Stroke has been considered the second leading cause of death worldwide, and ischemic stroke accounts for the vast majority of stroke cases. Some of the main features of ischemic stroke are increased brain permeability, ischemia/reperfusion injury, oxidative stress, and acute inflammation. Antagonism of cysLT1R has been shown to provide cardiovascular and neural benefits. In the present study, we investigated the effects of the cysLT1R antagonist zafirlukast both in vivo and in vitro using a middle cerebral artery occlusion (MCAO) mouse model and human brain microvascular endothelial cells (HBMVECs). In vivo, we found that zafirlukast pretreatment could reduce MCAO-induced increased brain permeability by rescuing the expression levels of the tight junction proteins occludin and ZO-1. In vitro, we found that zafirlukast could suppress the increase in endothelial monolayer permeability induced by OGD/R via rescue of occludin and ZO-1 expression; additionally, we found that zafirlukast prevented OGD/R-induced degradation of the extracellular matrix via inhibition of MMP-2 and MMP-9 expression. Finally, we found that zafirlukast could also inhibit OGD/R-induced activation of the critical proinflammatory regulator NF-κB by preventing phosphorylation and nuclear translocation of p65 protein. Together, our findings demonstrate a promising role for zafirlukast in preventing damage induced by ischemic stroke and reperfusion injury.

中文翻译：

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扎鲁司特保护缺血性脑损伤的血脑屏障完整性。

中风已被认为是世界范围内第二大死亡原因，缺血性中风占中风病例的绝大部分。缺血性中风的一些主要特征是脑通透性增加，缺血/再灌注损伤，氧化应激和急性炎症。cysLT1R的拮抗作用已显示可提供心血管和神经方面的益处。在本研究中，我们使用中脑动脉闭塞（MCAO）小鼠模型和人脑微血管内皮细胞（HBMVEC），研究了cysLT1R拮抗剂扎鲁司特在体内和体外的作用。在体内，我们发现扎鲁司特预处理可以通过挽救紧密连接蛋白occludin和ZO-1的表达水平来减少MCAO诱导的脑通透性增加。体外，我们发现扎鲁司特可以通过抢救occludin和ZO-1表达来抑制OGD / R诱导的内皮单层通透性的增加。此外，我们发现扎鲁司特通过抑制MMP-2和MMP-9的表达来阻止OGD / R诱导的细胞外基质降解。最后，我们发现扎鲁司特还可以通过防止p65蛋白的磷酸化和核易位来抑制OGD / R诱导的关键促炎性调节剂NF-κB的活化。在一起，我们的发现表明扎鲁司特在预防缺血性中风和再灌注损伤引起的损伤中具有有希望的作用。我们发现扎鲁司特通过抑制MMP-2和MMP-9的表达来阻止OGD / R诱导的细胞外基质降解。最后，我们发现扎鲁司特还可以通过防止p65蛋白的磷酸化和核易位来抑制OGD / R诱导的关键促炎性调节剂NF-κB的活化。在一起，我们的发现表明扎鲁司特在预防缺血性中风和再灌注损伤引起的损伤中具有有希望的作用。我们发现扎鲁司特通过抑制MMP-2和MMP-9的表达来阻止OGD / R诱导的细胞外基质降解。最后，我们发现扎鲁司特还可以通过防止p65蛋白的磷酸化和核易位来抑制OGD / R诱导的关键促炎性调节剂NF-κB的活化。在一起，我们的发现表明扎鲁司特在预防缺血性中风和再灌注损伤引起的损伤中具有有希望的作用。