Chang Liping, Hu Li, Wei Cong, Zhang Hui, Liu Shen
National Key Laboratory of Collateral Disease Research and Innovative Chinese Medicine, Hebei Yiling Chinese Medicine Research Institute, Shijiazhuang, China.
Department of Medical Imaging, The First Affiliated Hospital of Shandong First Medical University, Jinan, China.
J Stroke Cerebrovasc Dis. 2020 Sep;29(9):105071. doi: 10.1016/j.jstrokecerebrovasdis.2020.105071. Epub 2020 Jun 30.
Chinese medicine Tongxinluo capsule (TXL) has been extensively used to treat ischemic stroke in China, and one of its mechanisms is to protect against blood brain barrier (BBB) disruption after stroke. However, the underlying protective mechanisms are not fully illuminated. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP-1) is involved in BBB disruption after brain ischemia. In this study, we explored whether TXL could downregulate LRP-1 expression and subsequently protect against BBB disruption after stroke using permanent middle cerebral artery occlusion (pMCAO) in mice.
The animal model of ischemic stroke was induced by pMCAO in male adult C57BL/6J mice. The mice were orally administered TXL (3.0 g/kg) at 1, 3 and 21 h after pMCAO. Meanwhile, the LRP-1 antagonist receptor associated protein (RAP) was intracerebroventricularly injected at 1 and 21 h after stroke. We measured the following parameters at 6 and 24 h: LRP-1 protein level, BBB leakage, and the expression of tight junction (TJ) proteins including occludin, claudin-5 and zonula occludens-1 (ZO-1).
Our results showed that TXL downregulated LRP-1 level, upregulated these TJ proteins level, and reduced BBB leakage in peri-infarct regions after pMCAO. Further study found that the inhibitor RAP played the same role as did TXL in upregulating these TJ proteins level and reducing BBB leakage after stroke.
Our study demonstrates that TXL protects against BBB disruption after stroke via inhibiting the LRP-1 pathway.
中药通心络胶囊（TXL）在中国已被广泛用于治疗缺血性中风，其作用机制之一是预防中风后血脑屏障（BBB）的破坏。然而，其潜在的保护机制尚未完全阐明。据报道，低密度脂蛋白受体相关蛋白1（LRP-1）参与脑缺血后血脑屏障的破坏。在本研究中，我们探讨了通心络胶囊是否能下调LRP-1表达，进而通过对小鼠进行永久性大脑中动脉闭塞（pMCAO）来预防中风后血脑屏障的破坏。
采用pMCAO法诱导雄性成年C57BL/6J小鼠建立缺血性中风动物模型。在pMCAO后1、3和21小时给小鼠口服通心络胶囊（3.0 g/kg）。同时，在中风后1和21小时脑室内注射LRP-1拮抗剂受体相关蛋白（RAP）。在6和24小时测量以下参数：LRP-1蛋白水平、血脑屏障渗漏以及紧密连接（TJ）蛋白包括闭合蛋白、Claudin-5和闭锁小带蛋白1（ZO-1）的表达。
我们的结果表明，通心络胶囊下调了LRP-1水平，上调了这些TJ蛋白水平，并减少了pMCAO后梗死周围区域的血脑屏障渗漏。进一步研究发现，抑制剂RAP在中风后上调这些TJ蛋白水平和减少血脑屏障渗漏方面与通心络胶囊发挥了相同的作用。
我们的研究表明，通心络胶囊通过抑制LRP-1途径预防中风后血脑屏障的破坏。
