Chen Keren, Park Eunyoung, Abd-Elrahman Khaled S
Department of Anaesthesiology, Pharmacology and Therapeutics, and Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada.
Department of Anaesthesiology, Pharmacology and Therapeutics, and Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada; Department of Medical Sciences, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Mol Pharmacol. 2025 Apr;107(4):100027. doi: 10.1016/j.molpha.2025.100027. Epub 2025 Feb 28.
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 Ca 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.
多发性硬化症（MS）的患病率正在上升；然而，仍需要能够逆转该疾病进展的治疗方法。一种显示出有望逆转MS的策略是通过抑制M1受体进行髓鞘再生，M1受体是毒蕈碱型乙酰胆碱受体（mAChR）家族的成员。拮抗M1 mAChR被认为是氯马斯汀发挥促髓鞘形成作用的机制，氯马斯汀是一种正在研发的药物，在动物研究和II期临床试验中已观察到其可增强髓鞘形成。最近的研究表明，阻断M1 mAChR可能通过细胞外信号调节激酶途径促进少突胶质细胞分化，调节钙浓度振荡，并与N-甲基-D-天冬氨酸和Notch-1受体相互作用。然而，最近发现氯马斯汀会加速MS患者的残疾，这阻碍了其临床试验的进一步进展。尽管如此，仍可使用其他抗毒蕈碱药物靶向氯马斯汀拮抗M1 mAChR后的潜在机制。本综述总结了我们对拮抗M1 mAChR促进髓鞘再生机制的最新认识进展，并概述了未来可用于治疗MS的其他抗毒蕈碱药物。意义声明：目前用于治疗多发性硬化症的方法仅限于疾病管理，需要能够逆转疾病进展形式的恢复性治疗方法。本综述旨在总结拮抗M1毒蕈碱型乙酰胆碱受体促进髓鞘再生的潜在机制，并详细阐述一系列有前景的抗毒蕈碱药物，整合针对这些机制和开发可逆转多发性硬化症等脱髓鞘疾病进展的治疗方法所需的知识。
