小胶质细胞激活具有不同的极化表型和双重作用，诱导小胶质细胞由M1表型向M2表型转化是急性脑梗死再通治疗后抗脑缺血再灌注损伤的关键切入点。申请者发现：熊果酸可以通过激活PPARγ下调MCAO/R大鼠脑内M1表型标志物、上调M2表型标志物，由此纠正MMP/TIMP失衡，发挥神经保护作用。信息学预测PPARγ可与MMP-9及TIMP-1启动子结合，提示熊果酸可能是通过PPARγ调节MMP/TIMP失衡，诱导小胶质细胞向M2表型转化，但尚需研究证实。本项目在确认PPARγ与MMP-9及TIMP-1启动子结合关键位点的基础上，阐明熊果酸诱导小胶质细胞向M2表型转化的药理作用和分子机制，进一步明确熊果酸能改善脑缺血再灌注中神经元损伤。本研究有望为熊果酸成为有效的脑梗死急性期治疗药物提供新的理论基础，为调控小胶质细胞极化从而影响神经免疫微环境成为急性脑梗死治疗的切入点提供新的实验依据。

Microglia activation has different polarization phenotypes and dual effects, and the induction of microglia transformation from M1 phenotype to M2 phenotype is the key to neuroprotection in cerebral ischemia-reperfusion injury after acute cerebral infarction recanalization therapy. In precious studies, we found that ursolic acid can down-regulate M1 phenotypic markers in MCAO/R rats brain and up-regulate M2 phenotypic markers through activating PPARγ, thereby reducing MMP/TIMP imbalance and exerting neuroprotective effects. Bioinformatics predicted that PPARγ bound with MMP-9 and TIMP-1 promoters, suggesting that ursolic acid can reduce MMP/TIMP imbalance through PPARγ， and induce microglial M2 polarization. However, it still needs to be further studied. Based on the key PPAR response element confirmation of PPARγ bound with MMP-9 and TIMP-1 promoters, this project elucidated the molecular mechanism of ursolic acid promoted microglial M2 polarization and reduce MMP/TIMP imbalance via PPARγ activation. Furthermore, we also will establish a microglia/neuron co-culture system to verify the neuronal beneficial effects of ursolic acid mediated by inducing microglial M2 polarization. This study is expected to provide a new ideas for ursolic acid to be an effective treatment, and find novel targets for acute cerebral infarction therapy.