A potential one-two punch to treat multiple sclerosis (MS) comes in the form of an estrogen receptor β (ERβ) ligand that could both reduce the inflammation that limits current treatment efficacy and provide a more favorable environment for promoting myelin repair, new research suggests.
Treatment with several ERβ ligands in a mouse model of MS was associated with an increase in a neutrophil chemoreactant called CXCL1. Elevated levels of CXCL1 in the brain and periphery, in turn, correlated with increased axon remyelination.
“Existing therapies for MS are immunomodulatory and slow disease disability, but fail to reverse or prevent disease progression or restore and repair myelin,” study author Seema K. Tiwari-Woodruff, PhD, associate professor of biomedical sciences at the University of California (UC), Riverside, School of Medicine, told Medscape Medical News.
Identifying the mechanism behind therapeutic benefits of ERβ ligands is critical for developing new therapies that promote remyelination, she added. The study revealed the promise of one of these ligands in particular: indazole chloride.
“Although we weren’t surprised at the effectiveness of ERβ ligands, we were surprised by the finding that indazole chloride can curb ‘bad’ inflammation and enhance the ‘good’ inflammation,” Tiwari-Woodruff said.
Inflammation in the setting of autoimmune diseases like MS is harmful but inflammation in other settings, such as fighting infection and wound healing, is beneficial, she noted. The researchers found that indazole chloride reduces harmful inflammation and promotes beneficial inflammation by strengthening production of CXCL1, making new oligodendrocytes more resistant to harmful inflammatory signals while they remyelinate.
In addition to upregulation of CXCL1, compared with vehicle only, ERβ ligands improved axon myelination, decreased pro-inflammatory cytokines, and had no effect on leukocyte infiltration into the central nervous system.
“The finding is unique and encouraging as treating a complex disease such as MS requires modulating the immune system,” Tiwari-Woodruff said. “Indazole chloride has the potential to do just that.”
The results were published online May 29 in Proceedings of the National Academy of Sciences of the United States of America.
Building on Earlier Findings
Previous research by the UC Riverside team demonstrated that a modestly selective ERβ ligand, diarylpropionitrile, provided neuroprotection in a mouse model of MS but did little to limit inflammation caused by the disease.
“Recently, we, along with our collaborator Dr John Katzenellenbogen of the University of Illinois at Urbana-Champaign, found that the more selective ERβ ligand indazole chloride improves clinical disease and motor function in the same mouse model,” said Tiwari-Woodruff.
The current research also reflects initial estrogen studies. They showed that nonselective endogenous estrogens present during pregnancy reduced MS relapse frequency and severity through ER-α–mediated suppression of inflammation.