSCI.4814-06.2007

    Enabling nerve regeneration means evicting the cleanup crew
    Macrophages are the immune cells that engulf and destroy the debris of damaged tissue to enable the healing process to begin. Their presence at the scene of damage is critical, but once their task is complete, it is just as critical that macrophages exit rapidly, ending the inflammatory process and making way for regrowth. In fact, the continued presence of macrophages could damage tissue, compromising repair.

    While researchers know a great deal about the molecular machinery that launches this cellular cleanup crew into action, little has been known about the just-as-critical exit process.

    Now, researchers have identified a key process by which macrophages are cleared from sites of peripheral nerve injury. The scientists say their findings could also have implications for understanding the same fundamental mechanism in spinal cord injury, stroke and multiple sclerosis.

    Samuel David and colleagues published their findings in the March 1, 2007 issue of the journal Neuron, published by Cell Press.

    The researchers concentrated on a family of cell receptors known as Nogo receptors, already known to be present on nerve cells and to play a role in nerve growth. Specifically, David and colleagues explored the role of one such Nogo receptor, NgR1. Receptors such as NgR1 are protein switches that nestle in the membranes of cells, and which induce a cellular response when triggered by a specific chemical signal, or ligand.

    In the researchers' experiments, they induced damage in the sciatic nerve in the thigh of rats and mice and analysed the role of NgR1 in the repair process.

    They found that macrophages showed the presence of NgR1 on their surface once they arrive at the injury site and began their cleanup. Further experiments revealed that as the healing nerve began to form the protein myelin—the insulating sheath around nerves—this receptor not only caused a reduction in the macrophages' binding to myelin, but also an outright repulsion from the forming myelin. In fact, when the researchers created nerve injury such that new myelin would not be formed, the macrophages continued to lurk around the injury site. The researchers' experiments also identified specific molecules on myelin that triggered such repulsion.

    The findings could also apply to nerves other than peripheral nerves, because macrophages activated during stroke, multiple sclerosis injury, and spinal cord injury also express NgR1 on their surface, pointed out the researchers.

    "Our discovery of this novel (to our knowledge) role for NgRs in mediating the efflux of macrophages from inflamed neural tissue via interactions with myelin could therefore have broader implications for the regulation of inflammatory responses not only in other peripheral nerve pathologies, but also in [central nervous system] inflammation such as in spinal cord injuries, stroke, and multiple sclerosis," they concluded.

    The researchers include Elizabeth J. Fry and Samuel David of The McGill University Health Center in Montreal, Quebec, Canada; Carole Ho of Stanford University Medical Center in Stanford, CA and Genentech Inc. in South San Francisco, CA.

    This work was supported by a grant from the Canadian Institutes of Health Research to S.D. E.J.F. was supported by a Multiple Sclerosis Society of Canada post-doctoral fellowship and an award from the McGill University Health Center and Department of Medicine. C.H. was supported by an NINDS KO8 Career Development NS048058 Award.

    Fry et al.: "A Role for Nogo Receptor in Macrophage Clearance from Injured Peripheral Nerve." Publishing in Neuron 53, 649–662, March 1, 2007. DOI 10.1016/j.neuron.2007.02.009.

    Source: Cell Press

    Getting On Your Nerves ... And Repairing Them
    In a study to be published in the March 2007 issue of The FASEB Journal, scientists from East Carolina University report that a key molecular mechanism, RNA interference (RNAi), plays a role in the regeneration and repair of periphery nerves, which are the nerves located outside of the brain and spinal column. This research may lead to new therapies that manipulate RNAi to treat people with damaged nerves resulting from degenerative disorders and injury.

    Andrew Z. Fire of Stanford University and Craig C. Mello of the University of Massachusetts won the 2006 Nobel Prize for the discovery of RNAi. This study builds on this and other RNAi research, which was reviewed in the July 2006 issue of The FASEB Journal, showing that RNAi regulates the creation of proteins in the body. Until now, there has been no direct evidence that RNAi controls local protein synthesis in axonal nerve fibers, which act as "pavement" for the nervous system's "information superhighway." In addition, the mechanism involved in the nerve fiber creation did not depend on communication with, or transport from, the nerve cell body or its nucleus, or from surrounding support cells. Axonal nerve fibers can be as long as three feet (sciatic nerve), and this independence makes RNAi a promising drug target.

    "Repairing and rebuilding damaged nerve tissue is one of the greatest medical advances not yet achieved," said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal, "and this research is a huge leap forward. It's no accident that a Nobel Prize discovery should be followed up by great new science."

    The FASEB Journal  is published by the Federation of American Societies for Experimental Biology (FASEB) and is consistently ranked among the top three biology journals worldwide by the Institute for Scientific Information. FASEB comprises 21 nonprofit societies with more than 80,000 members, making it the largest coalition of biomedical research associations in the United States. FASEB advances biological science through collaborative advocacy for research policies that promote scientific progress and education and lead to improvements in human health.

    Source: ScienceDaily Copyright © 1995-2007 ScienceDaily LLC

    Brain creates 'new' nerve cells
    Researchers have discovered a type of brain cell that continuously regenerates in humans.

    A pool of "resting cells" migrate to create new nerve cells in the part of the brain which deals with smell.

    The system has been shown in mice and rats but it was believed it did not exist in the human brain.

    Experts said the findings, published in Science, opened up the potential for research into repairing brains in conditions such as Alzheimer's disease and Multiple Sclerosis.

    The researchers from the University of Auckland, New Zealand and the Sahlgrenska Academy in Sweden showed stem cells rest in certain areas of the brain, just beneath large fluid-filled chambers called ventricles.

    But then they needed to work out how they got to the right part of the brain. 

    In many species, it was known that a tube filled with brain fluid enabled these cells to travel to the olfactory bulb - the region of the brain that registers smells - turning into nerve cells as they went.

    But until now, this system had not been shown in humans.

    Using several techniques, including a powerful electron microscope, the team identified the tube, and showed it contained stem cells as well as cells which were gradually turning into nerve cells as they travelled along.

    The researchers said the addition of new nerve cells in the olfactory bulb in humans helped the system respond to different stimuli throughout a person's life.

    Brain repair

    Experts said the findings could be important for future research into brain cell repair in patients with neurodegenerative diseases such as Alzheimer's disease and Multiple Sclerosis and, importantly, that studies in mice would be applicable to humans.

    Dr Mark Baxter, Wellcome Trust senior research fellow at Oxford University, said: "This study is exciting because it reveals a group of brain cells in the adult human brain that are continuously regenerating.

    "This opens another direction by which we may discover ways to repair human brains that are damaged from injury or diseases, and underscores the importance of animal research in guiding biomedical research in humans."

    Professor Sebastian Brandner, head of the division of neuropathology at the Institute of Neurology, University College London, said it has been known for decades that such cells were present in mice and rats.

    "Understanding stem cell biology is essential to study brain repair in neurodegenerative diseases such as Alzheimer's and it is even possible that stem cells are the source of some brain tumours."

    Source: BBC News Copywrite BBC MMVII

    Time-Lapse Movies Reveal Surprisingly Dynamic Process Of Insulating Nerves
    Much like the electrical wiring in your house, the nerves in your body need to be completely covered by a layer of insulation to work properly.

    Instead of red, white or black plastic, however, the wiring in the nervous system is protected by layers of an insulating protein called myelin. These layers increase the speed that nerve impulses travel throughout the brain and the body. The critical role they play is dramatically illustrated by the symptoms of multiple sclerosis, which is caused by lesions that destroy myelin. These include: blindness, muscle weakness and paralysis, loss of coordination, stuttering, pain and burning sensations, impotence, memory loss, depression and dementia.

    The formation of myelin sheaths during development requires a complex choreography generally considered to be one of nature's most spectacular examples of the interaction between different kinds of cells. Now, a group of Vanderbilt researchers has successfully produced movies that provide the first direct view of the initial stage of this process: the period when the cells that ultimately produce the myelin sheathing spread throughout the developing nervous system. The results were published online in the journal Nature Neuroscience on Nov. 12 and should aid in the design of new therapies to promote the repair of this protective layer following disease or injury.

    "We discovered that this process is far more dynamic than anyone had dreamed," says Bruce Appel, the associate professor of biological sciences and Kennedy Center investigator who headed up the study.

    In the central nervous system, the myelin membranes are produced by cells called oligodendrocytes. These cells must be distributed uniformly along axons — the long, wire-like extensions from neurons that carry nerve impulses — so that the membranes, which wrap the nerve fibers like millions of microscopic pieces of electrician's tape, can cover the axons completely and uniformly. The wrapping process takes place near the end of fetal development and actually continues for some time after birth.

    In order to study this process, Appel and his research group — graduate students Brandon Kirby and Jimann Shin along with post doctoral fellows Norio Takada and Andrew Latimer — created a transgenic zebrafish which incorporates fluorescent proteins in the cells involved in myelination. The zebrafish is a small tropical fish that has become a popular species for studying the process of development in vertebrates (animals with backbones). Because zebrafish embryos are transparent and develop within a few days, they allow biologists to watch developmental processes as they take place: something they cannot do with mice or other mammals. These characteristics allowed the Vanderbilt researchers to obtain images of the cells involved in myelination using a confocal microscope and edit them into time-lapse movies.

    The oligodendrocytes that produce the myelin membranes arise from mobile, dividing cells called "oligodentrocyte progenitor cells" or OPCs. OPCs are made in special locations in the brain and spinal cord. These cells seek out axons and spread out along them. Then, at a certain point, a fraction of the OPCs transform themselves into oligodentrocytes and begin wrapping axons. Each of these cells can wrap portions of several different axons and each axon is wrapped by a large number of oligodentrocytes.

    Before the Vanderbilt study, there were a number of different theories about how OPCs space themselves along axons. One was that the axons themselves produce some kind of positional cues that the OPCs follow. Another was that the OPCs sense each other and adjust their position accordingly: a mechanism somewhat similar to that which soldiers on the parade ground use to align a formation by extending their right arm and adjusting their position until their outstretched fingers touch the shoulder of the person on the right.

    Previous studies of OPCs grown in tissue culture had seen that they could generate small pseudopods, called filopodia, but no one knew what their purpose might be. So, when the researchers began viewing their movies, they were excited to observe that the cells were continually sending out filopodia in different directions. They found that OPCs not only generate these tiny tentacles, but keep them extending and contracting in a fashion reminiscent of the party noise-makers called blow-outs that unroll when you blow on them and snap back when you stop. They observed that when one of these tiny tentacles touches a neighboring OPC, the cells react by moving in the opposite direction. This caused a surprising amount of movement as the OPCs repeatedly readjusted their positions.

    "This could serve as a surveillance mechanism that allows the OPCs to determine the presence or absence of nearby cells of the same type," says Appel, "and could explain how they distribute themselves along the axons."

    The researchers used the same system to see how the OPCs respond to injuries and conditions like multiple sclerosis. They did so by using a laser to destroy the OPCs along a short length of the embryo's spine a day before the axon-wrapping stage begins. They found that the OPCs in the vicinity of the gap start dividing to produce additional cells that move into the gap. After a day, the number of OPCs in the gap had grown to 50 percent of normal and after four days it had risen to 70 percent.

    "Now that we have a better understanding of OPC and oligodendrocyte behaviors, we are in a much better position to identify and study the genes that are necessary for myelination," says Appel, "and having these genes in hand should aid in the design of drugs to promote remyelination following disease or injury."

    Robert Kelsh from the University of Bath and Thomas Carney now at the Max-Planck Insitute for Immunobiology also contributed to the study. The research was supported by funding from the National Institutes of Health, the National Multiple Sclerosis Foundation and Vanderbilt University.

    Source: ScienceDaily Copyright © 1995-2006 ScienceDaily LLC

    Cause of nerve fibre damage in multiple sclerosis identified
    Researchers have identified how the body's own immune system contributes to the nerve fibre damage caused by multiple sclerosis, a finding that can potentially aid earlier diagnosis and improved treatment for this chronic disease.

    The study reveals how immune system B-cells damage axons during MS attacks by inhibiting energy production in these nerve fiber cells, ultimately causing them to degenerate and die. Study results appear in the Oct. 15 issue of the Journal of Immunology.

    B-cell-axon activity is an emerging area of MS research, one that is changing how scientists and clinicians can look at this disease. In this study, Dr. Yufen Qin and fellow researchers from UC Irvine's School of Medicine analysed spinal fluid and tissue samples from MS patients to identify substances that stimulate a B-cell immune response. They noted an increased level of B-cell antibodies on lesions and in spinal fluid bound to two specific enzymes -- GAPDH and TPI.

    These two enzymes are essential for efficient energy production. The researchers believe that the binding of these antibodies to these enzymes -- GAPDH, in particular -- may lower the amounts of ATP -- the chemical fuel for cells -- available in cells, which eventually can lead to axon cell degeneration and death. In addition to the energy-production function, GAPDH is involved with a number of genetic activities, such as RNA translocation, DNA replication and DNA repair.

    Other recent studies have shown that binding of inhibitors to GAPDH and TPI causes decreased ATP production in neurons, followed by progressive neuronal degeneration and death. Moreover, patients with TPI deficiency can develop progressive neurological disorders.

    "This research is exciting and potentially important for future treatments because it identifies new antibodies associated with MS that can be targeted with emerging therapies," said Qin, an assistant professor of neurology. "Significantly, these are the first antibodies to be identified with axon activity, which is a new area researchers are exploring in the pathology of MS."

    Much MS research is focused on an autoimmune process in which T-cells attack and damage myelin, the fatty insulating tissue of axons. These T-cells do not attack axons themselves; the process of demyelination interrupts electrical impulses that run through these nerve fibres, thus causing MS symptoms. Demyelination has been considered the central feature of MS.

    Recently, however, Qin has been among a group of researchers who have discovered that B-cells too are involved with the autoimmune response to MS. Instead of targeting myelin, these B-cells attack axons directly. Axons are the long, slender fibres of a neuron that serve as the primary transmission lines of the nervous system, and as bundles they help make up nerves.

    Research at UCI and elsewhere has shown that myelin grows back if the T-cell autoimmune response is turned off, and drugs exist or are in development to block demyelination. Axons, in turn, repair very slowly, which implies that B-cell attacks on axons may have a significant impact on the chronic central nervous system damage caused by MS.

    "Since this area of research is in its early stage, it's important to understand the process by which these B-cell responses happen," Qin said. "Hopefully, by identifying these two crucial enzymes, it will lead to a greater understanding of MS and lead to more effective treatments for people who live with this disease."

    Source: University of California - Irvine

    In The Growth Process Of Neurons, Most Important Actors Identified
    Defects in the growth process of our neurons often underlie brain or nerve diseases, such as Alzheimer's disease or multiple sclerosis. Scientists from the Flanders Interuniversity Institute for Biotechnology (VIB) connected to the Katholieke Universiteit Leuven, led by Bassem Hassan, have achieved a major step in unraveling the growth process of axons, the offshoots of neurons. They have identified the JNK, Wnt and FGF signaling cascades as the most important actors and have also discovered their respective roles. Their research shows that the growth of axons and the activity of neurons are completely independent of each other. This new finding can lead to better understanding of a variety of nerve diseases.

    A complex network

    A human being has approximately 100 billion neurons, the body's information and signal processors. The great majority of them are found in the central nervous system. The brain contains complex networks of neurons that regulate a large number of bodily functions. Because the brain and the nervous system are a delicate system, something can sometimes go seriously wrong and a brain or nerve disease appears - for example, Alzheimer's or Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), or Multiple Sclerosis (MS). In the quest for possible cures for these diseases, it is important that we understand how connections are established between neurons.

    Neurons have a number of long thin offshoots - called axons - that conduct electrical impulses. These primary elements of information transfer in the nervous system can sometimes be more than a meter long. The axon's orientation as it grows is also of great importance in forming the right connection. As in-coming stimuli are converted into signals that determine the direction and speed of an axon's growth, three things can happen: the axon can grow further, pull back, or change direction. Therefore, axon growth is a process that consists of several components: growth of the axon, orientation, recognition of objectives, and finally formation of synapses in order to transmit stimuli. Unraveling precisely how this whole process works is important for understanding the development of the brain and for helping develop therapies for diseases that are the consequence of damaged or diseased neurons.

    The fruit fly as model Bassem Hassan is using the fruit fly (Drosophila melanogaster) as model for his research. Many processes in this small fly are in fact comparable to processes in humans, even for something as complex as the nervous system. Axon growth is a complicated process in that it involves growth as well as orientation and recognition. So it's not surprising that many different genes are involved. To bring clarity to this complex organisation, Mohammed Srahna and his colleagues, led by Bassem Hassan, have been studying the DCN (Dorsal Cluster Neurons), a group of cells in the fruit fly's brain. The DCN belong to the visual system of the adult fruit fly and stimulate the visual cortex. The axons of the DCN form a very stereotypical connection pattern. This well-ordered pattern gave the researchers the perfect starting point for studying the influence of various genes on the axon growth process.

    Regulation by several genes

    From their study of the developing brain of an adult fruit fly, the researchers have found that axon growth is mediated by an interaction among three signal cascades: Wnt, FGF and JNK. JNK is necessary for stimulating the growth of axons. Wnt activates JNK and FGF inactivates JNK, so the right balance between Wnt and FGF provides for a precise regulation of the growth of neurons. Axonal growth turns out to be completely independent of neuronal activity. This finding brings greater clarity to the axon's growth process - knowledge that constitutes a major step forward in understanding neuronal disorders.

    Relevant scientific publication
    This research appears in the authoritative journal PLoS Biology (Srahna et al., A signaling network for patterning neuronal connectivity in the Drosophila brain; PloS Biology, 2006).

    This research has been funded by the Katholieke Universiteit Leuven, VIB, and FWO.

    VIB, the Flanders Interuniversity Institute for Biotechnology, is a research institute where 900 scientists conduct gene technological research in a number of life-science domains, such as human health care and plant systems biology. Through a joint venture with four Flemish universities (Ghent University, the Katholieke Universiteit Leuven, the University of Antwerp, and the Vrije Universiteit Brussels) and a solid funding program for strategic basic research, VIB unites the forces of nine university science departments in a single institute. Through its technology transfer activities, VIB strives to convert the research results into products for the benefit of consumers and patients. VIB also distributes scientifically substantiated information about all aspects of biotechnology to a broad public.

    Source: Medical News Today © 2006 MediLexicon International Ltd

    Can a vitamin alleviate chronic, progressive multiple sclerosis?
    Ongoing nerve-fiber damage, disability prevented in animal study.

    Researchers have found a possible way to protect people with multiple sclerosis (MS) from severe long-term disability: increase nervous-system levels of a vital compound, called nicotinamide adenine dinucleotide (NAD), by giving its chemical precursor – nicotinamide, a form of vitamin B3.

    Current therapies for MS mainly address the  relapsing-remitting phase of the disease, but some of these have severe side effects, and most patients eventually enter a chronic progressive phase for which there is no good treatment. Using a mouse model of MS, researchers in the Neurobiology Program at Children's Hospital Boston found strong evidence that nicotinamide may protect against nerve damage in the chronic progressive phase, when the most serious disabilities occur. Their findings appear in a cover article in the September 20 Journal of Neuroscience.

    MS is a neurologic disorder in which nerve fibers, or axons, are damaged through inflammation, loss of their insulating myelin coating, and degeneration. This damage disrupts nerves' ability to conduct electrical impulses to and from the brain, causing such symptoms as  fatigue, difficulty walking, pain, spasticity, and emotional and cognitive changes. Current treatments mainly protect against inflammation and myelin loss, but do not completely prevent long-term axon damage.

    A team led by Shinjiro Kaneko, MD, a research fellow at Children's, and senior investigator Zhigang He, PhD, also from Children's, worked with mice that had an MS-like disease called experimental autoimmune encephalitis (EAE). Through careful experiments, they showed that nicotinamide protected the animals' axons from degeneration – not only preventing axon inflammation and myelin loss, but also protecting axons that had already lost their myelin from further degradation.

    Intriguingly, mice with EAE who received daily nicotinamide injections under their skin had a delayed onset of neurologic disability, and the severity of their deficits was reduced for at least eight weeks after treatment. The greater the dose of nicotinamide, the greater the protective effect.

    On a scale of 1 to 5 (1 indicating mild weakness only in the tail, 4 indicating paralysis involving all four limbs, and 5, death from the disease), mice receiving the highest doses of nicotinamide had neurologic scores between 1 and 2, while control mice had scores between 3 and 4. All differences between treated groups and controls were statistically significant.

    Mice with the greatest neurologic deficits had the lowest levels of NAD in their spinal cord, and those with the mildest deficits had the highest NAD levels. Mice that had higher levels of an enzyme that converts nicotinamide to NAD (known as Wlds mice) responded best to treatment.

    Moreover, nicotinamide significantly reduced neurologic deficits even when treatment was delayed until 10 days after the induction of EAE, raising hope that it will also be effective in the later stages of MS. "The earlier therapy was started, the better the effect, but we hope nicotinamide can help patients who are already in the chronic stage," says Kaneko.

    In other experiments, the researchers demonstrated that nicotinamide works by increasing levels of NAD in the spinal cord and that NAD levels decrease when axons degenerate. Finally, they showed that giving NAD directly also prevented axon degeneration.

    NAD is used extensively by cells to produce energy through the breakdown of carbohydrates. Its chemical precursor, nicotinamide, has several characteristics that make it a promising therapeutic agent: it readily crosses the blood-brain barrier, is inexpensive and available in any drugstore, and its close relative, vitamin B3, is already used clinically to treat pellagra (vitamin B3 deficiency), high cholesterol, and other disorders. Although nicotinamide is thought to have few side effects, the doses used in mice would translate to much higher human doses than are normally used clinically, so would need to be tested for safety.

    "We hope that our work will initiate a clinical trial, and that nicotinamide could be used in real patients," Kaneko says. "In the early phase of MS, anti-inflammatory drugs may work, but long-term you need to protect against axonal damage."

    The research was funded by the National Multiple Sclerosis Society and the National Institute of Neurological Disorders and Stroke.

    Source: Children's Hospital Boston (20/09/06)

    Harvard scientists identify compounds that stimulate stem cell growth in the brain
    Scientists at Harvard University have identified key compounds that stimulate stem cell growth in the brain, which may one day lead to restored function for people affected by Parkinson's disease, strokes, multiple sclerosis, and a wide range of neurological disorders. These findings, which appear in the September 2006 issue of The FASEB Journal, provide important clues as to which compounds may be responsible for causing key brain cells, neurons, to regenerate and ultimately restore brain function.

    The research study focused on two compounds--LTB4 and LXA4. Both play a role in inflammation and are regulators of proliferation of several cell types. When stem cells isolated from the brains of mouse embryos were exposed to LTB4 they proliferated and differentiated, giving rise to additional stem cells and to differentiated neurons with limited or absent capacity to divide. When exposed to LXA4, these cells experienced decreased growth and apoptosis.

    "This study opens doors to new therapeutic approaches for a wide range neurological disorders and injuries that were once considered incurable," said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal.

    The study also provided so insight into the cellular and molecular mechanisms involved when LTB4 stimulates neuronal stem cells. According to the study, cells generated as the result of LTB4 exposure had high levels of LTB4 receptors, whereas the level of LTB4 receptors was considerably lower in similar cells not generated by LTB4 stimulation. The investigators were further able to show that LTB4 up-regulated several molecules involved in cell cycling and growth, such as cyclins and epidermal growth factor receptor, and decreased those such as caspase 8 which play a role in apoptosis. LXA4 had the opposite effects.

    The FASEB Journal ( ) is published by the Federation of American Societies for Experimental Biology (FASEB) and is consistently ranked among the top three biology journals worldwide by the Institute for Scientific Information. FASEB comprises 21 nonprofit societies with more than 80,000 members, making it the largest coalition of biomedical research associations in the United States. FASEB's mission is to enhance the ability of biomedical and life scientists to improve – through their research – the health, well-being and productivity of all people. FASEB serves the interests of these scientists in those areas related to public policy, facilitates coalition activities among member societies and disseminates information on biological research through scientific conferences and publications.

    Source: Federation of American Societies for Experimental Biology

    Multiple sclerosis damage found in 'normal' brain tissue
    The effects of multiple sclerosis (MS) extend beyond visibly affected areas into large portions of the brain that outwardly appear normal, according to a study appearing in the September issue of Radiology.

    "This disease process in the normal-appearing brain tissue affects the brain globally and has substantial clinical impact," said the study's lead author, Hugo Vrenken, Ph.D., from the Multiple Sclerosis Center at VU University Medical Center in Amsterdam, The Netherlands.

    MS is a chronic, autoimmune disease characterised by the destruction of myelin, the protective layers that surround nerve cells. It can affect numerous body functions, and symptoms may include  visual and speech impairment, memory loss, depression, muscle weakness, loss of coordination, numbness or pain,  bowel and bladder problems and sexual dysfunction.

    MS affects approximately 400,000 people in the United States and as many as 2.5 million worldwide, mostly women between the ages of 20 and 50, according to the National Multiple Sclerosis Society.

    "The areas of demyelination, or lesions, in patients with MS can be visualised with magnetic resonance imaging (MRI). However, the volume of lesions visible at MRI only correlates moderately with clinical disability measurements," Dr. Vrenken said. "This may be due to disease activity outside the visible lesions."

    To gain a better understanding of the effects of MS on the whole brain, Dr. Vrenken and colleagues studied T1 changes in normal-appearing white and grey brain matter in patients with MS.

    T1 is a measurement of proton relaxation after exposure to a magnetic field and a radiofrequency (RF) pulse. Due to this RF pulse, protons in the body first reach an excited state and then relax back to a state of equilibrium by funneling the excess energy to the surrounding tissues. T1 refers to the time required for protons to relax to the equilibrium state in this particular manner.

    The researchers investigated T1 changes in 67 patients with MS and 24 healthy control volunteers. T1 graphs of normal appearing white and grey matter were significantly different for patients with MS than for controls. Moreover, these graphs differed among patients with MS based on the type of disease: secondary progressive (SP), relapsing-remitting (RR) or primary progressive (PP). The results were most pronounced in patients with SP disease, where at least 31 percent of normal-appearing white matter and 20 percent of cortical normal-appearing grey matter were affected. In RR disease, 16 percent of normal-appearing white matter and 9 percent of cortical normal-appearing grey matter were affected. In PP disease, the normal-appearing white and grey matter affected were 11 percent and 8 percent, respectively. These changes were found throughout the brain, including areas remote from localised lesions that are typically associated with MS.

    "These findings demonstrate that in MS, disease processes outside MR-visible lesions are not limited to a few sites but act throughout the brain and affect large fractions of normal-appearing white and grey matter," Dr. Vrenken said.

    The researchers also explored correlations between the areas of the brain being analysed in the patients with MS and the level of atrophy or clinical disability present.

    "The results suggest that the damage to normal-appearing brain tissue plays a larger role in the progression of atrophy and clinical disability than do the visible lesions," Dr. Vrenken said.

    Radiology is a monthly scientific journal devoted to clinical radiology and allied sciences. The journal is edited by Anthony V. Proto, M.D., School of Medicine, Virginia Commonwealth University, Richmond, Va. Radiology is owned and published by the Radiological Society of North America, Inc. (

    The Radiological Society of North America (RSNA) is an association of more than 38,000 radiologists, radiation oncologists, medical physicists and related scientists committed to promoting excellence in radiology through education and by fostering research, with the ultimate goal of improving patient care. The Society is based in Oak Brook, Ill. (

    "Whole-Brain T1 Mapping in Multiple Sclerosis: Global Changes of Normal-appearing Gray and White Matter." Collaborating with Dr. Vrenken on this paper were Jeroen J. G. Geurts, M.Sc., Ph.D., Dirk L. Knol, Ph.D., L. Noor van Dijk, M.D., Vincenzo Dattola, M.D., Bas Jasperse, M.D., Ronald A. van Schijndel, M.Sc., Chris H. Polman, M.D., Ph.D., Jonas A. Castelijns, M.D., Ph.D., Frederik Barkhof, M.D., Ph.D., and Petra J. W. Pouwels, Ph.D.

    Source: Radiological Society of North America

    Brain cells said to adapt as do stem cells
    University of Florida researchers say ordinary human brain cells may be able to self-renew in adaptability normally associated with stem cells.

    Scientists at the school's McKnight Brain Institute say they used mature human brain cells taken from epilepsy patients to generate new brain tissue in mice.

    Furthermore, the researchers said they can coax such pedestrian human cells to produce large amounts of new brain cells in culture, with one cell theoretically able to begin a cycle of division that doesn't stop until the cells number about 10 to the 16th power.

    "We can theoretically take a single brain cell out of a human being and -- with just this one cell -- generate enough brain cells to replace every cell of the donor's brain and conceivably those of 50 million other people," said Dennis Steindler, the institute's executive director.

    "This is a completely new source of human brain cells that can potentially be used to fight Parkinson's disease, Alzheimer's disease, stroke and a host of other brain disorders," added Steindler. "It would probably only take months to get enough material for a human transplant operation."

    The research is detailed in the journal Development.

    Source: United Press International © Copyright 2006 United Press International, Inc. All Rights Reserved

    Autoimmune brain inflammation studied
    U.S. scientists say a key factor in development of brain inflammation may provide a new target for inflammatory diseases of the central nervous system.

    In separate studies, Nico Ghilardi of Genentech Inc. in San Francisco and Christopher Hunter of the University of Pennsylvania studied different mouse models of brain inflammation that resemble human diseases, such as multiple sclerosis.

    Both studies show brain inflammation is worse in mice that cannot respond to interleukin 27, a factor that communicates messages to immune cells. Such increased brain inflammation is associated with an influx of T cells that produce a molecule known to promote inflammation -- interleukin 17 -- into the brain.

    The researchers found treatment of T cells with interleukin 27 blocks the development of cells that produce interleukin 17.

    Therefore, the scientists posit preventing harmful interleukin 17-producing cells from developing, interleukin 27 could represent a potential therapeutic target for treating autoimmune diseases.

    The study appears in the journal Nature Immunology.

    Source: United Press International© Copyright 2006 United Press International, Inc. All Rights Reserved

    Life and death in the hippocampus: what young neurons need to survive
    Whether newborn nerve cells in adult brains live or die depends on whether they can muscle their way into networks occupied by mature neurons. Neuroscientists at the Salk Institute for Biological Studies pin-pointed the molecular survival gear required for a young neuron to successfully jump into the fray and hook up with other cells.

    In a study published in a forthcoming issue of Nature, researchers in the lab of Fred H. Gage, Ph.D., a professor in the Gene Expression Laboratory and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases, identify a subunit of the NMDA receptor, a protein complex that transduces signals sent by neighbouring cells, as the cells' life-saving equipment that allows them to integrate into the existing brain circuitry.

    The NMDA receptor is activated by the neurotransmitter glutamate, a chemical released by neurons in order to transmit information to neighboring cells. Whenever the receptor picks up a glutamate signal it is stimulated and relays the signal. But for newborn neurons that signal means something else entirely -- survival.

    "When we removed the NMDA receptor, that is when cells make connections in response to glutamate in the environment, the newborn neurons withered and died at a specific stage of their maturation," explains Gage. " The NMDA receptor modulates synapse formation and determines what pattern of input activity new neurons receive, which in turn determines survival or death."

    Combining mouse genetics and gene transfer techniques, Gage and a team headed by former postdoctoral fellow Ayumu Tashiro, Ph.D., injected a virus carrying a pair of molecular shears capable of deleting a gene encoding part of the NMDA receptor into the hippocampus, a brain region harboring neural stem cells that give rise to new neurons. Newly born neurons infected with virus were marked by a fluorescent dye enabling detection of neurons derived from those cells.

    A few weeks later, animals that received the virus showed fewer fluorescent neurons compared to mice injected with a benign virus lacking the shears, meaning fewer new neurons had survived originating from neural stem cells in which the NMDA receptor had been eliminated.

    Listening to Gage, one gets the impression that the hippocampus is a dangerous place for a fledgling neuron trying to elbow its way into pre-existing networks. "It's rough in there!" he concedes. "The NMDA receptor-mediated event is a competition between mature cells vying for connectivity and young guys competing with both the mature cells and their peers to fit in. You are selecting for the cell that performs best in this environment."

    The Gage lab previously showed that the rate at which new neurons emerge from stem cells depends on an animal's activity. "If you put animals in an enriched environment and give them access to running wheels, you increase survival of new brain cells," says Gage. "Now we show that stimulation may, in part, be mediated through the NMDA receptor."

    Those studies had also shown that young and middle-aged "exercised" rats perform better on learning tasks such as maze swimming, indicating that new neurons are more than just a backup supply but actually enhance learning.

    "Remarkably, new neurons are born in the hippocampus, a structure whose function is to acquire new information," says Gage. "That suggests that new cells are involved in how we learn."

    This ongoing struggle for connections between young and mature neurons is apparently more than just a spectacle designed to keep Mother Nature amused: the fact that enhanced learning is correlated with adult neurogenesis suggests constant rearrangements within neural networks are absolutely necessary for learning to occur.

    In fact, data emerging from studies in the Gage lab reinforces the commonly held belief that using one's brain cells is the best way to optimise brain function throughout one's lifetime.

    "In the natural course of aging there is cognitive decline," says Gage. "We know we lose the ability to generate new neurons with age. We are currently trying to figure out how to generate as many neurons as possible to potentially enhance learning or increase the amount of neurogenesis in adults."

    Also contributing to this study were Gage lab postdoctoral fellows Vladislav Sandler, Ph.D., Nicolas Toni, Ph.D., and Chunmei Zhao, Ph.D. Tashiro now does research at the Norwegian University of Science and Technology in Trondheim.

    The Salk Institute for Biological Studies in La Jolla, California is an independent nonprofit organisation dedicated to fundamental discoveries in the life sciences, the improvement of human health, and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

    Source: Salk Institute

    Alleviating the burden of Multiple Sclerosis
    Researchers discover a cellular signal that aggravates the symptoms of MS and might be targeted in new therapeutic approaches.

    Depression, coordination and speech problems, muscle weakness and disability are just a few of the symptoms of Multiple Sclerosis (MS). Researchers from the Mouse Biology Unit of the European Molecular Biology Laboratory (EMBL) in Italy and the Department of Neuropathology at the Faculty of Medicine, University of Göttingen, Germany, have now discovered that these symptoms are aggravated by a specific signal in cells in the nervous system. The study, which will appear in this week's online issue of Nature Immunology, suggests that blocking the proteins that regulate the signal might be an efficient strategy for new therapies against MS.

    Nerve cells in our brain and spinal cord communicate with each other using electrical signals. This communication is fast and efficient because - just like wires in an electrical circuit - the axons of our nerves are surrounded by an insulating layer. In MS this protective sheath, made up of a mixture of lipids and proteins called myelin, gets destroyed by cells of our own immune system, and the communication between nerve cells gets disrupted. A central player in the molecular mechanisms behind MS is a signaling molecule called NF-kB.

    "We have known for a long time that NF-kB is crucially involved in MS," says Manolis Pasparakis, a former Group Leader at EMBL's Mouse Biology Unit who now works as a Professor at the Institute for Genetics at the University of Cologne, "but until now it was not clear if it was friend or foe. We were not sure whether it protects the brain cells against the consequences of the disease or actually aggravates the damage." 

    To get a clear picture of NF-kB's role in MS, Pasparakis and his scientific collaborators at the University of Göttingen investigated what happens to mice with an MS-like condition if the action of NF-kB is blocked. To shut down the signal they inactivated IKK2 and NEMO, two proteins that activate NF-kB.

    "This was quite a challenge because NF-kB is involved in many crucial processes throughout the entire body, and shutting down its activation in all cells kills the mouse before it is born," says Pasparakis, "To observe the effect of NF-kB in MS, we used sophisticated genetic techniques to generate mice that do not express IKK2 and NEMO in brain cells only."

    The results were mice that showed much milder MS symptoms than normal, an effect that is very likely to be linked to the lower amount of inflammatory messengers produced by their brain cells.

    "NF-kB regulates the production of messengers that are released during inflammation to recruit and activate immune cells," says Marco Prinz, whose group at the University of Göttingen collaborated in the research. "Generally this is a good strategy to protect the body from infections. But in MS it is exactly these immune cells that cause the problem and their hyperactivation through NF-kB only makes the situation worse."

    Blocking IKK2 and  NEMO interfered with this pathological action of NF-kB and alleviated the symptoms of MS. This makes the proteins promising as potential drug targets for new therapies against the disease. The human NF-kB signaling network is very similar to that of mice, so that compounds that inhibit IKK2 and NEMO are likely to lead to the same alleviation of symptoms in humans.

    Source: European Molecular Biology Laboratory

    Central nervous system beckons attack in MS-like disease
    It may sound like a case of blame the victim, but researchers at Washington University School of Medicine in St. Louis have shown that cells in the central nervous system can sometimes send out signals that invite hostile immune system attacks. In mice the researchers studied, this invitation resulted in damage to the protective covering of nerves, causing a disease resembling multiple sclerosis.

    "It's been clear for quite a while that our own lymphocytes (white blood cells) have the ability to enter the central nervous system and react with the cells there," says John Russell, Ph.D., professor of molecular biology and pharmacology. "Under normal circumstances, the brain and the immune system cooperate to keep out those cells that might harm the brain. But in people with multiple sclerosis, they get in."

    The researchers found that they could prevent destructive immune cells from entering nervous system tissue by eliminating a molecular switch that sends "come here" messages to immune cells. Ordinarily, flipping that switch would cause immune cells to rush to the vicinity of the cells that sent the signals and destroy whatever they consider a danger — including nerve cell coatings.

    But in the mice in which the switch was removed, the researchers saw that immune cells previously primed by the scientists to attack the central nervous system (CNS) did not enter the CNS, and the mice stayed healthy.

    In contrast, normal mice treated with the same hostile immune cells had numerous immune cells in their CNS tissue and developed symptoms similar to multiple sclerosis.

    "What allows the primed lymphocytes into the CNS are signals from the CNS asking them in," Russell says. "We determined that the astrocytes, the specialized cells that provide nutrients to neurons, are among the cells most active in sending signals to attract lymphocytes."

    The molecular switch that sends the call to immune cells is termed the tumor necrosis factor receptor (TNFR). When TNFR is activated, it causes cells to send out signal molecules called chemokines that direct immune cells to the site of damage or infection. The researchers found that astrocytes in mice were producing chemokines in response to activation of their TNFR molecules.

    TNFR activation also makes the astrocytes bristle with specific adhesion molecules that act like Velcro to bind to similar molecules on the surface of the immune cells. That allows the immune cells that are attracted by the chemokines to stick around and do more harm.

    One of the most promising new drugs for treating multiple sclerosis, natalizumab (tradename Tysabri), works by blocking the ability of the immune cells to stick in the CNS through this Velcro mechanism, Russell notes. Natalizumab is being tested in clinical trials and appears to be much better at preventing the nerve cell destruction associated with multiple sclerosis than previous therapies.

    "Experiments by others suggested that natalizumab prevented immune cells from crossing the blood-brain barrier — it was thought to prevent the cells from leaving the blood stream," Russell says. "We are working on that question, and we think that it doesn't necessarily prevent them from getting out of the blood, but it does keep them from getting further into the brain. The immune cells pile up in the space around the blood vessels. This space, the perivascular space, serves as a gatekeeper to determine what gets in and what doesn't."

    Next, the research team will study various regions of the brain to determine the types of signals sent to and from different areas of the CNS to the immune system.

    Gimenez MA, Sim J, Archambault AS, Klein RS, Russell JH. A tumor necrosis factor dependent receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. American Journal of Pathology 2006;168(4):1200-1209.

    Source: Washington University in St. Louis Copyright 2000-2006, Washington University in St. Louis

    Scientific Paper Confirms Mechanism of Allon's Drugs
    Allon Therapeutics Inc., The Neuro Protection Company(TM), today announced that results of a preclinical study published in the Journal of Molecular Neuroscience demonstrate that the cellular mechanism that gives neuroprotective properties to its clinical-stage products also occurs in the Company's pipeline of preclinical-stage product candidates.

    Dr. Illana Gozes, Chief Scientific Officer of Allon and the corresponding author for the study, said the neuroprotective activity of the Company's clinical-stage products has been established in earlier studies, but the new published results confirm the earlier results and demonstrate that this activity extends to all the Company's compounds.

    "These published results are exciting because they imply broad neuroprotective activity of all of Allon's proprietary compounds to protect neurons against multiple degenerative diseases and injuries," said Dr. Gozes.

    The published study shows that Allon's proprietary compounds, ADNF-9 (AL-209), D-NAP (AL-408) and D-ADNF-9 (AL-309) bind to and interact with tubulin, the proteins that form microtubules. Microtubules are the communication pathways inside nerve cells (neurons). Assembly of microtubules is essential for the ongoing regeneration of the nervous system and for combating neurodegenerative diseases.

    Allon derived its first and second products, AL-108 and AL-208, from NAP. The Company has also derived several promising product candidates from ADNF-9, including AL-309 which is now undergoing pre-clinical studies.

    AL-108 is being evaluated in Phase I human clinical trials as a treatment for Alzheimer's disease. AL-208 is in Phase I human clinical trials and at mid-year will enter a Phase II human clinical trial to be evaluated as a treatment for the mild cognitive impairment (MCI) associated with coronary artery bypass graft (CABG) surgery.

    Allon's compounds have shown efficacy in 14 different pre-clinical models of eight central nervous system diseases, disorders or injuries.

    Allon is developing drugs that protect against and treat the causes of neurodegenerative conditions. Currently available therapies treat only the symptoms of neurodegenerative diseases and have an annual market value of approximately $24.4 billion. Many of these illnesses are age-related and their impact will grow as the elderly population increases.

    About Allon

    Allon Therapeutics Inc. is a Canadian biotechnology company developing drugs that protect against neurodegenerative conditions such as Alzheimer's disease, mild cognitive impairment, stroke, traumatic brain injury, multiple sclerosis and neuropathy. The company is listed on the Toronto Stock Exchange under the trading symbol "NPC" (Neuro Protection Company) and based in Vancouver.

    Source: Allon Therapeutics Inc.

    Potential new treatment strategy identified for Alzheimer's disease and other brain and spinal cord damage
    A study led by researchers at the San Francisco VA Medical Center and the University of North Carolina, Chapel Hill has identified several new compounds that could play a role in preventing or treating Alzheimer's disease and other degenerative conditions of the nervous system.

    In culture, the compounds bind with a receptor found in the brain and spinal cord called p75NTR. In the body, p75NTR is a binding site for molecules known as neurotrophins, which normally promote the growth and development of neurons and other brain cells but, according to other studies, can also kill them, depending on how and where they bind to a cell.

    Evidence suggests neurotrophins may play a role in Alzheimer's disease and other brain diseases and conditions, says lead and co-corresponding author Stephen M. Massa, MD, PhD, a neurologist at SFVAMC. In Alzheimer's disease, some of the brain cells that die – including neurons in the hippocampus, which plays an essential role in memory – express the p75NTR binding site, indicating they may be dying because neurotrophins are binding to them, says Massa.

    Because the new compounds bind with p75NTR in place of neurotrophins, they may provide a means of preventing damage that neurotrophins would otherwise be causing in Alzheimer's disease and other neurodegenerative diseases and conditions, he says.

    "In binding to p75 in place of neurotrophins, these compounds promote the survival of neurons, including hippocampal neurons, in culture," noted Massa, who is also a clinical assistant professor of neurology at the University of California, San Francisco.

    The study appears in the May 17, 2006 issue of the Journal of Neuroscience.

    Massa noted that the protective quality of neurotrophins has led other researchers to explore their potential therapeutic value; however, their destructive attributes have so far prevented their development as medicines.

    "When Dr. Rita Levi-Montalcini won the Nobel Prize for Medicine in 1986 for her discovery of neurotrophins, she remarked that the next critical milestone would be to develop pharmacological approaches that could achieve the actions of these potent proteins and make possible their potential application in the clinic," said co-corresponding author Frank Longo, MD, PhD, of the University of North Carolina, Chapel Hill at the time of the study and currently of Stanford University. "Our team is thrilled to have been able attain this decades-long goal."

    In further tests, the research team discovered that the compounds can also inhibit the death of oligodendrocytes, the cells in the central nervous system that form myelin, the insulating sheath surrounding nerve cells.

    Normally, oligodendrocytes die when exposed to proneurotrophins – precursor forms of neurotrophins that have been implicated as agents of tissue damage in multiple sclerosis, spinal cord injury and Alzheimer's disease. "The compounds were able to inhibit the processes induced by proneurotrophins that lead to oligodendrocyte death," recounted Massa. To identify the compounds, the researchers developed an innovative computer-based method.

    They created a virtual three-dimensional model of a section of a neurotrophin known to interact with p75NTR, and then tested virtual representations from a library of over one million known molecules for potential binding action. A group of 800 candidate molecules was eventually reduced to four, of which two were chosen for extensive study because they showed the greatest potential to be turned into drugs.

    Currently, the research team is investigating a number of other promising compounds that they identified using the same method. "The range of diseases to which this group of compounds might have applicability is enormous," said Massa.

    "We have already started to test them in preclinical studies of neurological disorders," added Longo.

    Co-authors of the study were Youmei Xie, MD, PhD, Tao Yang, PhD, and Laura A. Moore, BA, of the University of North Carolina-Chapel Hill; Anthony W. Harrington, PhD, Mi Lyang Kim, BA, and Sung Ok Yoon, PhD, of Ohio State University; and Rosemary Kraemer, PhD and Barbara Hempstead, MD, PhD, of Cornell University.  

    Source: The University of California, San Francisco Copyright 2006, The Regents of the University of California.

    Selectively blocking inflammatory signals may protect mice from MS
    fA new way to preserve the cells that surround and protect nerves could lead to new treatments for demyelinating diseases such a multiple sclerosis, a research team reports in the May 10, 2006, issue of the Journal of Neuroscience.

    The approach grew out of a novel explanation, quickly gaining followers, for the mechanism of nerve damage caused by multiple sclerosis. Instead of concentrating on the alterations that result in autoimmune assaults on the nervous system, researchers led by Brian Popko of the University of Chicago have focused on a set of factors that prevent recovery from the inflammatory attacks.

    A series of papers from Popko's lab has demonstrated that interferon-gamma -- a chemical signal used to activate the immune system -- plays a critical role in damaging the cells that produce myelin, the protective coating that lines healthy nerves. Interferon not only leaves these cells, called oligodendrocytes, incapable of repairing the damage but can also kill them directly.

    "Interferon-gamma is not normally found in the nervous system," said Popko, the Jack Miller Professor of Neurological Diseases at the University of Chicago, "but it can gain entry after an inflammatory flare-up. We previously showed how it harmed oligodendrocytes. Here we confirm its direct harmful effects on those cells and demonstrate one way of protecting them."

    The researchers produced a series of transgenic mice. In one set they introduced genes that produced interferon-gamma within the central nervous system. In another set they also introduced a gene (known as suppressor of cytokine signaling 1, or SOCS1) that blocked the response of myelin-producing cells to interferon-gamma.

    Although transgenic mice with low levels of interferon-gamma showed no symptoms of nervous system damage, 18 out of 20 mice exposed to higher interferon levels developed difficulty walking, including mild to moderate tremors, within two weeks of birth. Only four out of 20 mice with both high interferon levels and the SOCS1 gene had symptoms.

    On autopsy, mice with high interferon levels in the nervous system had severe loss of oligodendrocytes, ranging from 20 to 40 percent. Those with the protective SOCS1 gene lost only eight to 15 percent.

    High interferon levels were also associated with loss of myelin sheaths around nerve connections and unprotected axons in the brain. Again, SOCS1 was able to reduce the damage.

    "Together," the researchers wrote, "these data demonstrate that oligodendroglial expression of SOCS1 protects mice from the clinical and morphological consequences of IFN-gamma expression in the central nervous system during development."

    "We found this tremendously encouraging," said Popko. "SOCS1 prevented or reduced the harmful effects of interferon gamma on myelin-producing cells. This study solidifies our suspicions about interferon's specific role in demyelinating disease and suggests ways to block it."

    Although there is currently no reliable way to deliver SOCS1 directly to the nerves of a patient with multiple sclerosis, this protective approach could be combined with stem cell therapy to repair nerve damage. Several research groups are already studying the use of stem cells to repair damaged myelin sheaths, but in the long term those stem cells would be vulnerable to ongoing immune-mediated damage.

    But if stem cells could be engineered to resist harmful signals such as interferon-gamma, they might be protected from the "harsh environment" present in immune mediated demyelinated lesions, said Popko.

    Source: University of Chicago Medical Center

    Knowledge of dendritic cells branches out
    A new type of cell that generates crucial cells of the immune system has been discovered at The Walter and Eliza Hall Institute. With this new knowledge, medical researchers can begin to consider the development of customized immune therapies using this new cell to target specific infections such as HIV, malaria and influenza; certain cancers; and even autoimmune diseases.

    Dendritic cells (or "DC") are specialised white blood cells that patrol the body, searching for infections. DC seize and then internally break apart any infectious organisms that they find. These fragments are then presented on the waving branches or "dendrites" of the DC to activate the immune system's killer T cells. These activated T cells then eliminate the existing infection and resist any future attack by memorizing that infection.

    DC also have an important educative role to play in preventing autoimmune diseases, such as type 1 diabetes and Multiple Sclerosis, where the body's immune system mistakes "self" for "foreign" and launches an attack. Since DC are central to many immune responses, they are potential targets for the development of new immune therapies.

    Since their discovery in the US in 1975, it has been known that DC, like other white blood cells, develop from stem cells in the bone marrow. Exactly how that process happens has been a mystery – until now.

    Using a mouse model, PhD student Shalin Naik, group leader Professor Ken Shortman and a team of colleagues at The Walter and Eliza Hall Institute have discovered the different "precursors" that produce DC. In doing so, they have also determined that the practical operations of DC are more specialized than previously believed. Rather than being generalized "police" within the body, it seems that DC are effectively organized as specialized squads that deal with specific problems – just as a police force might have different departments to deal with armed robberies, homicides and fraud. These discoveries at WEHI have profoundly altered our understanding of this important aspect of the immune system.

    The research received advance online publication on the Nature Immunology website on 7 May 2006.

    The authors of the paper are Professor Ken Shortman, Professor Don Metcalf, Professor Ian Wicks, Dr Li Wu, Dr Meredith O'Keefe, Dr Annemarie van Nieuwenhuijze and Mr Shalin Naik.

    Source: WEHI Press Release

    Neurons In CNS Can Regulate Immune System And Suppress Inflammatory Conditions Of CNS
    The neurons in the central nervous system (CNS) are reported to have a previously unknown ability to regulate the immune system and suppress inflammatory conditions of the CNS.

    This was published by scientists at Lund University in Sweden in an article in the journal of Nature Medicine. This pioneering discovery paves the way for future therapeutic targets for inflammatory and degenerative diseases of CNS like multiple sclerosis (MS), Alzheimer's, and Parkinson's.

    It is generally known that motor neurons regulate basic functions like movement, learning, and memory. But Swedish scientists are now able to show that the neurons are also capable of combating CNS inflammation.

    The role of neurons in the regulation of immune response in the CNS has been neglected as brain and spinal cord are well protected against immune cells surveillance by a tight barrier and because neurons do not express molecules known to be involved in immune response.

    "Now, we show that motor neurons are capable of actively regulating immune response and indeed they have a central role in prevention of CNS inflammation", says Associate Professor Shohreh Issazadeh-Navikas at Lund University.

    In this report, Swedish scientists have demonstrated that neurons can transmit signals to harmful T cells (a type of white blood cells important for immune defense) in the brain. These signals cause these T cells to alter their function, transforming them from harmful to benign T cells that counteract inflammation and neuronal cell death.

    Pathogenic T cells can enter the CNS because of several reasons such as during viral infection of CNS, as a result of mechanical damage to CNS or inflammatory diseases of CNS or autoimmune reactions, for example in case of MS (an inflammatory disease of CNS believed to be caused by autoimmune T cells). Inflammation is now implicated to be involved also in other neurodegenerative diseases such as Alzheimer's and Parkinson's.

    The impetus for this research work came from previous observations made by Shohreh Issazadeh-Navikas at the Karolinska Institute and at Harvard Medical School. There she found in different experimental conditions that neurons appeared to be able to secrete certain immunological proteins that could have potential to combat inflammations.

    "These observations indicated that neurons could actually play a role in the regulation of the immune cells causing CNS inflammation. This was a new concept that had virtually been unexplored, since it was believed that neurons were mainly targets of inflammatory attack rather than active player in its regulation."

    Dedicated work by a research team under supervision of Shohreh Issazadeh-Navikas at Lund University in collaboration with Dr. Bryndis Birnir resulted in the current pioneering publication in the Nature Medicine.

    According to Shohreh Issazadeh-Navikas, their findings provide new knowledge about how chronic inflammation of the brain is regulated, and it could have implications for novel therapeutic approaches of inflammatory and neurodegenerative diseases such as Alzheimer, Parkinson and MS.

     Source: Medical News Today © 2006 MediLexicon International Ltd

    MS Research Into Reparative Cells Offers New Avenue for Fighting Disease
    Plaques that form around the nerve cells of people with multiple sclerosis are apparently what disable people with the disease. But partly developed reparative cells within the plaques provide hope for a treatment, a UT Southwestern physician reports in the New England Journal of Medicine.

    Dr. Elliot Frohman, professor of neurology and ophthalmology, is lead author on an overview of MS. It is the first time in five years that Journal editors have had researchers provide an overview of the debilitating disease.

    Presently, the primary focus of research is on plaques, which are now known to contain certain predictable features consistent with tissue injury, such as loss of nerve insulation, scarring, inflammation and loss of the ability of nerves to transmit electrical and chemical information to other nerves.

    “Recognizing these different injury cascades has catalyzed novel investigations into strategies for treatment that are aimed at promoting preservation of tissue architecture (neuroprotection) and even potentially neurorestoration,” said Dr. Frohman, who directs the Multiple Sclerosis Program and Clinical Center at UT Southwestern and holds the Irene Wadel and Robert I. Atha Distinguished Chair in Neurology and the Kenney Marie Dixon-Pickens Distinguished Professorship in Multiple Sclerosis Research.

    In MS, nerve cells lose their insulating fatty covering, called myelin. Myelin comes from nearby cells called oligodendrocytes, which send out projections that wrap around nerve cells. Myelin allows electrical signals to travel quickly and with high fidelity.

    The damaged area becomes surrounded by plaques, which contain a wide variety of cells. Although much of the content of a plaque is harmful to nerves, there are some cells that provide hope, Dr. Frohman said.

    Even though the oligodendrocytes are damaged, there exists a reservoir of oligodendrocyte precursor cell, or OPCs, left over from development that could be activated to repair the damage, he said. The problem is how to trigger them to grow.

    “Those are progenitor cells that will grow up into mature cells,” Dr. Frohman said. “We know more why they don’t grow up.”

    Proteins called repressor proteins keep the OPCs in an immature state. Activating the OPC, however, might help a severed or demyelinated nerve in the central nervous system become the target for repair.

    Treatments for MS are difficult, but researchers are examining the regulation of the genes Nogo, Lingo-1, Jagged and Notch for potential treatment.

    The proteins Nogo and Lingo-1 appear to have the ability to block nerve cells from growing, so if they can be blocked, the nerve cells might be able to recover.

    “With the advent of new technologies, we have a much better understanding of the events that occur during the MS disease process,” said co-author Dr. Michael Racke, professor of neurology and in the Center for Immunology. “In particular, we will see a much greater emphasis on the molecular events that occur during MS and will likely see new strategies to intervene in the disease.” Dr. Racke holds the Lois C.A. and Darwin E. Smith Distinguished Chair in Neurological Mobility Research.

    Dr. Cedric Raine at the Albert Einstein College of Medicine was also an author of the review.

    The paper was supported in part by the National Multiple Sclerosis Society, Once Upon A Time …, the Hawn Foundation and the Department of Health and Human Services.

    Source: © 2006 Newswise. All Rights Reserved.

    Researchers Discover New Way To Stimulate Brain To Release Antioxidants

    Research published as cover story in Proceedings of National Academy of Sciences.

    A joint research effort between researchers at the Burnham Institute for Medical Research in La Jolla, CA, and a team from Japan (Iwate University, Osaka City University, Gifu University, Iwate Medical University) has discovered a novel way to treat stroke and neurodegenerative disorders. This approach works by inducing nerve cells in the brain and the spine to release natural antioxidants that protect nerve cells from stress and free radicals that lead to neurodegenerative diseases. Until this discovery, researchers were unable to induce release of these specific antioxidants directly in nerve cells, at the site where damage and degeneration occurs.

    In stroke and various neurodegenerative disorders, such as Alzheimer’s disease, Multiple Sclerosis and Lou Gehrig’s disease, glutamate, an amino acid found in high quantities in the brain, is thought to accumulate. At normal concentrations, glutamate acts as a neurotransmitter that nerves use to communicate. However, at excessive levels glutamate is toxic, resulting in over stimulation of nerve cells, known as excitotoxicity, and causing excessive stress on the nerve cells eventually ending in cell death. Studies described in this report suggest that NEPPs (short for NEurite outgrowth-Promoting Prostaglandins), compounds that accumulate in nerve cells, prevent nerve damage by activating the Keap1/Nrf2 pathway that regulates the production of antioxidants which relieve cells of damaging free radicals that result from excitotoxicity.

    “This is the first reported evidence that this protective response can be activated directly in nerve cells to release antioxidants and counter oxidative stress,” said Stuart Lipton, M.D., Ph.D., Director of the Del E. Webb Center for Neurosciences and Aging at the Burnham Institute and senior author of the study. “These findings provide support for further investigation of NEPP drugs to potentially treat ischemic stroke, multiple sclerosis, Alzheimer’s disease, Lou Gehrig’s disease and other neurodegenerative disorders.”

    Researchers found that NEPPs were able to activate a pathway in nerve cells that is designed to protect against oxidative and nitrosative stress (which produces free radicals) and excitotoxicity. This pathway, known as Keap1/Nrf2, regulates the production of natural antioxidants, such as bilirubin, that can protect against oxidative stress resulting from ischemic stroke and degenerative disorders.

    A paper detailing the findings of this study, entitled “Activation of the Keap1/Nrf2 Pathway for Neuroprotection by Electrophilic Phase II Inducers” (Satoh, et al.), will be published as the cover story for the January 17th issue of the Proceedings of the National Academy of Sciences. In addition, the findings will be made available by expedited publication at the journal’s website the week of January 9th. This research was supported with grants from the National Institutes of Health.

    Breakthrough in brain injury study at Leicester University
    A breakthrough by scientists at the University of Leicester in understanding mechanisms within the brain which cause injury could lead to better treatments in the future for conditions such as as cerebral palsy and multiple sclerosis.

    Drs Robert Fern and Mike Salter of the Department of Cell Physiology and Pharmocology at the University of Leicester had their findings published in the science journal Nature.

    Their study is particularly important as it identifies the cause of damage to the brain and the mechanism by which this occcurs - thereby raising the possibility of drugs being developed in the future which may help to reduce injury and the disease states that follow.

    Dr Fern said: "This project has taken over a year to complete and has produced some rather important findings. We believe that we may have opened a new window into how the brain becomes damaged in a number of important diseases ranging from stroke to multiple sclerosis and spinal cord injury. We will now continue to study the particular brain receptor that is involved in the hope of discovering a way to block the receptor and therefore avert brain injury for a large number of patients."

    This work was supported by a grant from the National Institutes of Neurological Disorders and Stroke to R.F.

    More about glutamate:

    The brain is the organ responsible for our thoughts, memories, sensations and emotions. All these functions occur because neurons, the "little grey cells" of Agatha Christie's Hercule Poirot, are able to pass signals between one another using a chemical called glutamate.

    Glutamate is released by neuronal structures called synapses and interacts with special receptors on neighbouring neurons. While most people will have heard of neurons, it is not commonly known that only about half of the brain is actually made up of these cells, with the remainder being made up of non-neuronal cells called glial cells.

    Neurons rely on glial cells for protection and sustenance and form a particularly close partnership with a kind of a glial cell called an oligodendrocyte. Oligodendrocytes have processes that wrap tightly around neurons, insulating them and allowing signals to speed quickly from neuron to neuron. They produce a white substance called myelin which acts like an electrical insulator and these cells can be thought of as the "little white cells" of the brain, with areas of the brain rich in oligodendrocytes having a characteristic white appearance. Damage to oligodendrocytes is catastrophic to the brain, producing debilitating diseases such as cerebral palsy and multiple sclerosis.

    We have been working to identify potential causes of this injury and have found that glutamate release acting upon glutamate receptors is causing damage to the oligodendrocyte cell processes. As a result of this damage the oligodendrocytes are not able to insulate the neurons and this manifests itself in sufferers as an inability to control basic functions such as speech and movement.

    The work we have completed shows that glutamate receptors are located on oligodendrocyte processes and that over activation of the receptor leads to injury. It is ironic that the receptor that is responsible for transmitting signals between neurons in healthy brain is also the cause of suffering in many cases of neurological disease. The identification of a specific receptor as being responsible is particularly important as it raises the possibility of drugs being developed in the future which may help to reduce injury and the disease states that follow.

    Source News-Medical.Net ©2005 News-Medical.Net  

    Prompting Neurons to Protect Themselves

    A team of American and Japanese scientists has found a way to induce nerve cells in the brain and spinal cord to release natural antioxidants that protect the cells from the damage that stress and free radicals can cause.

    The finding may help in the development of new treatments for stroke, Alzheimer's disease,multiple sclerosis, and other neurodegenerative disorders, the researchers said.

    "This is the first reported evidence that this protective response can be activated directly in nerve cells to release antioxidants and counter oxidative stress," senior author Dr. Stuart Lipton, director of the Del E. Webb Center for Neurosciences and Aging at the Burnham Institute for Medical Research in La Jolla, Calif., said in a prepared statement.

    He and his colleagues found that compounds called NEurite outgrowth-Promoting Prostaglandins (NEPPs) can activate a pathway in nerve cells that's designed to protect the cells against oxidative and nitrosative stress and excitotoxicity (overstimulatoin of nerve cells).

    This pathway is called Keap1/NrF2. It regulates production of natural antioxidants that can protect nerve cells against oxidative stress resulting from ischemic stroke and neurodegenerative diseases.

    "These findings provide support for further investigation of NEPP drugs to potentially treat ischemic stroke, multiple sclerosis, Alzheimer's disease, Lou Gehrig's disease and other neurodegenerative disorders," Lipton said.

    Source: Yahoo News

    Researchers Discover A Protein Responsible For Shaping The Nervous System

    A team of researchers led by The Hospital for Sick Children (SickKids), the University of Toronto (U of T) and Cold Spring Harbor Laboratory have discovered a protein that is responsible for shaping the nervous system. This research was made possible with the support of a $1.5-million NeuroScience Canada Brain Repair ProgramTM team grant that enabled scientists from across Canada to work together and fast track their research. This research is reported in the December 8, 2005 issue of the journal Neuron.

    "We discovered that p63 is the major death-promoting protein for nerve cells during fetal and post-natal development," said Dr. David Kaplan, the paper's senior author, senior scientist at SickKids, professor of Molecular Genetics, Medical Genetics & Microbiology at U of T, Canada Research Chair in Cancer and Neuroscience, and co-team leader on the NeuroScience Canada Brain Repair Program grant with Dr. Freda Miller of SickKids. "Proteins such as p63 that regulate beneficial cell death processes during development may cause adverse affects later in life by making us more sensitive to injury and disease."

    At birth, the nervous system has twice the number of nerve cells than needed. The body disposes of the excess cells by eliminating those that go to the wrong place or form weak or improper connections. If this process does not happen, the nervous system cannot function properly. The expression of the p63 protein guides the nervous system in disposing of the ineffective nerve cells. The protein is from the p53 family of tumour suppressor proteins that is mutated in many human cancers.

    While p63 is involved in determining which nerve cells die, the research team also suspects that it determines whether nerve cells die when injured or in neurological and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases.

    "The discovery of this new protein represents hope for thousands of people affected by neurological and neurodegenerative disorders, such as multiple sclerosis, Parkinson's, Alzheimer's and schizophrenia, as well as spinal cord injury," says the Honourable Michael H. Wilson, Chair of NeuroScience Canada, a national umbrella organisation for neuroscience research, whose Brain Repair Program helped support this research. "Because this protein is responsible for the death of nervous systems cells, understanding how we could inhibit its functions could represent survival for many patients across Canada."

    Ten million Canadians of all ages will be affected by a disease, disorder or injury of the brain, spinal cord or nervous system. These conditions number more than 1,000. Fifty per cent of all Canadians -- about 15 million people -- have had a brain disorder impact their family. Based on Health Canada data, the economic burden of these disorders is conservatively estimated at 14 per cent of the total burden of disease, or $22.7 billion annually; however, when disability is included, the economic burden reaches 38 per cent or more, according to the World Health Organization. However, despite the magnitude of the problem, neuroscience research, with just $100 million total in operating grants in Canada annually, is still greatly under funded in this country.

    To this end, future research for the research team involves testing whether p63 is the key protein that determines whether nerve cells die when injured or in neurodegenerative diseases, and will identify drugs that will prevent p63 from functioning that may be used to treat these conditions.

    Other members of the research team include Dr. Freda Miller, Canada Research Chair in Developmental Neurobiology, Dr. W. Bradley Jacobs, Daniel Ho and Dr. Fanie Barnabe-Heider, all from SickKids, Dr. William Keyes and Dr. Alea Mills from Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and Dr. Jasvinder Atwal and Dr. Gregory Govani of Dr. Miller's and Kaplan's former group from McGill University.

    This research was also supported by the Canadian Institutes of Health Research, the National Science and Engineering Research Council of Canada, a McGill Major Studentship, a McGill Tomlinson fellowship, the Canada Research Chairs Program and SickKids Foundation.

    Founded in 1988, NeuroScience Canada is Canada's umbrella organization and voice for the neurosciences. Through partnering with the public, private and voluntary sectors, NeuroScience Canada connects the knowledge and resources available in this area to accelerate neuroscience research and funding, and maximize the output of Canada's world-class scientists and researchers. The mission of NeuroScience Canada's Brain Repair Program is to fast-track neuroscience research in order to develop treatments and therapies more quickly. Through the Brain Repair Program, NeuroScience Canada and its donors and partners have already invested $4.5 million to research teams conducting breakthrough work in the area of brain repair. The goal of the Brain Repair Program is to initially fund five teams, for a total investment of $8 million.

    The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health.

    Source: Medical News Today © 2003-2005 Medical News Today

    $15.6 million awarded for nervous system repair in multiple sclerosis
    Part of $30 million National MS Society promise 2010 initiative for targeted research -

    The largest awards ever made for research aimed at protecting and reversing neurological damage and restoring function in people with multiple sclerosis (MS) are going to four teams in the U.S. and Europe, who will use $15.6 million from the National Multiple Sclerosis Society to lay the groundwork for clinical trials over the next five years. These awards are part of the National MS Society's Promise 2010 Campaign, a nationwide effort to raise at least $30 million for targeted areas of research and patient care that hold great potential in the fight to end the devastating effects of MS but which have so far been under-explored.

    The teams are based at Johns Hopkins University, University of Wisconsin Madison, University of Cambridge and University College London, with other collaborators in Canada, Europe and the U.S.

    "We're excited that these international 'dream teams' of leading scientists and physicians have accepted our challenge to develop the tools needed for conducting clinical trials aimed at protecting against and repairing nervous tissue damage in MS," said John R. Richert, MD, Vice President of Research & Clinical Programs at the National MS Society. "This is a new chapter in MS research and should serve as a springboard for translating basic lab findings into important new treatments for people with MS."

    MS involves a misdirected immune attack against myelin, the coating on nerve fibers that speeds nerve signals, and also destroys the underlying nerve fiber itself, causing symptoms like numbness, blindness, cognitive dysfunction and paralysis. Recent progress in controlling immune system attacks, coupled with rapid advances in the neurosciences, have made nervous tissue repair and protection emergent areas of MS research, prompting the National MS Society's unprecedented investment.

    The repair teams are taking multifaceted approaches to protecting brain tissues and finding ways to rebuild the central nervous system. The teams will meet regularly to help foster synergy and collaboration.

    "Collaboration is critical to achieving our goals with these projects. We know that sharing ideas and key findings will get us to the finish line that much faster," Dr. Richert continued.

    "Dream teams" Leading the Way

    Neurologist Dr. Peter A. Calabresi (Johns Hopkins University) and collaborators are searching for better ways to detect and quantify tissue injury in MS and testing agents that may protect the nervous system from further damage.

    The international team headed by Professor Charles ffrench-Constant (University of Cambridge, UK) is focusing on restoring myelin by identifying and amplifying natural repair factors in the brain and by attempting transplantation of replacement cells.

    Dr. Gavin Giovannoni (University College London, UK) and collaborators are attempting to turn cells into vehicles that will deliver repair molecules to sites of injury in the brain, and screening molecules for their protective properties as a prelude to clinical testing.

    Professor Ian D. Duncan (University of Wisconsin Madison) is leading a multidisciplinary team to develop better imaging technologies such as PET and MRI to visualize myelin and nerve fiber damage, and to detect its repair. They are also exploring repair cell transplantation techniques.

    Promise 2010: Giving people living with MS a future to look forward to rather than a past to look back upon

    To encourage innovative research into highly promising areas and to improve MS medical care, the National MS Society launched the Promise 2010 Campaign. This nationwide effort is fueled by nearly 50 local Society chapters who have committed to raise at least $30 million to fund the four targeted initiatives.

    In addition to the repair initiative, these include the establishment of Pediatric MS Care Centers to improve care and propel research into childhood MS; the MS Lesion Project, an international pathology study seeking to map and understand the meaning of MS damage seen in the brain in order to develop better ways of treating people with MS; and the Sonya Slifka Longitudinal MS Study, a nationwide database to examine the impact of MS on people's lives.

    Source: Medical News Today

    Peptide Promotes New Growth In Injured Spinal Cords
    Researchers at Yale University have developed a synthetic peptide that promotes new nerve fibre growth in the damaged spinal cords of laboratory rats and allows them to walk better. This could help in MS.

    Dr Stephen Strittmatter, associate professor of neurology and neurobiology at Yale School of Medicine, said the study confirms which molecules block axon regeneration in the spinal cord and shows that a peptide can promote new growth.

    Axons are the telephone lines of the nervous system and carry a nerve impulse to a target cell.

    The rats were administered the peptide for four weeks through a catheter inserted into the spinal canal. A number of nerve fibres did grow back and the rats were able to walk better than without the treatment.

    The synthetic peptide Strittmatter and his colleagues developed is 40amino acids long and acts as an inhibitor at the Nogo receptor site.

    Ref: Nature

    © Multiple Sclerosis Resource Centre

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