Novel compound ZCAN262 restores lost myelin in MS mouse models

Compound stops toxic overactivation of nerve cells, may be new therapy

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Two mice climb among prescription medication bottles, while a third holds a capsule in its paws.

A novel compound that can lessen toxic overactivation of nerve cells was found to significantly reduce disease activity and restore lost myelin in two mouse models of multiple sclerosis (MS), a new study reports.

Researchers say the compound, ZCAN262, may be a potential new treatment for MS should future studies in the clinic support these early findings in the lab.

“Our compound had a stunning effect on rescuing myelin and motor function in the lab models, and I hope these effects will translate to the clinic to add to current treatments and bring new hope to patients with MS,” Fang Liu, MD, PhD, a senior scientist at the Centre for Addiction and Mental Health (CAMH), in Canada, and co-author of the study, said in a press release.

The study, “Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis,” was published in Science Advances.

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MS is caused by inflammation in the brain and spinal cord that damages myelin, a fatty substance that wraps around nerve fibers to help them send electrical signals more efficiently. Damage to myelin interferes with nerve signaling, which ultimately gives rise to disease symptoms.

Many treatments for MS are available, and all of them basically work by reducing inflammation in the brain and spinal cord. Here, researchers explored an alternative strategy for treating MS: stopping a process called glutamate-mediated excitotoxicity.

“As with cancer chemotherapy drug cocktails, simultaneous targeting of the MS disease pathway at multiple points can have synergistic effects and result in better outcomes,” Liu said.

Neurons, or nerve cells, communicate with each other using signaling molecules called neurotransmitters. One of the key neurotransmitters in the brain is called glutamate. When glutamate binds to molecular receptors on neurons, it prompts the cell to fire an electrical signal.

Although glutamate signaling plays important roles in normal brain functioning, MS and other neurological diseases are frequently marked by excessively high glutamate signaling. This can cause nerve cells to fire too much, so much so that the cell becomes damaged — a process that’s referred to as excitotoxicity, as the nerve cells are activated or excited to the point that it becomes toxic.

Theoretically, blocking glutamate signaling entirely would also stop excitotoxicity. But that’s not practical as a treatment strategy, as glutamate is needed for many normal brain functions. Instead, the researchers here used a more nuanced approach, in which they modulated the activity of AMPA, one of glutamate’s receptors. AMPA is key in driving excitotoxicity.

The scientists had previously identified a particular part of the AMPA receptor molecule that could be targeted to change the receptor’s function in a way that’s expected to reduce excitotoxicity. Now, the team used computer-based analyses of more than 500,000 molecules looking for a compound that could target this specific region of AMPA.

The top compounds from computer-based analyses underwent further screening and tests in cell models. Ultimately the researchers zeroed in on ZCAN262 as a compound that could modulate AMPA as desired. The drug also had other properties, such as being easily absorbed by the body when taken orally, that made it well suited for use as a potential treatment.

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ZCAN262 tested in 2 mouse models of MS

When tested in mice, treatment with ZCAN262 alone did not cause any noteworthy changes in brain activity, learning, or memory. That’s consistent with the idea that although this molecule could modulate AMPA activity it does not interfere with normal glutamate signaling.

The novel compound also was tested in two models of MS — the first in mice with experimental autoimmune encephalitis (EAE), a lab-induced autoimmune disease that’s commonly used to model MS. Mice treated with ZCAN262 had significantly reduced clinical scores, indicating less substantial disease.

Next, the researchers tested ZCAN262 in mice fed cuprizone, a toxic chemical that causes damage to myelin. In this model, treated mice had significantly better neurological and motor function and less myelin damage, which were improved to levels similar to healthy animals who had not received cuprizone treatment.

The ZCAN262-treated animals also had less damage to axons, or nerve fibers, as well as higher counts of oligodendrocytes, the brain cells chiefly responsible for making myelin.

“The data presented here suggest the potential for an MS treatment targeting AMPA-mediated excitotoxicity with a small-molecule … modulator,” the researchers concluded.

We are pleased to have helped enable the early development of a novel neuroprotective strategy for MS, and look forward to seeing it progress through the critical next stages needed to determine its potential benefits for people living with MS.

The scientists stressed that, while these results are promising, further work is needed to verify these results and move the findings into the clinic.

“In all my years as a medicinal chemist, I have never seen a more promising starting point for a drug development project,” said Iain Greig, PhD, from the University of Aberdeen, and co-author of the study.

“It has been a huge pleasure to be involved in this program and I am looking forward to continuing to drive it towards to the clinic,” Greig added.

This study was funded in part by the U.S.-based National Multiple Sclerosis Society through its Fast-Forward program.

“We are pleased to have helped enable the early development of a novel neuroprotective strategy for MS, and look forward to seeing it progress through the critical next stages needed to determine its potential benefits for people living with MS,” said Walt Kostich, PhD, head of the Fast Forward program.