UCLA researchers stimulated brain repair in mice with two of the most widely used analogues for multiple sclerosis by treating them with estrogen. The hormone induced the expression of cholesterol synthesis genes in cells that make myelin, the protective coating around nerves. The researchers found that mechanisms underlying this process, called remyelination, appeared to mimic known processes of myelination when the fetal brain is developing and is exposed naturally to a related estrogen in the mother's blood.
In MS, the body's immune system attacks the protective myelin coating around nerve fibers, leaving the nerves vulnerable to damage. Current treatments for MS help relieve inflammation but don't repair the underlying brain cell damage or loss of myelin.
Different types of estrogen already have been investigated in early studies as possible treatments for MS because there is evidence that they might have anti-inflammatory properties.
The researchers began by looking at how the expression patterns of genes in the brain changed in MS patients throughout the course of their disease and treatment. By looking at those patterns in individual brain cells and regions, rather than the brain as a whole, they found one cell type and two areas of the brain that showed critical changes. The most pronounced changes were in genes related to the production of cholesterol, which the brain must make from scratch because it doesn’t cross the blood-brain barrier. The researchers confirmed the importance of cholesterol in a mouse model of MS that undergoes some natural remyelination; as the myelin sheath was repaired, the same cholesterol synthesis genes were turned on.
Finally, the team tried to spur that cholesterol synthesis by treating adult mice with an estrogen receptor beta compound, mimicking the hormonal womb environment in which myelin is originally laid down to coat nerve fibers in both mice and humans. They found that the treatment induced remyelination in mice with two analogues for MS.
Nearly 1 million people in the U.S. have MS, and the incidence is increasing. Treatments that can reverse the course of disease, rather than temporarily ease symptoms, are needed. Estrogens are already well-studied and treatment with a pregnancy estrogen (estriol) is in initial trials for people with MS. The possibility that remyelination and brain repair could be induced warrants study into whether that phenomenon is occurring in people with MS in clinical trials.
The study's senior author is Dr. Rhonda Voskuhl, a UCLA professor of neurology, director of the UCLA MS Program, and the Jack H. Skirball Professor of Multiple Sclerosis Research; the other authors are Noriko Itoh, Alessia Tassoni, Macy Matsukawa, Emily Ren, Vincent Tse, Ellis Jang, Timothy Suen and Yuichiro Itoh, all of UCLA.
The study was published (PDF) in the journal Proceedings of the National Academy of Sciences.
The study was funded by the National Institutes of Health, the Conrad N. Hilton Foundation, the Tom Sherak MS Hope Foundation, the Rhoda Goetz Foundation for Multiple Sclerosis and Dunk MS.
