Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Japan.
Glia. 2013 Mar;61(3):420-31. doi: 10.1002/glia.22445. Epub 2012 Dec 22.
Estrogen exerts neuroprotective and promyelinating actions. The therapeutic effect has been shown in animal models of multiple sclerosis, in which the myelin sheath is specifically destroyed in the central nervous system. However, it remains unproven whether estrogen is directly involved in remyelination via the myelin producing cells, oligodendrocytes, or which estrogen receptors are involved. In this study, we found that the membrane-associated estrogen receptor, the G protein-coupled receptor 30 (GPR30), also known as GPER, was expressed in oligodendrocytes in rat spinal cord and corpus callosum. Moreover, GPR30 was expressed throughout oligodendrocyte differentiation and promyelinating stages in primary oligodendrocyte cultures derived from rat spinal cords and brains. To evaluate the role of signaling via GPR30 in promyelination, a specific agonist for GPR30, G1, was administered to a rat model of demyelination induced by cuprizone treatment. Histological examination of the corpus callosum with oligodendrocyte differentiation stage-specific markers showed that G1 enhanced oligodendrocyte maturation in corpus callosum of cuprizone-treated animals. It also enhanced oligodendrocyte ensheathment of dorsal root ganglion (DRG) neurons in co-culture and myelination in cuprizone-treated animals. This study is the first evidence that GPR30 signaling promotes remyelination by oligodendrocytes after demyelination. GPR30 ligands may provide a novel therapy for the treatment of multiple sclerosis.
雌激素具有神经保护和促进髓鞘形成的作用。这种治疗效果已在多发性硬化症的动物模型中得到证实，多发性硬化症是中枢神经系统中髓鞘被特异性破坏的疾病。然而，雌激素是否通过产生髓鞘的细胞——少突胶质细胞，直接参与髓鞘再生，以及涉及哪种雌激素受体，仍未得到证实。在这项研究中，我们发现膜相关的雌激素受体，G 蛋白偶联受体 30（GPR30），也称为 GPER，在大鼠脊髓和胼胝体的少突胶质细胞中表达。此外，GPR30 在源自大鼠脊髓和大脑的原代少突胶质细胞培养物中，在少突胶质细胞分化和促进髓鞘形成的阶段均有表达。为了评估 GPR30 信号转导在促进髓鞘形成中的作用，我们用 GPR30 的特异性激动剂 G1 处理由杯状醇诱导的脱髓鞘大鼠模型。用少突胶质细胞分化阶段特异性标志物对胼胝体进行组织学检查的结果表明，G1 增强了杯状醇处理动物胼胝体中的少突胶质细胞成熟。它还增强了少突胶质细胞对背根神经节（DRG）神经元的包绕以及杯状醇处理动物的髓鞘形成。这项研究首次证明，GPR30 信号转导在脱髓鞘后促进少突胶质细胞的髓鞘再生。GPR30 配体可能为多发性硬化症的治疗提供一种新的疗法。
