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FSD-C10，一种法舒地尔衍生物，通过间接和直接机制促进神经再生。

FSD-C10, a Fasudil derivative, promotes neuroregeneration through indirect and direct mechanisms.

机构信息

Institute of Brain Science, Datong key Laboratory of Molecular and Cell Immunology, Shanxi Datong University, Datong, 037009, China.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

出版信息

Sci Rep. 2017 Jan 23;7:41227. doi: 10.1038/srep41227.

DOI:10.1038/srep41227
PMID:28112256
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5255566/
Abstract

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.

摘要

FSD-C10 是法舒地尔的衍生物，已被证明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实验性自身免疫性脑脊髓炎（EAE），多发性硬化症（MS）的动物模型的严重程度。然而，FSD-C10 是否能促进神经再生尚不清楚。在这项研究中，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 治疗的小鼠在 CNS 中显示出更长、更厚和更强烈的 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，FSD-C10 治疗的小鼠的 CNS 中激活的巨噬细胞/小胶质细胞从 1 型向 2 型状态转变，少突胶质细胞前体细胞（OPC）和少突胶质细胞数量增加，神经营养因子 NT-3、GDNF 和 BDNF 水平升高。FSD-C10 处理的小胶质细胞显著抑制 Th1/Th17 细胞分化并增加 IL-10 CD4 T 细胞的数量，来自 FSD-C10 处理的小胶质细胞的条件培养基促进 OPC 存活和少突胶质细胞成熟。FSD-C10 的添加直接通过器官型切片培养中的化学诱导脱髓鞘模型以 BDNF 依赖性方式促进髓鞘再生。总之，这些发现表明 FSD-C10 通过涉及免疫调节和诱导神经营养因子的机制促进神经修复。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/9cc5ffa4f820/srep41227-f11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/9044a00c59da/srep41227-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/253429f566b0/srep41227-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/53e34e438b29/srep41227-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/f4f7a719659e/srep41227-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/970e11e9fef1/srep41227-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/2f7a7085dd52/srep41227-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/10f57911b859/srep41227-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/90f3e23560a0/srep41227-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/96b8b50cef49/srep41227-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/9cc5ffa4f820/srep41227-f11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/9044a00c59da/srep41227-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/cc68d9e10e39/srep41227-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/253429f566b0/srep41227-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/53e34e438b29/srep41227-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/f4f7a719659e/srep41227-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/970e11e9fef1/srep41227-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/2f7a7085dd52/srep41227-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/10f57911b859/srep41227-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/90f3e23560a0/srep41227-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/96b8b50cef49/srep41227-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc31/5255566/9cc5ffa4f820/srep41227-f11.jpg

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