Neurosteroids

Individuals with multiple sclerosis (MS) may have impaired production of important neurosteroid molecules in their brains, so replacement therapy could be helpful, researchers said.

Autopsy findings from 16 MS patients showed high expression of micro-RNA molecules in white matter that suppress enzymes responsible for neurosteroid synthesis, particularly allopregnanolone, according to Christopher Power, MD, of the University of Alberta in Edmonton, and colleagues.

The researchers also confirmed that levels of allopregnanolone and other steroids were depressed in the MS patients' white matter, they reported online in Brain.

Similar findings emerged from analyses of mice with experimental autoimmune encephalitis (EAE), a standard model of MS.

Most strikingly, treating the animals with allopregnanolone partly normalized their behavioral deficits and reduced levels of neuroinflammation and injury to nerve fibers, Power and colleagues indicated.

"These studies are the first report of perturbed neurosteroidogenesis in multiple sclerosis and the related model, EAE, which also showed improved outcomes in terms of neurobehavioural deficits, neuropathology and neuromolecular changes with neurosteroid (allopregnanolone) replacement," they wrote.

"The neurosteroid allopregnanolone, or perhaps closely related compounds, might represent unique therapeutic options for people with multiple sclerosis."

Micro-RNA molecules help regulate gene expression throughout the body. Power and colleagues guessed that up- or downregulation of these molecules could play a role in the MS disease process.

Although the broad outline of MS pathology is well established -- an autoimmune attack on the myelin sheaths that surround and protect nerve fibers -- how and why it arises and other details remain uncertain.

As Power and colleagues explained in the Brain paper, "the working hypothesis was that specific changes in micro-RNA profiles in the white matter of patients with multiple sclerosis point to disordered homeostatic mechanisms in the central nervous system, leading to new perspectives on multiple sclerosis pathogenesis."

They analyzed samples of white matter from the 26 individuals with high-throughput microarray techniques. Individual micro-RNA species showing more than 1.5-fold differences between MS patients and controls were flagged for closer examination.

Some two dozen micro-RNAs were differentially expressed to that degree, with about half upregulated and half downregulated.

Checking the biological pathways affected by these molecules led the researchers to hone in on just three -- dubbed miR-338, miR-155, and miR-491 -- as most likely involved in the MS disease process. All three were upregulated in the MS patients.

In vitro experiments showed that these species inhibited expression of hydroxysteroid dehydrogenase enzymes necessary for steroid synthesis in the brain. The steroid most affected was allopregnanolone, although dehydroepiandrosterone synthesis also was suppressed.

Studies in EAE mice also showed reduced neurosteroid levels in their brains. Intraperitoneal injections of allopregnanolone in mice shortly after induction of EAE led to improvements in several markers of disease, relative to sham-treated animals.

These included:

Preserved myelin in the spinal cord
Reduced reactivity in immune cells
Lower immunoreactive cell counts in the spinal cord
Reduced axonal injury
75% reduction in clinical disease severity scores

Although neurosteroids had not previously attracted much attention in MS research, their involvement should not be a surprise, Power and colleagues argued.

These substances "exert diverse effects on neural cell function and survival in the brain," they wrote. In particular, allopregnanolone is recognized as a regulator of GABAergic function, which in turn affects behavior and survival of glial cells and neurons.

Allopregnanolone also appears to diminish proinflammatory activity of at least some immune cells, the researchers indicated. But unlike glucocorticoids, it lacks broad immunosuppressive effects -- "hence, this and related molecules might provide new therapeutic options, devoid of the side-effects of common immunosuppressive therapies," Power and colleagues wrote.

Primary source: Brain
Source reference:
Noorbakhsh F, et al "Impaired neurosteroid synthesis in multiple sclerosis" Brain 2011; DOI: 10.1093/brain/awr200.

Source: Medpage Today © 2011 Everyday Health, Inc. (22/09/11)

A research team at the University of Alberta believes it may have stumbled upon a possible cause for Multiple Sclerosis, giving people living with the disease a renewed sense of hope.

41 year-old Jeff Junod has been battling MS since 2007. Over the past four years, the debilitating disease has taken away his ability to do the simple things he once enjoyed.

"We used to go for bike rides together. Now we don't, because we'd leave one of our members at home," said Junod's wife, Traci.

"I compare it to riding a roller coaster - some days are negative some days positive," explained Junod.

But there may be new hope on the horizon for him and others suffering from the disease, thanks to a discovery made by Junod's doctor and a team of researchers at the U of A.

"We've discovered that a network of molecules in the brain called neurosteroids seem to be deficient in the brains of patients with MS. And that's never been recognized before," said neurologist Dr. Chris Power.

Neurosteroids are involved in protecting brain cells, helping them grow, and controlling immune responses in the brain. When given to mice who exhibited signs and symptoms similar to MS, Dr. Power said they were able to prevent the disease.

Studies have also linked MS to a Vitamin D deficiency, possibly caused by a lack of sunlight, since the disease is more commonly found in people living in northern climates, with Alberta currently having the highest rate of MS in the world.

The potential new neurosteroid treatment would have an affect on Vitamin D because both are related to cholesterol.

Doctors are now hoping to extend the clinical trials to MS patients.

"We're excited about this research because it opens up a whole new avenue of treatment and understanding the disease process," said Dr. Power.

He said the existing treatments for MS are quite limited. One of them includes the so-called 'Liberation treatment,' which clears blockages in jugular veins. However, not only is the procedure not currently offered in Canada, leaving patients to bear a big financial burden if they choose to undergo the procedure elsewhere, it does not always work.

The new discovery at the U of A may soon give patients a new option, in a less invasive and costly form, such as a pill.

While Dr. Power admitted getting to that point can usually take up to a decade, and cost billions of dollars, he said he hopes they can expedite the process in this case because of the previous proven results in helping treat other diseases of the brain, including epilepsy and depression.

For patients struggling with the disease, that time couldn't come soon enough.

"I'd be willing to start tomorrow, I have faith in it," said Junod. "If it brought back any little bit, that would be something."

Source: Global Edmonton © Shaw Media Inc., 2011 (22/09/11)

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