Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion
Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion
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DOI：
10.1161/01.str.0000083051.93319.28
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发表时间：
2003-08-01
期刊：
影响因子：
8.3
通讯作者：
Rosenberg, GA
中科院分区：
文献类型：
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作者：
Pfefferkorn, T;Rosenberg, GA
背景和目的：静脉注射重组组织纤溶酶原激活剂（rtPA）对缺血性卒中是有益的，尽管它会增加出血的风险和潜在的神经毒性作用。我们假设rtPA介导的不良反应取决于再灌注和损伤的血脑屏障（BBB）的时间。方法雄性Wistar大鼠有大脑中动脉闭塞（MCAO）的管腔内线程放置。缺血/再灌注的时间间隔分别为0/18、1.5/16.5、3/15、6/12、18/0和6/1小时。动物在再灌注时接受rtPA或生理盐水1小时，或者对于18/0试验，在MCAO后1小时开始。结果参数为死亡率、基质金属蛋白酶-2和-9（MMP-2和-9）浓度、组织血红蛋白和脑含水量。我们通过使用脑C-14[蔗糖]摄取方法分析了血脑屏障的通透性。分别在6/1和6/12只动物中检测MMP抑制剂BB-94对未接受rtPA治疗的BBB和接受rtPA治疗的死亡率的影响。
Background and Purpose-Intravenous recombinant tissue plasminogen activator (rtPA) can be beneficial in ischemic stroke despite an increased risk of hemorrhage and potential neurotoxic effects. We hypothesized that rtPA-mediated adverse effects depend on the timing of reperfusion and injury to the blood-brain barrier (BBB).Methods-Male Wistar rats had middle cerebral artery occlusion (MCAO) by intraluminal thread placement. Intervals of ischemia/reperfusion, respectively, in hours were 0/18, 1.5/16.5, 3/15, 6/12, 18/0, and 6/1. Animals received either rtPA or saline for 1 hour at the time of reperfusion or, for the 18/0 trial, starting 1 hour after MCAO. Outcome parameters were mortality, matrix metalloproteinase-2 and -9 (MMP-2 and -9) concentrations, tissue hemoglobin, and brain water content. We analyzed the permeability of the BBB by using the brain C-14[sucrose] uptake method. Effects of the MMP inhibitor BB-94 on the BBB without rtPA treatment and on mortality with rtPA were tested in animals with 6/1 and 6/12, respectively.Results-In delayed reperfusion (6/12), rtPA increased mortality from 17% to 83% (P