FSD-C10, a Fasudil derivative, promotes neuroregeneration through indirect and direct mechanisms.
FSD-C10, a Fasudil derivative, promotes neuroregeneration through indirect and direct mechanisms.
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FSD-C10 是 Fasudil 衍生物，通过间接和直接机制促进神经再生
DOI：
10.1038/srep41227
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发表时间：
2017-01-23
影响因子：
4.6
通讯作者：
Ma CG
中科院分区：
文献类型：
--
作者：
Li YH;Xie C;Zhang Y;Li X;Zhang HF;Wang Q;Chai Z;Xiao BG;Thome R;Zhang GX;Ma CG
FSD-C10是一种法舒地尔的衍生物，通过调节免疫反应和诱导中枢神经系统(CNS)中的神经保护分子来减轻多发性硬化症(MS)动物模型实验性自身免疫性脑脊髓炎(EAE)的严重程度。然而，FSD-C10是否能促进神经再生尚不清楚。在本研究中，我们进一步分析了FSD-C10对神经保护和髓鞘再生的影响。FSD-C10处理的小鼠在中枢神经系统显示出更长、更厚和更强的MAP2和突触素阳性信号，CD4+T细胞、巨噬细胞和小胶质细胞明显减少。重要的是，经FSD-C10处理的小鼠的中枢神经系统显示激活的巨噬细胞/小胶质细胞从1型转变为2型，少突胶质前体细胞(OPC)和少突胶质细胞的数量增加，神经营养因子NT-3、GDNF和BDNF的水平增加。FSD-C10处理的小胶质细胞明显抑制Th1/Th17细胞的分化，增加IL-10+CD4+T细胞的数量；FSD-C10处理的小胶质细胞的条件培养液可促进OPC存活和少突胶质细胞成熟。在器官类型切片培养的化学诱导的脱髓鞘模型中，添加FSD-C10以BDNF依赖的方式直接促进重新髓鞘形成。总之，这些发现表明，FSD-C10通过涉及免疫调节和神经营养因子诱导的机制促进神经修复。
FSD-C10, a Fasudil derivative, was shown to reduce severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through the modulation of the immune response and induction of neuroprotective molecules in the central nervous system (CNS). However, whether FSD-C10 can promote neuroregeneration remains unknown. In this study, we further analyzed the effect of FSD-C10 on neuroprotection and remyelination. FSD-C10-treated mice showed a longer, thicker and more intense MAP2 and synaptophysin positive signal in the CNS, with significantly fewer CD4+T cells, macrophages and microglia. Importantly, the CNS of FSD-C10-treated mice showed a shift of activated macrophages/microglia from the type 1 to type 2 status, elevated numbers of oligodendrocyte precursor cells (OPCs) and oligodendrocytes, and increased levels of neurotrophic factors NT-3, GDNF and BDNF. FSD-C10-treated microglia significantly inhibited Th1/Th17 cell differentiation and increased the number of IL-10+CD4+T cells, and the conditioned medium from FSD-C10-treated microglia promoted OPC survival and oligodendrocyte maturation. Addition of FSD-C10 directly promoted remyelination in a chemical-induced demyelination model on organotypic slice culture, in a BDNF-dependent manner. Together, these findings demonstrate that FSD-C10 promotes neural repair through mechanisms that involved both immunomodulation and induction of neurotrophic factors.