PSD95通路在微循环障碍相关的急性缺血性卒中血管开通后无复流现象中的作用及机制研究

血管再通被证实是急性缺血性卒中有效的治疗方法，术后血管成功开通率极高，但由于开通后无复流导致“无效再灌”使部分病人无法获得良好神经功能预后，其发生机制尚不明确。最新临床研究显示，PDS95抑制剂可能通过减少下游产物过氧亚硝酸盐改善急性血管再通治疗患者预后。同时基础研究证实，过氧亚硝酸盐水平升高可引起周细胞收缩，导致微循环结构改变及功能异常。故我们提出假说，脑缺血后GluN2B-PSD95-nNOS通路介导过氧亚硝酸盐产生，引起微循环周细胞持续收缩，导致微循环障碍及血管开通后无复流。本研究将通过建立缺血再灌注动物模型，采用阻断GluN2B-PSD95-nNOS通路靶点的分组设计，使用动物组织学、结构影像学、免疫组化及行为学评价，多维联合验证PSD95信号通路对脑微循环结构及功能的作用，探索其对脑灌注及神经功能的影响，寻找产生无效再灌这一临床难题的靶点，为血管开通转化及临床研究提供新的理论依据

Endovascular therapy is an effective treatment for acute ischemic stroke. The successful rate of recanalization is as high as 90%. However, due to the no-reflow phenomenon after recanalization, some patients can not get a good prognosis of neurological function, and its mechanism and upstream pathway are still not clear. The latest clinical research shows that PDS95 pathway inhibitor can improve the neurological function of some patients underwent acute Endovascular therapy, which may be related to the reduction of peroxynitrite downstream of the pathway. Furthermore, the basic research confirmed that peroxynitrite injection into the brain can cause the contraction of pericyte, thus leading to the changes in microcirculation structure and dysfunction. Therefore, we propose the hypothesis that GluN2B-PSD95-nNOS pathway mediates the production of peroxynitrite, which causes the continuous contraction of microcirculatory cells, leads to microcirculation disorder and no-reflow after recanalization. In this study, we will establish the animal model of cerebral ischemia-reperfusion, through blocking the target pathway or grouping design of intervention products, use the multi-dimensional evaluation include of animal histology, imaging, immunohistochemistry, and behavior to verify the role of PSD95 pathway on the structure and function of microcirculation, and explore its impact on brain perfusion and nerve function. It provides a new theoretical basis for the basic and clinical research of reperfusion treatment and is of great significance to supplement the basic theory of invalid recanalization.