Edaravone, a Free Radical Scavenger, Inhibits MMP-9-Related Brain Hemorrhage in Rats Treated With Tissue Plasminogen Activator
Edaravone, a Free Radical Scavenger, Inhibits MMP-9-Related Brain Hemorrhage in Rats Treated With Tissue Plasminogen Activator
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DOI：
10.1161/strokeaha.108.520262
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发表时间：
2009-02-01
期刊：
影响因子：
8.3
通讯作者：
Nagahiro, Shinji
中科院分区：
文献类型：
--
作者：
Yagi, Kenji;Kitazato, Keiko T.;Nagahiro, Shinji
背景和目的：缺血性卒中中重组组织型纤溶酶原激活剂（rtPA）诱导的脑出血可归因于基质金属蛋白酶-9（MMP-9）活性的增加。急性脑梗死患者可从神经保护药物依达拉奉（一种自由基清除剂）中获益。我们研究了依达拉奉可能有助于抑制rtPA诱导的脑出血的机制。方法-对体重250至280 g的雄性Wistar大鼠进行3小时短暂性大脑中动脉闭塞（MCAO），并随机分为3组。再灌注后即刻1组静脉注射rtPA 10 mg/kg，另1组静脉注射rtPA+依达拉奉3 mg/kg，第3组不作任何处理。检测脑缺血后24小时脑出血量和MMP-9活性。我们还研究了MMP-9的活性，其mRNA的表达，和核因子-κ B（NF-κ B）的活性在rtPA刺激的人微血管内皮细胞（HBECs. Results-the出血程度和内皮细胞衍生的MMP-9的水平与rtPA单独治疗的大鼠和rtPA加依达拉奉治疗的大鼠减弱。在rtPA刺激的HBEC中，依达拉奉以剂量依赖性方式抑制MMP-9的活性和mRNA表达。依达拉奉也抑制NF-κ B activation. Conclusion-We证明依达拉奉抑制rtPA诱导的脑出血大鼠缺血脑通过抑制MMP-9的表达在体内，这是由抑制MMP-9的表达和NF-κ B激活HBECs证实。依达拉奉可能使rtPA溶栓治疗在缺血性卒中患者中更安全。（中风。2009;40：626-631）。
Background and Purpose-Intracerebral hemorrhage, induced by recombinant tissue plasminogen activator (rtPA) in ischemic stroke, is attributable to the increased activity of matrix metalloproteinase-9 (MMP-9). Patients with acute infarct benefit from the neuroprotective drug edaravone, a free radical scavenger. We examined the mechanisms by which edaravone may help to suppress rtPA-induced brain hemorrhage.Methods-Male Wistar rats weighing 250 to 280 g were subjected to 3-hour transient middle cerebral artery occlusion (MCAO) and divided randomly into 3 groups. Immediately after reperfusion, 1 group was intravenously injected with 10 mg/kg rtPA, another with rtPA plus 3 mg/kg edaravone, and the 3rd group received no treatment. We assessed the hemorrhage volume and the activity of MMP-9 in the brain 24 hours postischemia. We also studied the activity of MMP-9, its mRNA expression, and nuclear factor-kappa B (NF-kappa B) activity in rtPA-stimulated human microvascular endothelial cells (HBECs).Results-The degree of hemorrhage and the level of endothelial cell-derived MMP-9 were elevated in rats treated with rtPA alone and attenuated in rats treated with rtPA plus edaravone. In rtPA-stimulated HBECs, edaravone suppressed the activity and mRNA expression of MMP-9 in a dose-dependent manner. Edaravone also inhibited NF-kappa B activation.Conclusions-We demonstrate that edaravone inhibits rtPA-induced cerebral hemorrhage in the ischemic brain of rats via the inhibition of MMP-9 expression in vivo, which is substantiated by inhibition of MMP-9 expression and NF-kappa B activation in HBECs. Edaravone may render thrombolytic therapy safer for the administration of rtPA in patients with ischemic stroke. (Stroke. 2009;40:626-631.)