Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke.
Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke.
复制标题
DOI：
10.2174/138161212802002625
复制
发表时间：
2012
影响因子：
3.1
通讯作者：
Davis TP
中科院分区：
文献类型：
--
作者：
Ronaldson PT;Davis TP
血脑屏障（BBB）是中枢神经系统稳态的重要调节因子。此外，BBB是有效CNS药物递送的最显著障碍。它具有特定的特征（即，紧密连接蛋白复合物、流入和流出转运蛋白），其控制包括治疗剂的循环溶质的渗透。为了形成这种“屏障”，脑微血管内皮细胞需要相邻星形胶质细胞和小胶质细胞的支持。这种复杂的关系也发生在内皮细胞和CNS的其他细胞类型和结构（即，周细胞、神经元、细胞外基质），这意味着存在“神经血管单位”。缺血性中风会在结构和功能水平上破坏神经血管单元，从而导致BBB泄漏增加。最近的研究已经确定了几种病理生理机制（即，氧化应激，激活精氨酸介导的细胞内信号传导系统），其介导缺血性中风期间神经血管单位的变化。这篇综述总结了这一领域的现有知识，并强调了途径（即，氧化应激、烟碱介导的细胞内信号传导、神经胶质表达的受体/靶标），其可以被操纵以i）在缺血性中风期间保持BBB和神经胶质完整性和ii）控制药物渗透和/或转运穿过BBB，以努力鉴定用于在缺血性中风的情况下优化治疗剂的CNS递送的新靶标。
The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. Additionally, the BBB is the most significant obstacle to effective CNS drug delivery. It possesses specific charcteristics (i.e., tight junction protein complexes, influx and efflux transporters) that control permeation of circulating solutes including therapeutic agents. In order to form this “barrier,” brain microvascular endothelial cells require support of adjacent astrocytes and microglia. This intricate relationship also occurs between endothelial cells and other cell types and structures of the CNS (i.e., pericytes, neurons, extracellular matrix), which implies existence of a “neurovascular unit.” Ischemic stroke can disrupt the neurovascular unit at both the structural and functional level, which leads to an increase in leak across the BBB. Recent studies have identified several pathophysiological mechanisms (i.e., oxidative stress, activation of cytokine-mediated intracellular signaling systems) that mediate changes in the neurovascular unit during ischemic stroke. This review summarizes current knowledge in this area and emphasizes pathways (i.e., oxidative stress, cytokine-mediated intracellular signaling, glial-expressed receptors/targets) that can be manipulated pharmacologically for i) preservation of BBB and glial integrity during ischemic stroke and ii) control of drug permeation and/or transport across the BBB in an effort to identify novel targets for optimization of CNS delivery of therapeutics in the setting of ischemic stroke.