School of Psychology, University of Leicester, Leicester, UK.
J Neurochem. 2014 Jun;129(5):816-26. doi: 10.1111/jnc.12681. Epub 2014 Mar 18.
Ischaemic strokes evoke blood-brain barrier (BBB) disruption and oedema formation through a series of mechanisms involving Rho-kinase activation. Using an animal model of human focal cerebral ischaemia, this study assessed and confirmed the therapeutic potential of Rho-kinase inhibition during the acute phase of stroke by displaying significantly improved functional outcome and reduced cerebral lesion and oedema volumes in fasudil- versus vehicle-treated animals. Analyses of ipsilateral and contralateral brain samples obtained from mice treated with vehicle or fasudil at the onset of reperfusion plus 4 h post-ischaemia or 4 h post-ischaemia alone revealed these benefits to be independent of changes in the activity and expressions of oxidative stress- and tight junction-related parameters. However, closer scrutiny of the same parameters in brain microvascular endothelial cells subjected to oxygen-glucose deprivation ± reperfusion revealed marked increases in prooxidant NADPH oxidase enzyme activity, superoxide anion release and in expressions of antioxidant enzyme catalase and tight junction protein claudin-5. Cotreatment of cells with Y-27632 prevented all of these changes and protected in vitro barrier integrity and function. These findings suggest that inhibition of Rho-kinase after acute ischaemic attacks improves cerebral integrity and function through regulation of endothelial cell oxidative stress and reorganization of intercellular junctions. Inhibition of Rho-kinase (ROCK) activity in a mouse model of human ischaemic stroke significantly improved functional outcome while reducing cerebral lesion and oedema volumes compared to vehicle-treated counterparts. Studies conducted with brain microvascular endothelial cells exposed to OGD ± R in the presence of Y-27632 revealed restoration of intercellular junctions and suppression of prooxidant NADPH oxidase activity as important factors in ROCK inhibition-mediated BBB protection.
缺血性中风通过一系列涉及 ROCK 激活的机制引起血脑屏障（BBB）破坏和水肿形成。本研究使用人类局灶性脑缺血动物模型，通过显示 fasudil 治疗组动物的功能结果明显改善，并且脑损伤和水肿体积减少，评估并证实了 ROCK 抑制在中风急性期的治疗潜力。在再灌注起始时用 fasudil 或载体处理的小鼠的对侧和同侧脑样本的分析表明，这些益处与氧化应激和紧密连接相关参数的活性和表达的变化无关。然而，在经历氧葡萄糖剥夺加再灌注的脑微血管内皮细胞中对相同参数进行更仔细的检查，揭示出促氧化剂 NADPH 氧化酶酶活性、超氧阴离子释放以及抗氧化酶过氧化氢酶和紧密连接蛋白 Claudin-5 的表达明显增加。细胞共处理 Y-27632 可防止所有这些变化，并保护体外屏障完整性和功能。这些发现表明，急性缺血攻击后 ROCK 抑制通过调节内皮细胞氧化应激和细胞间连接的重排来改善脑完整性和功能。与载体处理的对照相比，在人类缺血性中风的小鼠模型中，ROCK 活性的抑制显著改善了功能结果，同时减少了脑损伤和水肿体积。在存在 Y-27632 的情况下，用 OGD ± R 处理的脑微血管内皮细胞进行的研究揭示了细胞间连接的恢复和促氧化剂 NADPH 氧化酶活性的抑制作为 ROCK 抑制介导的 BBB 保护的重要因素。
