Mei Feng, Mayoral Sonia R, Nobuta Hiroko, Wang Fei, Desponts Caroline, Lorrain Daniel S, Xiao Lan, Green Ari J, Rowitch David, Whistler Jennifer, Chan Jonah R
Department of Neurology, University of California, San Francisco, California 94158, Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, 400038, China, and.
Department of Neurology, University of California, San Francisco, California 94158.
J Neurosci. 2016 Jul 27;36(30):7925-35. doi: 10.1523/JNEUROSCI.1493-16.2016.
Remyelinating therapies seek to promote restoration of function and normal cellular architecture following demyelination in diseases, such as multiple sclerosis (MS). Functional screening for small molecules or novel targets for remyelination is a major hurdle to the identification and development of rational therapeutics for MS. Recent findings and technical advances provide us with a unique opportunity to provide insight into the cell autonomous mechanisms for remyelination and address this unmet need. Upon screening a G-protein-coupled receptor small-molecule library, we report the identification of a cluster of κ-opioid receptor (KOR) agonists that significantly promotes oligodendrocyte differentiation and myelination. KOR agonists were validated in purified rat oligodendroglial cultures, and the (±)U-50488 compound proved to be most effective for differentiation. (±)U-50488 treatment significantly enhances differentiation and myelination in purified oligodendroglial cocultures and greatly accelerates the kinetics of remyelination in vivo after focal demyelination with lysolecithin. The effect of (±)U-50488 is attenuated by KOR antagonists and completely abolished in KOR-null oligodendroglia. Conditional deletion of KOR in murine oligodendrocyte precursor cells (OPCs) greatly inhibits remyelination after focal demyelination lacking any response to (±)U-50488 treatment. To determine whether agonism of KOR represents a feasible therapeutic approach, human induced pluripotent stem cell-derived OPCs were treated with (±)U-50488. Consistent with findings, differentiation of human OPCs into mature oligodendrocytes was significantly enhanced. Together, KOR is a therapeutic target to consider for future remyelination therapy.
Remyelination represents a promising strategy to achieve functional recovery in demyelinating diseases, like MS. Thus, identification of potent compounds and targets that promote remyelination represents a critically unmet need. This study reports a cluster of compounds that are highly effective in enhancing remyelination and identifies κ-opioid receptor (KOR) as a positive regulator for oligodendroglial differentiation, implicating KOR agonism as a potential strategy to accelerate remyelination.
髓鞘再生疗法旨在促进疾病（如多发性硬化症，MS）脱髓鞘后功能和正常细胞结构的恢复。对小分子或新型髓鞘再生靶点进行功能筛选是确定和开发MS合理疗法的主要障碍。最近的研究发现和技术进步为我们提供了一个独特的机会，来深入了解髓鞘再生的细胞自主机制，并满足这一未被满足的需求。在筛选G蛋白偶联受体小分子文库后，我们报告鉴定出一组κ-阿片受体（KOR）激动剂，它们能显著促进少突胶质细胞分化和髓鞘形成。KOR激动剂在纯化的大鼠少突胶质细胞培养物中得到验证，（±）U-50488化合物被证明对分化最有效。（±）U-50488处理显著增强了纯化的少突胶质细胞共培养物中的分化和髓鞘形成，并极大地加速了卵磷脂局部脱髓鞘后体内髓鞘再生的动力学。（±）U-50488的作用被KOR拮抗剂减弱，并在KOR基因敲除的少突胶质细胞中完全消除。在小鼠少突胶质前体细胞（OPC）中条件性删除KOR，极大地抑制了局部脱髓鞘后的髓鞘再生，且对（±）U-50488处理无任何反应。为了确定KOR激动是否代表一种可行的治疗方法，用人诱导多能干细胞衍生的OPC用（±）U-50488处理。与研究结果一致，人OPC向成熟少突胶质细胞的分化显著增强。总之，KOR是未来髓鞘再生治疗可考虑的一个治疗靶点。
髓鞘再生是在脱髓鞘疾病（如MS）中实现功能恢复的一种有前景的策略。因此，鉴定促进髓鞘再生的有效化合物和靶点是一个迫切未被满足的需求。本研究报告了一组在增强髓鞘再生方面非常有效的化合物，并确定κ-阿片受体（KOR）是少突胶质细胞分化的正调节因子，这意味着KOR激动是加速髓鞘再生的一种潜在策略。
