Chemical that Stimulates Estrogen Receptors Seen to Promote Myelin Repair Through ‘Good’ Inflammation in Mouse MS Model

Jose Marques Lopes, PhD avatar

by Jose Marques Lopes, PhD |

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A chemical compound called indazole chloride promotes repair of myelin, the protective layer of nerve fibers, through “beneficial” inflammation in a mouse model of multiple sclerosis (MS), a study reports.

The preclinical research, “Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination,” was published in the journal Proceedings of the National Academy of Sciences.

Current treatments for MS are not able to repair the damage to nerve fibers and myelin, both characteristic features of MS that lead to the symptoms marking this disease.

In the brain and spinal cord, myelin is formed by cells called oligodendrocytes after they mature from precursor cells. In contrast to healthy individuals, whose nervous system is able to regenerate damaged myelin, patients with MS cannot and such damage is permanent.

Prior work in mice with MS has shown that indazole chloride, a synthetic chemical that binds to and stimulates the estrogen receptor ERβ, improves motor function, promotes remyelination, and eases inflammation.

Now, scientists at University of California, Riverside found that indazole chloride’s effect on remyelination correlates with increased levels of CXCL1 in the periphery and in astrocytes, a cell of the central nervous system (CNS).

CXCL1 is a type of small molecule called a cytokine with a key role in inflammation. It binds to CXCR2 in oligodendrocytes, and as such is implicated in myelination.

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The investigators also observed that the extensive remyelination was accompanied by immune cells accumulating in the CNS.

While inflammation is damaging in autoimmune diseases, they noted it can also be beneficial — inflammation is required to fight infections and speed wound healing. Their findings suggest that indazole chloride promotes “good” inflammation, protecting oligodendrocytes while they remyelinate.

“Our data show that ERβ ligand neuroprotection/remyelination may be partly mediated by skewing the proinflammatory phenotype to a protective phenotype,” the researchers wrote.

“Indazole chloride and similar drugs may represent a promising new avenue of treating the underlying loss of myelin in [MS],” Seema Tiwari-Woodruff, PhD, the study’s senior author, said in a press release.

“With remyelination of axons, nerve impulses travel faster than before, thus decreasing multiple sclerosis disability. 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” Tiwari-Woodruff added.

The team considers indazole chloride an attractive compound because it does not cause the side effects of estrogen therapy. As ERβ receptors are present in other types of CNS cells beyond oligodendrocytes, as well as in immune T-cells, the scientists believe that indazole chloride may benefit not just MS patients, but also those with other autoimmune diseases.

Molecules chemically similar to indazole chloride are now being screened for potential testing in patients.

“It’s quite possible we may find an analog far superior to indazole chloride,” Tiwari-Woodruff concluded.

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