DPP4抑制剂通过AMPK/SIRT1途径改善糖尿病合并缺血性卒中的作用机制研究

糖尿病患者罹患缺血性卒中的发病风险高，而且发生卒中严重程度高、出血转化和复发风险大。新型降糖药DPP4抑制剂不仅在降糖方面表现优越，在神经保护和血管内皮方面也具有潜在作用。申请人前期的研究证实脑微血管内皮细胞有DPP4受体的表达，DPP4抑制剂对低氧高糖环境中的大鼠脑微血管内皮有保护作用，且发现与SIRT1通路有关。研究发现SIRT1可通过激活线粒体未折叠蛋白反应（UPRmt）以保护线粒体的功能，防止神经元死亡。然而DPP4抑制剂保护糖尿病合并缺血性卒中的机制仍不清楚。因此，本申请项目拟在前期研究基础上，应用分子生物学方法从在体水平进一步证实DPP4抑制剂通过AMPK/SIRT1途径保护神经元和脑血管内皮细胞；利用在体和离体干预实验证实DPP4抑制剂通过调控AMPK/SIRT1信号通路，激活UPRmt，进而改善糖尿病患者的卒中预后。预期研究结果将为糖尿病合并缺血性卒中的治疗提供新的靶点。

The incidence of ischemic stroke is high in diabetic patients (DM). In addition, DM patients have high severity of stroke, poor therapeutic effect of intravenous thrombolysis, high hemorrhage transformation rate and high stroke recurrence rate. Previous clinical studies have found that DPP4 inhibitors, a new group of hypoglycemic drugs, not only show superior hypoglycemic effects, but also play potential roles in neuroprotection and vascular endothelium maintenance. Previous basic studies have confirmed that DPP4 receptors are expressed in brain microvascular endothelial cells, and the DPP4 inhibitor liralitine exerts protective effects on rat brain microvascular endothelial cells in hypoxic and hyperglycemic environments, in association with the SIRT1 pathway. Further literature analysis showed that SIRT1 could protect mitochondrial function and prevent neuronal cell death by activating the mitochondrial unfolded protein response (UPRmt). However, the mechanism by which DPP4 inhibitors exert protective effects in diabetes mellitus with ischemic stroke remain unclear. Therefore, this project aims to further verify that DPP4 inhibitors could protect brain microvascular cells and neurons from injury in vivo experiments and could regulate the AMPK/SIRT1 signaling pathway and activate the UPRmt to improve the prognosis of ischemic stroke in diabetic patients.The results of this study will provide new insights into the treatment of diabetes mellitus complicated with ischemic stroke.