Chemical compound produces beneficial inflammation, remyelination that could help treat MS

May 29, 2018, University of California - Riverside
Chemical compound produces beneficial inflammation, remyelination that could help treat MS
Chemical structure of indazole chloride. Credit: J. Katzenellenbogen, UIUC.

Drugs available to treat multiple sclerosis, a leading cause of neurological disability affecting roughly 2.3 million people worldwide, alter the body's immune system to reduce disease symptoms and disability.

They do not induce, however, repair of damaged axons, the long threadlike parts of that conduct impulses between cells or restore , the protective sheath that surrounds the axons of neurons essential for the proper functioning of the brain and spinal cord.

Researchers at the University of California, Riverside, now report that indazole chloride, a synthetic compound that acts on one form of the body's estrogen receptors previously shown to reduce multiple sclerosis symptoms in mouse models, is able to do both: remyelinate (add new myelin to) damaged axons and alter the immune system.

"While additional translational studies are required, indazole chloride and similar drugs may represent a promising new avenue of treating the underlying loss of myelin in multiple sclerosis," said Seema Tiwari-Woodruff, an associate professor of biomedical sciences in the School of Medicine, who led the mouse study.

Multiple sclerosis is triggered when the immune system attacks and damages the . 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, precursor cells mature into myelin-producing oligodendrocytes when myelin is damaged.

This process often fails, however, in multiple sclerosis, resulting in permanent damage. The UCR researchers found the change in the immune system provides a protective shield for oligodendrocytes, preventing this damage and possibly even reversing it.

"With remyelination of axons, nerve impulses travel faster than before, thus decreasing multiple sclerosis disability," Tiwari-Woodruff said. "As a potential therapy for the treatment of multiple sclerosis, indazole chloride may represent the first in a novel class of drugs capable of reducing disability burden in patients with multiple sclerosis. We still don't know the mechanism of action of pre-clinical therapies like indazole chloride. Our report aims to understand how drugs like indazole chloride are working so we can make more selective and efficacious drugs."

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

Indazole chloride, a ligand, 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. Because ERβ are present not just in oligodendrocytes but also in microglia, neurons, and T-cells, indazole chloride may have therapeutic benefits not just for multiple , but also other .

Hawra Karim (left) and Seema Tiwari-Woodruff. Credit: I. Pittalwala. UC Riverside.

Tiwari-Woodruff 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. Tiwari-Woodruff and her group found that indazole chloride accomplishes this by strengthening the production of a molecule called "CXCL1," which makes oligodendrocytes resistant to "bad" inflammatory signals.

Tiwari-Woodruff's findings provide a stepping stone toward a way to repair the damage to axons and oligodendrocytes caused by . In collaboration with John Katzenellenbogen, a research professor of chemistry at the University of Illinois at Urbana-Champaign, Tiwari-Woodruff's group is screening chemically similar analogs of indazole chloride for more efficacious and safe therapy. Provisional patents have been filed for some of these analogs.

"It's quite possible we may find an analog far superior to indazole ," Tiwari-Woodruff said.

Explore further: Researchers identify chemical compound that decreases effects of multiple sclerosis

More information: Hawra Karim et al. Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1721732115

Related Stories

A supplement for myelin regeneration

December 7, 2015

Multiple sclerosis patients continually lose the insulating myelin sheath that wraps around neurons and increases the speed of impulses in the central nervous system. Whenever neurons are demyelinated, OPCs migrate toward ...

Recommended for you

Gut bacteria provide key to making universal blood

August 21, 2018

In January, raging storms caused medical emergencies along the U.S. East Coast, prompting the Red Cross to issue an urgent call for blood donations. The nation's blood supply was especially in need of O-type blood that can ...

Progress toward plugging an antibiotic pump

August 20, 2018

Each year in the U.S., at least 23,000 people die from infections caused by antibiotic resistant bacteria, according to the Centers for Disease Control and Prevention.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

TogetherinParis
1 / 5 (1) Jun 02, 2018
Pheromones have encouraged myelination, dam fecal pheromones in the mouse, rabbit, other species. This chemical looks a bit like them.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.