Blockade of platelet glycoprotein receptor Ib ameliorates blood-brain barrier disruption following ischemic stroke via Epac pathway
Blockade of platelet glycoprotein receptor Ib ameliorates blood-brain barrier disruption following ischemic stroke via Epac pathway
复制标题
阻断血小板糖蛋白受体 Ib 可通过 Epac 途径改善缺血性中风后血脑屏障的破坏。
DOI：
10.1016/j.biopha.2021.111698
复制
发表时间：
2021-05-22
影响因子：
7.5
通讯作者：
Zhou, Lanlan
中科院分区：
文献类型：
--
作者：
Chu, Wei;Sun, Xuemei;Zhou, Lanlan
糖蛋白（GP）Ib是暴露于血管损伤的血小板膜受体复合物，被提议作为中风治疗的有效靶点。以往的研究表明，GPIb拮抗剂Anfibatide（ANF）可减轻脑缺血/再灌注（CI/R）损伤后血脑屏障（BBB）的破坏。本研究旨在探讨ANF对血脑屏障的改善是否通过Epac信号通路介导。采用短暂性大脑中动脉闭塞（MCAO）90 min后建立小鼠CI/R损伤模型。再灌注后1h静脉注射ANF（4 μ g/kg）。ANF可改善血脑屏障破坏，增加紧密连接蛋白表达，抑制F-actin细胞骨架重排，降低缺血脑组织通透性，减轻脑水肿。ANF治疗的小鼠比MCAO小鼠有更小的梗死体积和更轻的神经功能缺损。此外，ANF和Epac 1激动剂在MCAO小鼠中的作用非常相似。用cAMP类似物8-CPT-2 '-O-Me-cAMP激活Epac减轻了BBB功能的破坏和CI/R损伤。Epac特异性拮抗剂ESI-09加重了屏障损伤和脑损伤，拮抗了ANF提供的保护作用。此外，ANF上调缺血大脑皮层Epac 1蛋白的表达。总的来说，我们的研究结果表明，脑缺血/再灌注后，心钠素对血脑屏障的保护作用，可以归因于Epac通路的激活。
Glycoprotein (GP) Ib is a platelet membrane receptor complex exposed to vascular injury, proposed as an effective target for stroke therapy. Previously, we have observed that the GPIb antagonist anfibatide (ANF) could mitigate blood-brain barrier (BBB) disruption following cerebral ischemia/reperfusion (CI/R) injury. The current study was designed to investigate whether the amelioration of the BBB by ANF is mediated via the Epac signaling pathway. A murine model of CI/R injury was induced following 90 min of transient middle cerebral artery occlusion (MCAO). ANF (4 mu g/kg) was intravenously injected 1 h after reperfusion. Herein, ANF ameliorated BBB disruption, increased the expression of tight junction proteins, suppressed F-actin cytoskeleton rearrangement, decreased the permeability of the ischemic brain tissue, and relieved brain edema. ANF-treated mice had smaller infarct volumes and less severe neurological deficits than the MCAO mice. Moreover, the effects of ANF and Epac1 agonists were very similar in the MCAO mice. Epac activation with a cAMP analog, 8-CPT-2 '-O-Me-cAMP, mitigated the breakdown of BBB function and CI/R injury. The Epac specific antagonist, ESI-09, worsened barrier damage and cerebral impairment, antagonizing the protective effects afforded by ANF. In addition, ANF upregulated the expression of Epac1 protein in the ischemic cerebral cortex. Collectively, our results indicate that the protective effect of ANF on the BBB after CI/R could be attributed to the activation of the Epac pathway.