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Drugs That Activate Brain Stem Cells May Reverse Multiple Sclerosis

Over-the-counter compounds may replace damaged cells

Two drugs already on the market — an antifungal and a steroid — may take on new roles as treatments for multiple sclerosis (MS). According to a study published April 20 in Nature, researchers have discovered that these drugs may activate stem cells in the brain to stimulate myelin-producing cells and repair white matter, which is damaged in MS. The study was partially funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health (NIH).

Specialized cells called oligodendrocytes lay down multiple layers of a fatty white substance known as myelin around axons, the long “wires” that connect brain cells. Myelin acts as an insulator and enables fast communication between brain cells. In MS there is breakdown of myelin, and this deterioration leads to muscle weakness, numbness, and problems with vision, coordination, and balance.

“To replace damaged cells, the scientific field has focused on direct transplantation of stem cell-derived tissues for regenerative medicine, and that approach is likely to provide enormous benefit down the road. We asked if we could find a faster and less invasive approach by using drugs to activate native nervous system stem cells and direct them to form new myelin. Our ultimate goal was to enhance the body’s ability to repair itself,” said senior author Paul J. Tesar, PhD, an associate professor at Case Western Reserve School of Medicine in Cleveland, Ohio.

It is unknown how myelin-producing cells are damaged, but research suggests that they may be targeted by malfunctioning immune cells and that MS may start as an autoimmune disorder. Current therapies for MS include anti-inflammatory drugs, which help prevent the episodic relapses common in MS, but are less effective at preventing long-term disability. Scientists believe that therapies that promote myelin repair might improve neurologic disability in people with MS.

Adult brains contain oligodendrocyte progenitor cells (OPCs) –– stem cells that generate myelin-producing cells. It has been found that OPCs multiply in the brains of MS patients, as if to respond to myelin damage, but for unknown reasons they are not effective in restoring white matter. In the new study, Tesar wanted to see whether drugs approved for other uses were able to stimulate OPCs to increase myelination.

OPCs have been difficult to isolate and study, but Tesar and his colleagues developed a method to investigate these cells in a petri dish. Using this technique, they were able to quickly test the effects of hundreds of drugs on the stem cells.

The compounds screened in this study were obtained from a drug library maintained by the NIH’s National Center for Advancing Translational Sciences (NCATS). All are approved for use in humans.

Tesar’s team found that two compounds in particular –– miconazole (an antifungal) and clobetasol (a steroid) –– stimulated mouse and human OPCs into generating myelin-producing cells.

Next, they examined whether these drugs, when injected into a mouse model of MS, could improve remyelination. They found that both drugs were effective in activating OPCs to enhance myelination and reverse paralysis. As a result, almost all of the animals regained the use of their hind limbs. They also found that the drugs acted through two different molecular mechanisms.

“The ability to activate white matter cells in the brain, as shown in this study, opens up an exciting new avenue of therapy development for myelin disorders, such as multiple sclerosis,” said Ursula Utz, PhD, program director at the NINDS.

Tesar and his colleagues caution that more research is needed before miconazole and clobetasol can be tested in MS clinical trials. The drugs are currently approved for use as creams or powders on the surface of the body, but their safety when administered in other forms, such as injections, in humans is unknown.

Source: NIH; April 20, 2015.

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