Enhancing remyelination in multiple sclerosis via M1 muscarinic acetylcholine receptor.

Abstract

Multiple sclerosis (MS) is growing in prevalence; yet, treatments that can reverse the progression of the disease are still needed. One strategy that has shown promise for reversing MS is remyelination by inhibiting the M1 receptor, a member of the muscarinic acetylcholine receptor (mAChR) family. Antagonizing the M1 mAChR is believed to be the mechanism by which clemastine, a developing drug that has been observed to enhance myelination in animal studies and phase II clinical trials, elicits its myelination-promoting effects. Recent studies have indicated that blocking M1 mAChR may promote oligodendrocyte differentiation via the extracellular signal-regulated kinase pathway, modulating Ca²⁺ concentration oscillations, and cross-talking with N-methyl-d-aspartate and Notch-1 receptors. However, clemastine has recently been found to accelerate disability in patients with MS, discouraging further progress in its clinical trials. Nevertheless, the underlying mechanisms following M1 mAChR antagonism by clemastine may still be targeted using alternative antimuscarinic drugs. This review consolidates recent advancements in our understanding of the mechanisms by which antagonizing M1 mAChR promotes remyelination and summarizes alternative antimuscarinic drugs that could be leveraged to treat MS in the future. SIGNIFICANCE STATEMENT: Current treatments for multiple sclerosis are limited to disease management, and there is a need for restorative treatments that can reverse progressive forms of the disease. This review aims to summarize the potential mechanisms by which antagonizing the M1 muscarinic acetylcholine receptor could promote remyelination and elaborate on a collection of promising antimuscarinic drugs, consolidating the knowledge needed to target these mechanisms and develop therapeutics that could reverse the progress of demyelinating diseases like multiple sclerosis.