Yagi Kenji, Kitazato Keiko T, Uno Masaaki, Tada Yoshiteru, Kinouchi Tomoya, Shimada Kenji, Nagahiro Shinji
Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Stroke. 2009 Feb;40(2):626-31. doi: 10.1161/STROKEAHA.108.520262. Epub 2008 Dec 18.
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.
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-kappaB) activity in rtPA-stimulated human microvascular endothelial cells (HBECs).
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-kappaB activation.
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-kappaB activation in HBECs. Edaravone may render thrombolytic therapy safer for the administration of rtPA in patients with ischemic stroke.
重组组织型纤溶酶原激活剂（rtPA）诱发的缺血性脑卒中脑出血与基质金属蛋白酶-9（MMP-9）活性增加有关。急性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抑制rtPA诱发脑出血的机制。
将体重250至280克的雄性Wistar大鼠进行3小时短暂大脑中动脉闭塞（MCAO），并随机分为3组。再灌注后立即给1组静脉注射10毫克/千克rtPA，另一组注射rtPA加3毫克/千克依达拉奉，第3组不进行治疗。我们在缺血24小时后评估脑内出血量和MMP-9活性。我们还研究了rtPA刺激的人微血管内皮细胞（HBECs）中MMP-9的活性、其mRNA表达以及核因子-κB（NF-κB）活性。
单独用rtPA治疗的大鼠出血程度和内皮细胞源性MMP-9水平升高，而用rtPA加依达拉奉治疗的大鼠则减轻。在rtPA刺激的HBECs中，依达拉奉以剂量依赖方式抑制MMP-9的活性和mRNA表达。依达拉奉还抑制NF-κB激活。
我们证明依达拉奉通过抑制体内MMP-9表达来抑制rtPA诱发的大鼠缺血性脑内出血，这在HBECs中MMP-9表达和NF-κB激活受到抑制得到证实。依达拉奉可能使rtPA在缺血性脑卒中患者中的溶栓治疗更安全。
