Murayama Rumi, Cai Yi, Nakamura Hiroyuki, Hashimoto Kenji
Laboratory of Chemical Pharmacology, Chiba University Graduate School of Pharmaceutical Sciences, Chiba 260-8675, Japan; Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
Laboratory of Chemical Pharmacology, Chiba University Graduate School of Pharmaceutical Sciences, Chiba 260-8675, Japan.
Neurosci Biobehav Rev. 2025 Jul;174:106209. doi: 10.1016/j.neubiorev.2025.106209. Epub 2025 May 12.
Demyelination, defined as the loss of myelin sheaths around neuronal axons, is increasingly recognized as a key factor in a broad range of psychiatric and neurological disorders, including schizophrenia, major depressive disorder, bipolar disorder, post-traumatic stress disorder, autism spectrum disorder, substance use disorders, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review investigates the core mechanisms driving demyelination, its clinical impact, and emerging therapeutic strategies aimed at maintaining or restoring myelin integrity. Disruption of myelin impairs crucial neural communication pathways, resulting in cognitive, motor, and behavioral deficits that substantially reduce quality of life and create significant economic and social challenges. Key contributors to demyelination include genetic predisposition, environmental triggers, immune dysregulation, neuroinflammation, and alterations in the gut-brain axis mediated by the vagus nerve. Promising therapies include sphingosine 1-phosphate receptor modulators and muscarinic acetylcholine receptor antagonists, both of which diminish immune-related myelin damage and may enhance neuroprotection. In addition, the novel antidepressant arketamine appears to boost myelination through transforming growth factor-β1 signaling pathways. Approaches targeting the gut-brain axis, such as noninvasive transcutaneous auricular vagus nerve stimulation and fecal microbiota transplantation, may also help reduce inflammation and support myelin repair. Future research should center on clarifying the precise molecular mechanisms of demyelination, developing targeted therapies, and leveraging advanced neuroimaging for earlier detection and personalized treatment. By combining immunomodulatory and neuroprotective strategies, there is potential to significantly improve outcomes for individuals affected by demyelinating psychiatric and neurological disorders.
脱髓鞘被定义为神经元轴突周围髓鞘的丧失，越来越被认为是包括精神分裂症、重度抑郁症、双相情感障碍、创伤后应激障碍、自闭症谱系障碍、物质使用障碍、阿尔茨海默病、帕金森病和多发性硬化症在内的广泛精神和神经疾病的关键因素。本综述研究了驱动脱髓鞘的核心机制、其临床影响以及旨在维持或恢复髓鞘完整性的新兴治疗策略。髓鞘的破坏会损害关键的神经通讯通路，导致认知、运动和行为缺陷，从而大幅降低生活质量，并带来重大的经济和社会挑战。脱髓鞘的主要促成因素包括遗传易感性、环境触发因素、免疫失调、神经炎症以及由迷走神经介导的肠-脑轴改变。有前景的治疗方法包括鞘氨醇-1-磷酸受体调节剂和毒蕈碱型乙酰胆碱受体拮抗剂，两者都能减少与免疫相关的髓鞘损伤，并可能增强神经保护作用。此外，新型抗抑郁药阿氯胺酮似乎通过转化生长因子-β1信号通路促进髓鞘形成。针对肠-脑轴的方法，如非侵入性经皮耳迷走神经刺激和粪便微生物群移植，也可能有助于减轻炎症并支持髓鞘修复。未来的研究应集中在阐明脱髓鞘的确切分子机制、开发靶向治疗方法以及利用先进的神经影像学进行早期检测和个性化治疗。通过结合免疫调节和神经保护策略，有可能显著改善受脱髓鞘性精神和神经疾病影响的个体的治疗效果。
