M1/M2型小胶质细胞的比例在神经炎症和神经元再生中扮演着重要角色。雌激素膜受体GPER、NF-κB和ERK信号可能参与这一过程。课题组前期研究发现，植物雌激素——淫羊藿素（ICT）对脑缺血具有很好的保护作用和较宽的治疗时间窗；减轻脑缺血再灌注诱导的炎症反应，提高新生神经元标志物的表达；减少小胶质细胞向M1型极化；抑制NF-κB活化，促进ERK激活。结合文献报道GPER对ERK和NF-κB的调控作用，提出假说：ICT通过GPER激活ERK，对NF-κB信号产生抑制，调控小胶质细胞极化，从而减轻脑缺血诱导的神经炎症并促进后期神经元再生。本项目拟从以下三个方面证明假说：①明确ICT是否调控脑缺血诱导的小胶质细胞极化；②ICT限制脑缺血诱导的炎症反应并促进神经元再生；③ICT对小胶质细胞极化的调控是通过GPER-ERK-NF-κB信号通路实现的。为缺血性脑病的防治提供新的线索。

The ratio of microglia M1/M2 phenotypes plays a very important role in the neuroinflammation and neurogenesis, that process may involved in G protein-coupled estrogen receptor, NF-κB and ERK. Our previous results shown that ICT, a Phytoestrogen, can protect the rats with cerebral ischemia reperfusion (CIR) injury very well with a quite wide therapeutic time window, reduce inflammatory response induced by cerebral ischemia-reperfusion and increase the expression of neonatal neuron markers, regulate microglia polarization, and also can inhibit the activation of NF-κB but increase the level of p-ERK. According to our findings and the regulating effect of GPER on ERK and NF-κB, we hypothesize that ICT activates ERK and inhibits NF-κB signaling via acting on GPER, which will regulate the microglia polarization, and then reduce the neuroinflammation and promote the neurogenesis in cerebral ischemia. To prove the hypothesis, we plan to carry out the project in vitro and in vivo for the three purposes as follow: firstly, to determine the role of ICT in the regulation of microglia polarization during CIR injury; secondly, to confirm that ICT limits inflammatory response induced by cerebral ischemia and promotes neuronal regeneration; lastly, to reveal that the molecular mechanism of ICT modulating microglia polarization is via GPER-ERK-NF-κB signal pathway. Thus, this project will provide a new clue for the clinical preventive medication and treatment of ischemic cerebrovascular disease.