Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection
Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection
复制标题
DOI：
10.1152/ajpcell.00095.2018
复制
发表时间：
2018-09-01
影响因子：
5.5
通讯作者：
Ronaldson, Patrick T.
中科院分区：
文献类型：
--
作者：
Abdullahi, Wazir;Tripathi, Dinesh;Ronaldson, Patrick T.
血脑屏障（BBB）是一种物理和生化屏障，精确地控制大脑的稳态。它还在调节内源性和外源性外源性异生物质和相关代谢物的血脑流量中发挥核心作用。这是通过脑微血管内皮细胞的分子特征，如紧密连接蛋白复合物和流入和流出转运蛋白的功能表达来实现的。缺血性卒中的病理生理学特征之一是血脑屏障的破坏，其显著促进脑损伤和随后的神经功能损害的发展。BBB损伤的生化特征包括紧密连接组成蛋白的表达降低和组织改变以及内源性BBB转运蛋白的功能表达的调节。因此，迫切需要开发可以保护免受BBB功能障碍（即，血管保护）。这些策略包括靶向紧密连接以确保它们保持其正确的结构或靶向转运蛋白以控制生理底物的通量以保护内皮稳态。在这篇综述中，我们将描述脑微血管内皮细胞导致脑卒中后血脑屏障功能障碍的病理生理机制。此外，我们将利用这一最先进的知识，提供新的药理学策略，可以开发，赋予缺血性中风的BBB保护的见解。
The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely controls cerebral homeostasis. It also plays a central role in the regulation of blood-to-brain flux of endogenous and exogenous xenobiotics and associated metabolites. This is accomplished by molecular characteristics of brain microvessel endothelial cells such as tight junction protein complexes and functional expression of influx and efflux transporters. One of the pathophysiological features of ischemic stroke is disruption of the BBB, which significantly contributes to development of brain injury and subsequent neurological impairment. Biochemical characteristics of BBB damage include decreased expression and altered organization of tight junction constituent proteins as well as modulation of functional expression of endogenous BBB transporters. Therefore, there is a critical need for development of novel therapeutic strategies that can protect against BBB dysfunction (i.e., vascular protection) in the setting of ischemic stroke. Such strategies include targeting tight junctions to ensure that they maintain their correct structure or targeting transporters to control flux of physiological substrates for protection of endothelial homeostasis. In this review, we will describe the pathophysiological mechanisms in cerebral microvascular endothelial cells that lead to BBB dysfunction following onset of stroke. Additionally, we will utilize this state-of-the-art knowledge to provide insights on novel pharmacological strategies that can be developed to confer BBB protection in the setting of ischemic stroke.