Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia
Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia
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DOI：
10.1161/01.str.0000126044.83777.f4
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发表时间：
2004-06-01
期刊：
影响因子：
8.3
通讯作者：
Dalkara, T
中科院分区：
文献类型：
--
作者：
Gürsoy-Özdemir, Y;Can, A;Dalkara, T
背景和目的--由于延迟再灌注可能会导致脑出血和水肿，因此在中风中使用溶栓治疗受到治疗窗口较短的限制。现有的证据表明，超氧化物，NO和过氧亚硝酸盐在再灌注损伤中的作用。然而，取决于它们的细胞起源和它们之间的相互作用，这些分子可能发挥保护或有害的作用，这两个都不是在完整的brain. Methods的特点，使用荧光探针，我们确定了超氧化物和过氧亚硝酸盐形成神经元，星形胶质细胞和内皮细胞，以及氧化/硝化应激与小鼠脑血管损伤之间的关系。结果两种信号共定位，表明再灌注脑中过氧亚硝酸盐的主要来源是超氧化物和NO之间的反应。超氧化物和过氧亚硝酸盐的形成在微血管和周围的星形胶质细胞终足中特别强烈，并与密集的线粒体标记重叠。微血管上的氧化/硝化应激位点与血管损伤的标志物如伊文思蓝（EB）渗漏和基质金属蛋白酶-9（MMP-9）表达共定位，表明过氧亚硝酸盐与微血管损伤之间存在关联。支持这一想法，部分抑制内皮细胞NO的合成在再灌注低剂量的L-硝基精氨酸（1毫克/公斤IP）减少3-硝基酪氨酸形成微血管和EB extravasation.Conclusion-During再灌注，激烈的超氧化物，NO和过氧亚硝基形成微血管和周围的末端足可能会导致脑出血和水肿，破坏微血管的完整性。溶栓与减少氧化/硝化应激的药物联合使用可能会减少再灌注诱导的损伤，并延长溶栓的治疗窗。
Background and Purpose-Use of thrombolysis in stroke is limited by a short therapeutic window because delayed reperfusion may cause brain hemorrhage and edema. Available evidence suggests a role for superoxide, NO, and peroxynitrite in reperfusion-induced injury. However, depending on their cellular origin and interactions between them, these molecules may exert protective or deleterious actions, neither of which is characterized in the intact brain.Methods-Using fluorescent probes, we determined superoxide and peroxynitrite formation within neurons, astrocytes, and endothelium, and the association between oxidative/nitrative stress and vascular injury in mice brains subjected to 2-hour middle cerebral artery occlusion and 3 or 5 hours of reperfusion.Results-Both signals were colocalized, suggesting that the main source of peroxynitrite in the reperfused brain was a reaction between superoxide and NO. Superoxide and peroxynitrite formation was particularly intense in microvessels and astrocytic end-feet surrounding them, and overlapped with dense mitochondrial labeling. Sites of oxidative/nitrative stress on microvessels were colocalized with markers of vascular injury such as Evans blue (EB) leakage and matrix metalloproteinase-9 (MMP-9) expression, suggesting an association between peroxynitrite and microvascular injury. Supporting this idea, partial inhibition of endothelial NO synthesis at reperfusion with a low dose of L-nitroarginine (1 mg/kg IP) reduced 3-nitrotyrosine formation in microvessels and EB extravasation.Conclusion-During reperfusion, intense superoxide, NO, and peroxynitrite formation on microvessels and surrounding end-feet may lead to cerebral hemorrhage and edema by disrupting microvascular integrity. Combination of thrombolysis with agents diminishing oxidative/nitrative stress may reduce reperfusion-induced injury and extend the therapeutic window for thrombolysis.