D1 receptor-mediated endogenous tPA upregulation contributes to blood-brain barrier injury after acute ischaemic stroke
D1 receptor-mediated endogenous tPA upregulation contributes to blood-brain barrier injury after acute ischaemic stroke
复制标题
D1 受体介导的内源性 tPA 上调导致急性缺血性中风后血脑屏障损伤。
DOI：
10.1111/jcmm.15570
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发表时间：
2020-08-01
影响因子：
5.3
通讯作者：
Zheng, Guoqing
中科院分区：
文献类型：
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作者：
Wang, Yan;Wang, Xiaona;Zheng, Guoqing
在溶栓时间窗内血脑屏障（BBB）完整性损伤正成为减少出血转化（HT）的关键目标。我们以前曾报道过，急性缺血性卒中后，血脑屏障损伤最初发生在非梗死纹状体。然而，其内在机制尚不清楚。由于急性缺血性脑卒中可诱导纹状体多巴胺释放显著增加，本研究旨在利用大鼠大脑中动脉闭塞模型，探讨多巴胺受体信号通路在急性缺血后血脑屏障完整性损伤中的作用。结果表明，脑缺血2 h可引起血脑屏障损伤区内源性组织纤溶酶原激活物（tPA）显著增加，纹状体内注射tPA抑制剂neuroserpin可明显减轻脑缺血2 h引起的血脑屏障损伤。此外，纹状体内输注D1受体拮抗剂SCH 23390可显著降低缺血诱导的内源性tPA上调，同时降低BBB损伤和occludin降解。更重要的是，缺氧诱导因子-1 α抑制剂YC-1显着降低2小时缺血诱导的内源性tPA上调和血脑屏障损伤。总之，我们的数据表明，急性缺血通过HIF-1 α上调激活内源性tPA破坏BBB，因此代表了一种新的治疗靶点，用于保护急性缺血性卒中后的BBB。
Blood-brain barrier (BBB) integrity injury within the thrombolytic time window is becoming a critical target to reduce haemorrhage transformation (HT). We have previously reported that BBB damage was initially damaged in non-infarcted striatum after acute ischaemia stroke. However, the underlying mechanism is not clear. Since acute ischaemic stroke could induce a significant increase of dopamine release in striatum, in current study, our aim is to investigate the role of dopamine receptor signal pathway in BBB integrity injury after acute ischaemia using rat middle cerebral artery occlusion model. Our data showed that 2-h ischaemia induced a significant increase of endogenous tissue plasminogen activator (tPA) in BBB injury area and intra-striatum infusion of tPA inhibitor neuroserpin, significantly alleviated 2-h ischaemia-induced BBB injury. In addition, intra-striatum infusion of D1 receptor antagonist SCH23390 significantly decreased ischaemia-induced upregulation of endogenous tPA, accompanied by decrease of BBB injury and occludin degradation. More important, inhibition of hypoxia-inducible factor-1 alpha with inhibitor YC-1 significantly decreased 2-h ischaemia-induced endogenous tPA upregulation and BBB injury. Taken together, our data demonstrate that acute ischaemia disrupted BBB through activation of endogenous tPA via HIF-1 alpha upregulation, thus representing a new therapeutic target for protecting BBB after acute ischaemic stroke.