他汀类药物调控脑缺血再灌注损伤的自噬和脑水肿的研究

Recent studies have found that there is autophagic death in ischemic stroke in addition to necrotic cell death and apoptosis. Statins is only the neuroprotective drug recommended by the latest Guidelines for the Early Management of Patients With Acute Ischemic Stroke from AHA/ASA, which were supported by plenty of clinical evidence. Statins can increase the expression of anti-apoptotic Bcl-2, wihch can inhibits autophagy. Whether statins can regulate autophagy after cerebral ischemia-reperfusion injury? Statins can increase the expression of anti-apoptotic Bcl-2, wihch can inhibits autophagy. Whether statins can regulate autophagy after cerebral ischemia-reperfusion injury? What is the mechanism? Statins was also reported to have ability to reduce cerebral edema caused by cerebral ischemia.what mechanism is it? There were no relevant reports at home and abroad. So we make a study for this subject, SD rats are randomly divided into sham group, cerebral infarction , cerebral infarction + statin intervention group, cerebral infarction + high concentration of statin intervention group. we will observe the expression of autophagy cerebral edema and associated markers using HE staining, TTC staining, immunohistochemistry, fluorescence quantitative PCR, Western blotting and RNA silencing experiments. The mechanisms of statins effected autophagy and edema after ischemia - reperfusion injury will be showed by comparison between groups. This project will not only further improve the mechanism of statins in the treatment of ischemic stroke, but also broadens the function of statins.

近年来的研究发现缺血性脑卒中细胞死亡除了坏死、凋亡，还存在着自噬性死亡。他汀类药物是最新版美国缺血性脑卒中早期治疗指南中唯一推荐的急性期神经保护药物（有大量的临床证据支持）。他汀能通过上调Bcl-2抗凋亡，而Bcl-2能抑制自噬。那么他汀是否能调控脑缺血再灌注损伤的细胞自噬？又是通过什么机制调控呢？他汀类药物能减轻脑缺血引起的脑水肿，那么是通过什么作用机制呢？国内外均未见相关报道。本课题就此展开研究，将SD大鼠随机分为假手术组、脑缺血组、脑缺血+他汀干预组、脑缺血+高浓度他汀干预组，运用HE染色、TTC染色、免疫组化、荧光定量PCR、蛋白质印迹法、RNA沉默等实验技术，观察细胞自噬、脑水肿和相关调控蛋白的表达，通过各组之间进行比较，研究他汀类药物对脑缺血再灌注损伤的细胞自噬和脑水肿的作用及调控机制。本项目不仅进一步完善了他汀类药物在缺血性脑卒中治疗中的作用机制，还拓宽了他汀类药物的内涵。

近年来的研究发现缺血性脑卒中细胞死亡除了坏死、凋亡，还存在着自噬性死亡。他汀类药物从2014年起一直是美国缺血性脑卒中早治疗指南中唯一推荐的急性期神经保护药物（有大量的临床证据支持）。那么他汀是否能调控脑缺血再灌注损伤的细胞自噬？脑水肿是急性脑梗死的致死致残的重要病理生理变化，临床研究发现他汀能降低急性期脑梗死的死亡率和致残率，他汀类药物能否减轻脑缺血引起的脑水肿，那么是通过什么作用机制呢？国内外均未见相关报道。本课题就此展开研究，将SD大鼠随机分为假手术组、脑缺血再灌注组、脑缺血再灌注+阿托伐他汀他汀干预组、脑缺血再灌注+高剂量阿托伐他汀干预组，运用HE染色、TTC染色、免疫组化、荧光定量PCR、蛋白质印迹法、RNA沉默等实验技术，观察细胞自噬、脑水肿和相关调控蛋白的表达，通过各组之间进行比较，研究他汀类药物对脑缺血再灌注损伤的细胞自噬和脑水肿的作用及调控机制。本研究发现阿托伐他汀能通过上调BCL-2来抑制细胞自噬。还发现阿托伐他汀能通过控制PKA的磷酸化来在调控AQP4蛋白的变化，继而抑制脑缺血再灌注的脑水肿。本项目不仅进一步完善了他汀类药物在缺血性脑卒中治疗中的作用机制，还拓宽了他汀类药物的治疗价值。