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    You are here : Home » MS Research News » The Blood Brain Barrier

    The Blood Brain Barrier

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    More news can be found in New Pathways Magazine, our bi-monthly publication, and also check daily at MSRC: Latest MS News.

    Scientists identify key biological mechanism in multiple sclerosis

    Blood Brain BarrierScientists at the Gladstone Institutes have defined for the first time a key underlying process implicated in multiple sclerosis (MS)—a disease that causes progressive and irreversible damage to nerve cells in the brain and spinal cord. This discovery offers new hope for the millions who suffer from this debilitating disease for which there is no cure.

    Researchers in the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, have identified in animal models precisely how a protein that seeps from the blood into the brain sets off a response that, over time, causes the nerve cell damage that is a key indicator of MS. These findings, which are reported in the latest issue of Nature Communications, lay the groundwork for much-needed therapies to treat this disease.

    MS, which afflicts more than two million people worldwide, develops when the body's immune system attacks the brain. This attack damages nerve cells, leading to a host of symptoms including numbness, fatigue, difficulty walking, paralysis and loss of vision. While some drugs can delay these symptoms, they do not treat the disease's underlying cause—which researchers are only just beginning to understand.

    "To successfully treat MS, we must first identify what triggers the disease and what enables its progression," said Dr. Akassoglou, who also directs the Gladstone Center for In Vivo Imaging Research and is a professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. "Here, we have shown that the leakage of blood in the brain acts as an early trigger that sets off the brain's inflammatory response—creating a neurotoxic environment that damages nerve cells."

    Dr. Akassoglou and her team reached this conclusion by using advanced imaging techniques to monitor the disease's progression in the brain and spinal cord of mice modified to mimic the signs of MS. Traditional techniques only show "snapshots" of the disease's pathology. However, this analysis allows researchers to study individual cells within the living brain—and to monitor in real-time what happens to these cells as the disease worsens over time.

    "In vivo imaging analysis let us observe in real-time which molecules crossed the blood-brain barrier," said Dimitrios Davalos, PhD, Gladstone staff research scientist, associate director of the imaging center and the paper's lead author. "Importantly, this analysis helped us identify the protein fibrinogen as the key culprit in MS, by demonstrating how its entry into the brain through leaky blood vessels impacted the health of individual nerve cells."

    Fibrinogen, a blood protein that is involved in coagulation, is not found in the healthy brain. In vivo imaging over different stages of disease revealed, however, that a disruption in the blood-brain barrier allows blood proteins—and specifically fibrinogen—to seep into the brain. Microglia—immune cells that act as the brain's first line of defense—initiate a rapid response to fibrinogen's arrival. They release large amounts of chemically reactive molecules called 'reactive oxygen species.' This creates a toxic environment within the brain that damages nerve cells and eventually leads to the debilitating symptoms of MS.

    Importantly, the team found a strategy to halt this process by genetically modifying fibrinogen in the animal models. This strategy disrupted the protein's interaction with the microglia without affecting fibrinogen's essential role as a blood coagulant. In these models, the microglia did not react to fibrinogen's arrival and did not create a toxic environment. As a result, the mice failed to show the type of progressive nerve cell damage seen in MS.

    "Dr. Akassoglou's work reveals a novel target for treating MS—which might protect nerve cells and allow early intervention in the disease process," said Ursula Utz, PhD, MBA, a program director at The National Institutes of Health's National Institute of Neurological Disorders and Stroke, which provided funding for this research.

    "Indeed, targeting the fibrinogen-microglia interactions to halt nerve-cell damage could be a new therapeutic strategy," said Dr. Akassoglou. "At present we are working to develop new approaches that specifically target the damaging effects of fibrinogen in the brain. We also continue to use in vivo imaging techniques to further enhance our understanding of what triggers the initiation and progression of MS. "

    Source: Science Codex (30/11/12)

    A2A adenosine receptor may be a key to Multiple Sclerosis treatment

    A2A Adenosine receptor (in red)A newly published study from researchers at Cornell University shows how the A2A adenosine receptor expressed on blood-brain barrier cells acts as a gateway, allowing immune cells to enter the brain, where they can cause havoc in people with multiple sclerosis.

    A receptor recently discovered to control the movement of immune cells across central nervous system barriers (including the blood-brain barrier) may hold the key to treating multiple sclerosis (MS), a neuroinflammatory disease of the central nervous system.

    In MS, immune cells enter the central nervous system and attack and destroy the myelin sheath surrounding the axons of nerve cells in the brain and spinal cord, resulting in blindness, paralysis, incontinence and many more symptoms.

    The research, appearing last month online and in print June 1 in the Journal of Immunology, reveals how the A2A adenosine receptor expressed on blood-brain barrier cells acts as a gateway, allowing immune cells to enter the brain, where they can cause havoc in people with MS.

    The blood-brain barrier is composed of specialized cells that selectively prevent substances from passing from the bloodstream into the brain.

    “We found that expression of this A2A adenosine receptor is important for regulating the entry of cells into the brain; whereby its activation allows immune cell entry and its inhibition blocks entry,” said Margaret Bynoe, associate professor of immunology at Cornell’s College of Veterinary Medicine and senior author of the paper, which was also selected as a featured publication in the “In This Issue” section of the journal, where the top 10 percent of manuscripts are featured. Jeffrey Mills, a postdoctoral associate in Bynoe’s lab, is the paper’s lead author.

    In this study, the researchers used mice where the A2A adenosine receptor was knocked out and then infused those mice with normal immune cells from wild-type mice expressing the A2A adenosine receptor. This produced chimeric mice expressing the A2A receptor on immune cells, but not on blood-brain barrier cells. Without A2A receptor on blood-brain barrier cells, the normal immune cells failed to effectively infiltrate the central nervous system, and thus, these mice were protected and developed less severe symptoms of MS-like disease.

    “The absence of the A2A receptor on blood-brain barrier cells is similar to the effect of pharmacologically blocking the receptor with antagonists [drugs], which also protected mice from MS-like disease,” Bynoe said.

    “The implications of these findings are that, potentially, modulation of this receptor can be beneficial for future treatment of MS,” she added.

    The study was funded by the National Institutes of Health.

    Source: SciTech Daily Copyright © SciTech Daily 1998 - 2012 (11/06/12)

    Sonic Hedgehog protein: Breakthrough in pinpointing protective mechanisms in MS

    SHH proteinIn an article published today in the prestigious journal Science, a team of researchers led by Dr Alexander Prat and postgraduate fellow Jorge Alvarez at the University of Montreal Hospital Research Centre (CRCHUM) sheds light on how the blood-brain-barrier (BBB) works to prevent the incursion of the immune system into the brain. "Our findings provide a better understanding of the mechanisms used by the brain in mounting a natural defence against immune system aggression, as is the case in Multiple Sclerosis" explains Dr Prat.

    There is no known cure for this auto-immune disease of the central nervous system (CNS). One of the characteristics of this debilitating disease is the inability of the BBB to restrict and control the passage of immune cells into the brain. This intrusion of the body's immune system into the brain affects the ability of neurons in the brain and in the spinal cord to communicate efficiently with one another, producing extensive and recurrent central nervous system damage.

    As such, Multiple Sclerosis (MS) symptoms can include paralysis, pricking or numbness, visual problems, repetitive difficulties with coordination and balance and in moving, which lead to chronic clinical handicap in MS patients.

    The BBB is a physical and metabolic barrier that prevents unwanted cells or molecules from entering the CNS. It is composed of, among other things, tightly bound endothelial cells (cells that line the interior surface of blood cells) and perivascular astrocytes (star-shaped cells that regulate the transmission of electrical signals in the brain) that maintain CNS balance. Prat and Alvarez show that these astrocytes also play a key role in secreting Sonic hedgehog, a protein that is involved in how the brain is organized, and that endothelial cells express Hedgehog receptors, which together promote proper BBB formation and integrity during embryonic development and adulthood.

    More importantly, they show, in a laboratory setting with animal and human brain cells, that the so-called Hedgehog pathway plays an important role in decreasing the adhesion and migration of immune cells into the brain. These findings demonstrate that the Hedgehog pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks. Its dysregulation is one of the pathological hallmarks of Multiple Sclerosis.

    "The results of this research open the door to designing therapeutic approaches to control immune cell migration to the CNS and thus improve their delivery to affected areas," notes Dr Prat.

    With more than 75,000 MS patients, Canada has the highest incidence of multiple sclerosis in the world.

    This study was supported by grants from the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada.

    Source: CNW Canadian Newswire © 2011 CNW Group Ltd (02/12/11)

    New finding may help drug delivery to the brain in MS patients

    Blood Brain BarrierCornell University researchers may have solved a 100-year puzzle: How to safely open and close the blood-brain barrier so that therapies to treat Alzheimer's disease, multiple sclerosis and cancers of the central nervous system might effectively be delivered. (Journal of Neuroscience, Sept. 14, 2011.)

    The researchers found that adenosine, a molecule produced by the body, can modulate the entry of large molecules into the brain. For the first time, the researchers discovered that when adenosine receptors are activated on cells that comprise the blood-brain barrier, a gateway into the blood-brain barrier can be established.

    Although the study was done on mice, the researchers have also found adenosine receptors on these same cells in humans. They also discovered that an existing FDA-approved drug called Lexiscan, an adenosine-based drug used in heart imaging in very ill patients, can also briefly open the gateway across the blood-brain barrier.

    The blood-brain barrier is composed of the specialized cells that make up the brain's blood vessels. It selectively prevents substances from entering the blood and brain, only allowing such essential molecules as amino acids, oxygen, glucose and water through. The barrier is so restrictive that researchers couldn't find a way to deliver drugs to the brain until now.

    "The biggest hurdle for every neurological disease is that we are unable to treat these diseases because we cannot deliver drugs into the brain," said Margaret Bynoe, associate professor of immunology at Cornell's College of Veterinary Medicine and senior author of a paper appearing Sept. 14 in the Journal of Neuroscience. Aaron Carman, a former postdoctoral associate in Bynoe's lab, is the paper's lead author. The study was funded by the National Institutes of Health.

    "Big pharmaceutical companies have been trying for 100 years to find out how to traverse the blood-brain barrier and still keep patients alive," said Bynoe, who with colleagues have patented the findings and have started a company, Adenios Inc., which will be involved in drug testing and preclinical trials.

    Researchers have tried to deliver drugs to the brain by modifying them so they would bind to receptors and "piggyback" onto other molecules to get across the barrier, but so far, this modification process leads to lost drug efficacy, Bynoe said.

    "Utilizing adenosine receptors seems to be a more generalized gateway across the barrier," she added. "We are capitalizing on that mechanism to open and close the gateway when we want to."

    In the paper, the researchers describe successfully transporting such macromolecules as large dextrans and antibodies into the brain. "We wanted to see the extent to which we could get large molecules in and whether there was a restriction on size," Bynoe said.

    The researchers also successfully delivered an anti-beta amyloid antibody across the blood-brain barrier and observed it binding to beta-amyloid plaques that cause Alzheimer's in a transgenic mouse model. Similar work has been initiated for treating multiple sclerosis, where researchers hope to tighten the barrier rather than open it, to prevent destructive immune cells from entering and causing disease.

    Although there are many known antagonists (drugs or proteins that specifically block signaling) for adenosine receptors in mice, future work will try to identify such drugs for humans.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011

    © Multiple Sclerosis Resource Centre (MSRC)

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