Platelet glycoprotein receptor Ib blockade ameliorates experimental cerebral ischemia-reperfusion injury by strengthening the blood-brain barrier function and anti-thrombo-inflammatory property
Platelet glycoprotein receptor Ib blockade ameliorates experimental cerebral ischemia-reperfusion injury by strengthening the blood-brain barrier function and anti-thrombo-inflammatory property
复制标题
DOI：
10.1016/j.bbi.2017.11.019
复制
发表时间：
2018-03-01
影响因子：
15.1
通讯作者：
Zhou, Lanlan
中科院分区：
文献类型：
--
作者：
Chen, Chunyan;Li, Tingting;Zhou, Lanlan
血脑屏障（BBB）破坏、血栓形成和免疫介导的炎症反应是脑缺血再灌注损伤的重要病理生理过程，但目前尚无法进行有效的治疗干预。最近的研究提供了越来越多的证据表明，阻断血小板糖蛋白（GP）受体Ib可能是治疗急性缺血性卒中的新靶点。本研究旨在探讨GPIB α抑制剂（安非巴肽）对小鼠脑缺血再灌注损伤模型的治疗效果及其潜在机制。雄性小鼠进行右侧大脑中动脉闭塞（MCAO）90分钟，然后再灌注24小时。再灌注后1h静脉注射安非巴肽（1、2、4 μ g/kg）或替罗非班。结果表明，安非巴肽能明显缩小脑梗死体积，增加完整神经细胞数，改善神经行为功能。此外，安非巴肽可通过显著降低缺血侧脑组织细胞旁通透性而减轻缺血后血脑屏障损伤。中风引起的巨噬细胞-1抗原（MAC-1）和P-选择素的活性和蛋白表达的增加也被安非巴肽干预减少。最后，安非巴肽通过减少微血栓形成的数量对中风发挥抗血栓形成作用。这是首次证明安非巴肽在保护BBB完整性和减少MAC-1介导的中性粒细胞炎症反应方面的功效，以及在再灌注期间抑制脑中的微血栓形成。安非巴肽作为一种很有前途的抗血栓-炎症药物，可能对缺血性脑卒中的治疗有益。(C)2017爱思唯尔公司All rights reserved.
Blood-brain barrier (BBB) disruption, thrombus formation and immune-mediated inflammation are important steps in the pathophysiology of cerebral ischemia-reperfusion injury but are still inaccessible to therapeutic interventions. Recent studies have provided increasing evidence that blocking of platelet glycoprotein (GP) receptor Ib might represent a novel target in treating acute ischemic stroke. This research was conducted to explore the therapeutic efficacy and potential mechanisms of GPIb alpha inhibitor (anfibatide) in a model of brain ischemia-reperfusion injury in mice. Male mice underwent 90 min of right middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. Anfibatide (1, 2, 4 ug/kg) or tirofiban were administered intravenously 1 h after reperfusion. The results showed that anfibatide could significantly reduce infarct volumes, increase the number of intact neuronal cells and improve neurobehavioral function. Moreover, anfibatide could reduce post ischemic BBB damage by attenuating increased paracellular permeability in the ischemia hemisphere significantly. Stroke-induced increases in activity and protein expression of macrophage-1 antigen (MAC-1) and P-selectin were also reduced by anfibatide intervention. Finally, anfibatide exerted antithrombotic effects upon stroke by decreased the number of microthrombi formation. This is the first demonstration of anfibatide's efficacy in protecting the BBB integrity and decreasing neutrophil inflammation response mediated by MAC-1 besides microthrombus formation inhibition in the brain during reperfusion. Anfibatide, as a promising anti-thrombo-inflammation agent, could be beneficial for the treatment of ischemic stroke. (C) 2017 Elsevier Inc. All rights reserved.