Gharagozloo Marjan, Mace Jackson W, Calabresi Peter A
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, United States.
Front Mol Neurosci. 2022 Nov 3;15:995477. doi: 10.3389/fnmol.2022.995477. eCollection 2022.
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). In people with MS, impaired remyelination and axonal loss lead to debilitating long-term neurologic deficits. Current MS disease-modifying drugs mainly target peripheral immune cells and have demonstrated little efficacy for neuroprotection or promoting repair. To elucidate the pathological mechanisms and test therapeutic interventions, multiple animal models have been developed to recapitulate specific aspects of MS pathology, particularly the acute inflammatory stage. However, there are few animal models that facilitate the study of remyelination in the presence of inflammation, and none fully replicate the biology of chronic demyelination in MS. In this review, we describe the animal models that have provided insight into the mechanisms underlying demyelination, myelin repair, and potential therapeutic targets for remyelination. We highlight the limitations of studying remyelination in toxin-based demyelination models and discuss the combinatorial models that recapitulate the inflammatory microenvironment, which is now recognized to be a major inhibitor of remyelination mechanisms. These models may be useful in identifying novel therapeutics that promote CNS remyelination in inflammatory diseases such as MS.
多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性、脱髓鞘性和神经退行性疾病。在MS患者中，髓鞘再生受损和轴突丢失导致长期使人衰弱的神经功能缺损。目前的MS疾病修正药物主要针对外周免疫细胞，对神经保护或促进修复的疗效甚微。为了阐明病理机制并测试治疗干预措施，已经开发了多种动物模型来重现MS病理的特定方面，特别是急性炎症阶段。然而，很少有动物模型有助于研究炎症存在时的髓鞘再生，而且没有一个能完全复制MS中慢性脱髓鞘的生物学过程。在这篇综述中，我们描述了一些动物模型，这些模型为脱髓鞘、髓鞘修复的潜在机制以及髓鞘再生的潜在治疗靶点提供了见解。我们强调了在基于毒素的脱髓鞘模型中研究髓鞘再生的局限性，并讨论了重现炎症微环境的组合模型，现在人们认识到炎症微环境是髓鞘再生机制的主要抑制剂。这些模型可能有助于识别促进MS等炎症性疾病中CNS髓鞘再生的新型疗法。
