Potential 'One-Two' Punch for Treating MS?

Damian McNamara

June 06, 2018

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 (Neurobiol Dis. 2013;56:131-144).

"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.

"Unfortunately, estrogenic signalling through ERα is also feminizing in males and associated with proliferative effects that increase cancer risk, limiting the usefulness of endogenous estrogens," write the investigators. "In contrast, selective ERβ ligands offer many of estrogen's benefits without these deleterious side effects."

"Fast Moving and Exciting" Research

The current study is part of a research movement, noted Bruce Bebo, PhD, executive vice president of research at the National MS Society, when asked to comment.

"It's a well-done, thorough paper that gets a little bit more at the mechanism for how estrogen receptor β ligands might be promoting repair," he told Medscape Medical News

"One of the things that stood out for me was the observation that they could induce repair even in the context of extensive immune cell accumulation in the nervous system. That's been one of the challenges in myelin repair — we pharmacologically promote repair in an area with a lot of active inflammation," said Bebo.

"The area of myelin repair has received a lot of attention in the last 5 years. It's a fast moving and exciting area of MS research," he added.

"A lot of exciting approaches are being studied" in both basic research and clinical trials underway evaluating repair agents, Bebo noted. "In my opinion, it's only a matter of time before we understand how we can promote repair in MS and…before we have a repair therapy in the clinics."

Encouraged to Search Further

Because indazole chloride works differently than many currently available pharmaceutical agents, "we are hopeful that the effects we see in mice will translate into the clinic," Tiwari-Woodruff said. "However, many encouraging preclinical studies in animals have ended in failure when brought to clinical trials, so more research is needed to say with certainty," she added.

In fact, other ERβ ligands may feature a more potent beneficial effect, she said. For this reason, she is collaborating further with Katzenellenbogen to test new and potentially better analogues of indazole chloride.

"We have screened and submitted a patent application for over 15 indazole chloride analogues and are in the process of publishing a report of their efficacy in comparison to indazole chloride coming out soon," Tiwari-Woodruff  said.

Finding an even more powerful ERβ ligand that inhibits critical elements of the immune attack and at the same time promote repair "would be a real potent combination," Bebo commented.

The Bigger Picture

The interplay between central nervous system–derived and immune-derived signals is central to the induction and regulation of neuroinflammatory diseases such as MS, Tiwari-Woodruff said. "Our study opens up new possibilities that ERβ ligands like indazole chloride modulate inflammation to potentially promote myelin repair and remyelination."

And the big picture potential could go beyond MS, she added. "We believe that indazole chloride-like compounds could be a potential targeted therapy for MS and other diseases with inflammatory demyelination."

Tiwari-Woodruff and Bebo have disclosed no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online May 29, 2018. Article

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