Maier Carolina M, Hsieh Lily, Crandall Trisha, Narasimhan Purnima, Chan Pak H
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5487, USA.
Ann Neurol. 2006 Jun;59(6):929-38. doi: 10.1002/ana.20850.
Early reperfusion after an ischemic stroke can cause blood-brain barrier injury with subsequent cerebral edema and devastating brain hemorrhage. These complications of early reperfusion, which result from excess production of reactive oxygen species, significantly limit the benefits of stroke therapies. In this article, we use a novel animal model that facilitates identification of specific components of the reperfusion injury process, including vascular injury and secondary brain damage, and allows assessment of therapeutic interventions.
Knock-out (KO) mice containing 50% manganese-superoxide dismutase activity (SOD2-KO) and transgenic mice overexpressing SOD2 undergo transient focal ischemia and reperfusion followed by assessment of infarct, edema, hemorrhage rates, metalloproteinase activation, and microvascular injury.
SOD2-KO mice demonstrate delayed (>24h) blood-brain barrier breakdown associated with activation of matrix metalloproteinases, inflammation, and high brain hemorrhage rates. These adverse consequences are absent in wild-type littermates and minocycline-treated SOD2-KO animals. Increased hemorrhage rates also are absent in SOD2 overexpressors, which have reduced vascular endothelial cell death. Finally, we show that the tight junction membrane protein, occludin, is an early and specific target in oxidative stress-induced microvascular injury.
This model is ideal for studying ischemia/reperfusion-induced vascular injury and secondary brain hemorrhage and offers a unique opportunity to evaluate antioxidant-based neurovascular protective strategies as potential adjunct treatments to currently approved stroke therapies such as thrombolysis and endovascular clot retrieval.
缺血性中风后的早期再灌注可导致血脑屏障损伤，继而引发脑水肿和严重的脑出血。这些早期再灌注并发症是由活性氧的过量产生所致，显著限制了中风治疗的益处。在本文中，我们使用了一种新型动物模型，该模型有助于识别再灌注损伤过程的特定组成部分，包括血管损伤和继发性脑损伤，并允许评估治疗干预措施。
含有50%锰超氧化物歧化酶活性的敲除（KO）小鼠（SOD2-KO）和过表达SOD2的转基因小鼠经历短暂性局灶性缺血和再灌注，随后评估梗死、水肿、出血率、金属蛋白酶激活和微血管损伤。
SOD2-KO小鼠表现出延迟（>24小时）的血脑屏障破坏，伴有基质金属蛋白酶激活、炎症和高脑出血率。野生型同窝小鼠和用米诺环素治疗的SOD2-KO动物不存在这些不良后果。SOD2过表达小鼠也不存在出血率增加的情况，其血管内皮细胞死亡减少。最后，我们表明紧密连接膜蛋白闭合蛋白是氧化应激诱导的微血管损伤的早期和特异性靶点。
该模型是研究缺血/再灌注诱导的血管损伤和继发性脑出血的理想模型，并提供了一个独特的机会来评估基于抗氧化剂的神经血管保护策略，作为目前批准的中风治疗（如溶栓和血管内取栓）的潜在辅助治疗方法。
