Study: Compound produces beneficial inflammation, remyelination

May 31, 2018
Drugs available to treat multiple sclerosis alter the body's immune system to reduce disease symptoms and disability. However, they do not induce repair of damaged axons or restore myelin. Researchers at the University of California, Riverside, report that indazole chloride is able to do both: remyelinate damaged axons and alter the immune system.

MS is triggered when the immune system attacks and damages the myelin sheath. As myelin is lost, nerve signals slow down or stop, affecting the patient's vision, movement, memory, and more. Oligodendrocytes are the mylenating cells of the central nervous system. Normally, oligodendrocyte precursor cells mature into myelin-producing oligodendrocytes when myelin is damaged. However, this process often fails in MS, resulting in permanent damage. The researchers found the change in the immune system provides a protective shield for oligodendrocytes, preventing this damage and possibly even reversing it.

Indazole chloride is a synthetic compound that acts on one form of the body's estrogen receptors previously shown to reduce MS symptoms in mouse models. It stimulates ERβ, an estrogen receptor in the body. Indazole chloride is an attractive drug because it does not produce the negative side-effects of estrogen therapy. ERβ is present not just in oligodendrocytes but also in microglia, neurons, and T-cells.

The researchers explained that while inflammation causes a lot of damage in autoimmune diseases, not all inflammation is harmful. Beneficial inflammation is required to fight infectious disease and speeds up wound healing by clearing dead cells and tissue. Indazole chloride reduces "bad" inflammation and promotes "good" inflammation, thereby protecting new oligodendrocytes while they remyelinate. The study’s authors found that indazole chloride accomplishes this by strengthening the production of a molecule called "CXCL1," which makes oligodendrocytes resistant to "bad" inflammatory signals.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, the researchers said the findings provide a stepping stone toward a way to repair the damage to axons and oligodendrocytes caused by MS. The researchers are screening chemically similar analogs of indazole chloride for more effective and safe therapy.

Study results appear in the Proceedings of the National Academy of Sciences.

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