A RHO KINASE (ROCK) INHIBITOR, FASUDIL, PREVENTS MATRIX METALLOPROTEINASE-9-RELATED HEMORRHAGIC TRANSFORMATION IN MICE TREATED WITH TISSUE PLASMINOGEN ACTIVATOR
A RHO KINASE (ROCK) INHIBITOR, FASUDIL, PREVENTS MATRIX METALLOPROTEINASE-9-RELATED HEMORRHAGIC TRANSFORMATION IN MICE TREATED WITH TISSUE PLASMINOGEN ACTIVATOR
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DOI：
10.1016/j.neuroscience.2012.06.015
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发表时间：
2012-09-18
期刊：
影响因子：
3.3
通讯作者：
Hara, H.
中科院分区：
文献类型：
--
作者：
Ishiguro, M.;Kawasaki, K.;Hara, H.
组织纤溶酶原激活剂(TPA)溶栓是FDA批准的唯一治疗急性缺血性中风的方法。然而，出血性转化、神经毒性和较短的治疗时间窗构成了溶栓治疗的主要限制。本研究的目的是研究Rho激酶(ROCK)抑制剂法舒地尔是否能阻止tPA相关的出血性转化，并延长实验性卒中小鼠的再灌流窗口。小鼠大脑中动脉闭塞6h后，分别给予延迟性tPA、tPA联合法舒地尔或辅助剂治疗。分别于再灌流后18h和7d采用组织学和神经行为学方法评价治疗效果。为了进一步探讨法舒地尔的作用机制，我们还进行了tPA和法舒地尔对人脑微血管内皮细胞的体外研究。组织型纤溶酶原激活剂与法舒地尔联合治疗可阻止出血性转化的发展，但不能缩小梗塞体积。这些变化显著降低了再灌流后7d的死亡率，增加了运动能力。此外，这两种药物的使用都通过降低基质金属蛋白酶-9(MMP-9)的活性来防止对人脑内皮细胞的损伤。这些发现表明，法舒地尔至少部分地通过抑制内皮细胞中增加的基质金属蛋白酶-9的活性来阻止tPA治疗的小鼠局灶性脑缺血所致的出血性转化。(C)2012年IBRO。爱思唯尔有限公司出版。保留所有权利。
Thrombolysis with tissue plasminogen activator (tPA) is the only FDA-approved therapy for acute ischemic stroke. However, hemorrhagic transformation, neurotoxicity, and a short treatment time window comprise major limitations for thrombolytic therapy. The purpose of the present study was to investigate whether fasudil, a Rho kinase (ROCK) inhibitor, would prevent tPA-associated hemorrhagic transformation and extend the reperfusion window in an experimental stroke model in mice. Mice subjected to 6-h middle cerebral artery occlusion were treated with delayed tPA alone, with combined tPA plus fasudil, or with a vehicle. We used histological and neurobehavioral measures to assess the effects of the treatment at 18 h and 7 days after the reperfusion. To investigate the mechanism of fasudil's beneficial effects further, we also performed an in vitro study with tPA and fasudil in human brain microvascular endothelial cells. Combination therapy with tPA plus fasudil prevented the development of hemorrhagic transformation, but did not reduce the infarct volumes. These changes significantly reduced mortality and increased locomotor activity at 7 days after the reperfusion. Furthermore, the administration of both drugs prevented injury to the human brain endothelial cells via the reduction of matrix metalloproteinase-9 (MMP-9) activity. These findings indicate that fasudil prevents the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA, at least in part, by inhibiting the increased activity of MMP-9 in endothelial cells. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.