麻醉药右美托咪定通过促进脑微血管内皮分泌CCN1保护血脑屏障的机制研究

项目名称： 麻醉药右美托咪定通过促进脑微血管内皮分泌CCN1保护血脑屏障的机制研究

项目编号： No.81501021

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 尹红

作者单位： 中国医科大学

项目金额： 17.5万元

中文摘要： 阐明全身麻醉药作用的分子机制具有重要的临床指导价值。新近研究指出，一些吸入麻醉药可能参与破坏血脑屏障进一步影响大脑微环境的稳定，造成脑损伤。申请者首次通过体内和体外实验发现，静脉麻醉药右美托咪定具有保护血脑屏障的作用；通过基因芯片筛选，申请者找到了右美托咪定的潜在靶分子——CCN1蛋白，观察到右美托咪定可以促进脑微血管内皮细胞分泌CCN1，且CCN1蛋白具有保护血脑屏障的作用。这促成了本项目的工作假说，即右美托咪定通过促进脑微血管内皮细胞分泌CCN1，作用于血脑屏障上的相应整联蛋白受体，从而维护血脑屏障完整性，减轻脑损伤。本项目拟深入分析右美托咪定保护血脑屏障的分子机制，并探讨右美托咪定对吸入麻醉药异氟烷破坏血脑屏障的阻断作用。本项目可望鉴定一条新的由右美托咪定启动的调控血脑屏障通透性的信号通路，拓展我们对右美托咪定作用机理的认识，并为全身麻醉药作用机制的研究提供新的切入点。

中文关键词： 全身麻醉药；右美托咪定；脑微血管内皮细胞；CCN1；血脑屏障

英文摘要： It is of great clinical significance to clarify the effects of general anesthetics and its underlying mechanism. Recent studies show that some of inhaled anesthetics may be involved in the disruption of the blood-brain barrier and changes of the homeostasis of micro-environment in brain. Our recent studies showed that the anesthetics dexmedetomidine played a role to protect the blood-brain barrier; the results of Microarray analysis showed that the potential target gene of dexmedetomidine is CCN1, and dexmedetomidine promotes the secretion of CCN1 from cerebral microvascular endothelial cells, and the purified protein of CCN1 has protective effect in maintenance of the blood-brain barrier. Here we raised the hypothesis that dexmedetomidine promotes the secretion of CCN1 from cerebral microvascular endothelial cells, and then the released CCN1 interacts with the specific integrin receptor, which help to maintain the integrity of the blood-brain barrier. In this study, the molecular mechanisms of dexmedetomidine in protecting the blood-brain barrier from disruption will be explored, and the blocking effect of dexmedetomidine to attenuate the damage of the blood-brain barrier induced by inhalation anesthetics isoflurane will be analyzed. A new signaling pathway induced by dexmedetomidine to regulate the permeability of the blood-brain barrier will be shown, which will expand our understanding of the mechanism of dexmedetomidine and provide a new research highlight to the study of the effects of general anesthetics.

英文关键词： General anesthetics;Dexmedetomidine;Brain microvascular endothelial cells;CCN1;Blood brain barrier