Diosgenin promotes oligodendrocyte progenitor cell differentiation through estrogen receptor-mediated ERK1/2 activation to accelerate remyelination
Diosgenin promotes oligodendrocyte progenitor cell differentiation through estrogen receptor-mediated ERK1/2 activation to accelerate remyelination
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作者：
Xiao, Lin;Guo, Dazhi;He, Cheng
少突胶质细胞祖细胞（oligodendrocytes, OPCs）分化为成熟的少突胶质细胞是脱髓鞘后再生的先决条件，这一过程的损伤被认为是再生失败的主要原因。薯蓣皂苷元是一种植物衍生的类固醇，已被用于许多疾病的治疗，但对其对中枢神经系统的作用知之甚少。在这项研究中，我们使用纯化的大鼠OPC培养模型，我们发现薯蓣皂苷元显著和特异性地促进OPC分化，而不影响OPC的活力、增殖或迁移。有趣的是，薯蓣皂苷元的作用可被雌激素受体（ER）拮抗剂ICI 182780阻断，而不能被糖皮质激素和孕激素受体拮抗剂RU38486阻断，也不能被矿皮质激素受体拮抗剂螺内酯阻断。此外，研究发现，ER- α和ER- β在OPC中均有表达，薯蓣皂苷元可通过ER激活OPC中的细胞外信号调节激酶1/2 （ERK1/2）。薯蓣皂苷元的促分化作用也可被ERK抑制剂PD98059阻断。此外，在铜酮诱导的脱髓鞘模型中，Luxol快速蓝染色、MBP免疫组织化学和实时RT-PCR检测表明，给药红皂素显著加速/增强了脱髓鞘。薯蓣皂苷元也增加了胼胝体中成熟少突胶质细胞的数量，但不影响OPCs的数量。综上所述，我们的研究结果表明，薯蓣皂苷元通过er介导的ERK1/2激活途径促进OPC向成熟少突胶质细胞的分化，从而加速髓鞘再生，这意味着这种甾体天然产物在多发性硬化症（MS）等脱髓鞘疾病中的新治疗用途。(C) 2012 Wiley期刊公司
Differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes is a prerequisite for remyelination after demyelination, and impairment of this process is suggested to be a major reason for remyelination failure. Diosgenin, a plant-derived steroid, has been implicated for therapeutic use in many diseases, but little is known about its effect on the central nervous system. In this study, using a purified rat OPC culture model, we show that diosgenin significantly and specifically promotes OPC differentiation without affecting the viability, proliferation, or migration of OPC. Interestingly, the effect of diosgenin can be blocked by estrogen receptor (ER) antagonist ICI 182780 but not by glucocorticoid and progesterone receptor antagonist RU38486, nor by mineralocorticoid receptor antagonist spirolactone. Moreover, it is revealed that both ER-alpha and ER-beta are expressed in OPC, and diosgenin can activate the extracellular signal-regulated kinase 1/2 (ERK1/2) in OPC via ER. The pro-differentiation effect of diosgenin can also be obstructed by the ERK inhibitor PD98059. Furthermore, in the cuprizone-induced demyelination model, it is demonstrated that diosgenin administration significantly accelerates/enhances remyelination as detected by Luxol fast blue stain, MBP immunohistochemistry and real time RT-PCR. Diosgenin also increases the number of mature oligodendrocytes in the corpus callosum while it does not affect the number of OPCs. Taking together, our results suggest that diosgenin promotes the differentiation of OPC into mature oligodendrocyte through an ER-mediated ERK1/2 activation pathway to accelerate remyelination, which implicates a novel therapeutic usage of this steroidal natural product in demyelinating diseases such as multiple sclerosis (MS). (C) 2012 Wiley Periodicals, Inc.