Developmental Biology Institute of Marseille-Luminy, French National Center for Scientific Research Joint Research Unit, Universite de la Mediterranee, France.
Ann Neurol. 2012 Feb;71(2):213-26. doi: 10.1002/ana.22593.
Multiple sclerosis is a neurodegenerative disease characterized by episodes of immune attack of oligodendrocytes leading to demyelination and progressive functional deficit. One therapeutic strategy to address disease progression could consist in stimulating the spontaneous regenerative process observed in some patients. Myelin regeneration requires endogenous oligodendrocyte progenitor migration and activation of the myelination program at the lesion site. In this study, we have tested the ability of olesoxime, a neuroprotective and neuroregenerative agent, to promote remyelination in the rodent central nervous system in vivo.
The effect of olesoxime on oligodendrocyte progenitor cell (OPC) differentiation and myelin synthesis was tested directly in organotypic slice cultures and OPC-neuron cocultures. Using naive animals and different mouse models of demyelination, we morphologically and functionally assessed the effect of the compound on myelination in vivo.
Olesoxime accelerated oligodendrocyte maturation and enhanced myelination in vitro and in vivo in naive animals during development and also in the adult brain without affecting oligodendrocyte survival or proliferation. In mouse models of demyelination and remyelination, olesoxime favored the repair process, promoting myelin formation with consequent functional improvement.
Our observations support the strategy of promoting oligodendrocyte maturation and myelin synthesis to enhance myelin repair and functional recovery. We also provide proof of concept that olesoxime could be useful for the treatment of demyelinating diseases.
多发性硬化症是一种神经退行性疾病，其特征是寡突胶质细胞发生免疫攻击，导致脱髓鞘和进行性功能缺陷。一种针对疾病进展的治疗策略可能包括刺激一些患者中观察到的自发再生过程。髓鞘再生需要内源性少突胶质前体细胞迁移和在病变部位激活髓鞘形成程序。在这项研究中，我们测试了 olesoxime（一种神经保护和神经再生剂）促进啮齿动物中枢神经系统内髓鞘再生的能力。
直接在器官型切片培养物和少突胶质前体细胞-神经元共培养物中测试 olesoxime 对少突胶质前体细胞（OPC）分化和髓鞘合成的影响。使用未处理的动物和不同的脱髓鞘小鼠模型，我们从形态和功能上评估了该化合物在体内对髓鞘形成的影响。
在发育过程中，olesoxime 加速了少突胶质细胞的成熟并增强了体外和体内未处理动物的髓鞘形成，在成年大脑中也增强了髓鞘形成而不影响少突胶质细胞的存活或增殖。在脱髓鞘和髓鞘再生的小鼠模型中，olesoxime 促进了修复过程，促进了髓鞘形成，从而导致功能改善。
我们的观察结果支持促进少突胶质细胞成熟和髓鞘合成以增强髓鞘修复和功能恢复的策略。我们还提供了概念验证，表明 olesoxime 可用于治疗脱髓鞘疾病。
