Wang Xiaoying, Rosell Anna, Lo Eng H
Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
CNS Neurol Disord Drug Targets. 2008 Jun;7(3):235-42. doi: 10.2174/187152708784936635.
To date, tPA-based thrombolytic therapy is the only FDA-approved treatment for achieving vascular reperfusion and clinical benefit, but this agent is given to only about 2-5% of stroke patients in the United States of America. This may be related, in part, to the elevated risks of symptomatic intracranial hemorrhage, and the consequently reduced therapeutic time window. Recent efforts have aimed at identifying new combination strategies that might increase thrombolytic efficacy of tPA to benefit reperfusion, while reducing its associated neurotoxicity and hemorrhagic complications. Emerging experimental studies demonstrate that the breakdown of neurovascular matrix initiates blood-brain barrier disruption with edema and/or hemorrhage. Perturbation of extracellular homeostasis triggered by dysregulated extracellular proteases may underlie processes responsible for the hemorrhagic complications of thrombolytic stroke therapy. This short review summarizes experimental investigations of this field in pre-clinical stroke models. The data strongly suggest that targeting the extracellular matrix proteolytic imbalance within the neurovascular unit may provide new approaches for improving the safety and efficacy of thrombolytic reperfusion therapy of stroke.
迄今为止，基于组织型纤溶酶原激活剂（tPA）的溶栓疗法是美国食品药品监督管理局（FDA）批准的唯一可实现血管再灌注并带来临床益处的治疗方法，但在美国只有约2% - 5%的中风患者接受这种治疗。这可能部分与症状性颅内出血风险升高以及随之而来的治疗时间窗缩短有关。最近的研究致力于寻找新的联合策略，以提高tPA的溶栓效果，促进再灌注，同时降低其相关的神经毒性和出血并发症。新出现的实验研究表明，神经血管基质的破坏会引发血脑屏障破坏，并伴有水肿和/或出血。细胞外蛋白酶失调引发的细胞外稳态紊乱可能是溶栓性中风治疗出血并发症的潜在原因。这篇简短的综述总结了该领域在临床前中风模型中的实验研究。数据强烈表明，针对神经血管单元内细胞外基质蛋白水解失衡可能为提高中风溶栓再灌注治疗的安全性和有效性提供新方法。
