Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia

被引:245
作者
Gürsoy-Özdemir, Y
Can, A
Dalkara, T
机构
[1] Hacettepe Univ, Inst Neurol Sci & Psychiat, Fac Med, Dept Neurol, Ankara, Turkey
[2] Ankara Univ, Sch Med, Dept Histol Embryol, TR-06100 Ankara, Turkey
关键词
blood-brain barrier; matrix metalloproteinases; nitric oxide; peroxynitrite; reactive oxygen species; reperfusion injury; thrombolysis;
D O I
10.1161/01.STR.0000126044.83777.f4
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:1449 / 1453
页数:5
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