Myelin Regeneration Achieved in Mouse Model of MS
Therapies aimed at regenerating the myelin sheath can work to restore proper brain activity and may be a viable way of treating multiple sclerosis (MS), according to researchers at the University of California San Francisco.
In the study, “Accelerated Remyelination During Inflammatory Demyelination Prevents Axonal Loss And Improves Functional Recovery,” published in the journal eLife, researchers used mice with MS to understand exactly how remyelination could be triggered.
The myelin sheath — a coating made of myelin proteins that protects neurons and enhances the transmission of electrical impulses between them — is progressively lost in patients with MS, due to aberrant immune system attacks that destroy myelin. Myelin degeneration destabilizes neuronal function and ultimately leads to nerve cell death, contributing to disease progression and disability in MS patients. Many therapies have been developed in an attempt to promote remyelination and rescue neuronal function, but results did not support their viability.
“The key thing we learned from this study is that if we can design therapies that promote remyelination — especially when myelin has been damaged by inflammation as it is in MS — we can prevent neuronal loss and restore function,” the senior author of the study, Jonah Chan, PhD, said in a news release. “This is something I and other investigators have wanted to promise to MS patients, but we simply didn’t have the data.”
Researchers injected mice with a protein found in the myelin sheath that triggers a form of MS, called experimental autoimmune encephalomyelitis (EAE), which has an inflammatory response with physiological and behavioral consequences similar to those seen in human patients. At the same time, the mice also received an injection of clemastine, a drug the team had previously shown to be capable of promoting remyelination. This drug activates a group of proteins, called the muscarinic receptors, that are present in the cells that produce myelin, the oligodendrocytes.
They observed that mice treated with clemastine had less severe MS-like symptoms, and that a certain degree of remyelination occurred in their brain and spinal cord, which protected neurons from degeneration.
Because the researchers did not know the exact mechanism of action of clemastine, they tested the drug on several different receptors to identify which ones were affected by the treatment. They then identified the M1 receptors as one of the targets of clemastine, and observed that blocking these proteins induced the production of more oligodendrocytes, which is critical for remyelination.
However, because clemastine also targets other, similar receptors, and no drug is known to selectively block the M1 receptors, researchers used genetic tools to deplete the mouse brain of these receptors. In these animals, the team observed significant remyelination and reduced neuronal death, including restored neuronal function even when EAE inflammation was at its maximum. These results support the idea that inhibition of M1 receptors promotes remyelination by increasing the number of oligodendrocytes in the brain.
“Now that we’ve shown we can promote repair during the peak inflammation period, and that new myelin may remain stable,” Chan said, “we can now say to MS patients that focusing on this remyelination space has the potential to not only restore function, but to improve their quality of life.”