Adibhatla Rao Muralikrishna, Hatcher James F
Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
CNS Neurol Disord Drug Targets. 2008 Jun;7(3):243-53. doi: 10.2174/187152708784936608.
Today there exists only one FDA-approved treatment for ischemic stroke; i.e., the serine protease tissue-type plasminogen activator (tPA). In the aftermath of the failed stroke clinical trials with the nitrone spin trap/radical scavenger, NXY-059, a number of articles raised the question: are we doing the right thing? Is the animal research truly translational in identifying new agents for stroke treatment? This review summarizes the current state of affairs with plasminogen activators in thrombolytic therapy. In addition to therapeutic value, potential side effects of tPA also exist that aggravate stroke injury and offset the benefits provided by reperfusion of the occluded artery. Thus, combinational options (ultrasound alone or with microspheres/nanobubbles, mechanical dissociation of clot, activated protein C (APC), plasminogen activator inhibitor-1 (PAI-1), neuroserpin and CDP-choline) that could offset tPA toxic side effects and improve efficacy are also discussed here. Desmoteplase, a plasminogen activator derived from the saliva of Desmodus rotundus vampire bat, antagonizes vascular tPA-induced neurotoxicity by competitively binding to low-density lipoprotein related-receptors (LPR) at the blood-brain barrier (BBB) interface, minimizing the tPA uptake into brain parenchyma. tPA can also activate matrix metalloproteinases (MMPs), a family of endopeptidases comprised of 24 mammalian enzymes that primarily catalyze the turnover and degradation of the extracellular matrix (ECM). MMPs have been implicated in BBB breakdown and neuronal injury in the early times after stroke, but also contribute to vascular remodeling, angiogenesis, neurogenesis and axonal regeneration during the later repair phase after stroke. tPA, directly or by activation of MMP-9, could have beneficial effects on recovery after stroke by promoting neurovascular repair through vascular endothelial growth factor (VEGF). However, any treatment regimen directed at MMPs must consider their pleiotropic nature and the likelihood of either beneficial or detrimental effects that might depend on the timing of the treatment in relation to the stage of brain injury.
目前，美国食品药品监督管理局（FDA）仅批准了一种用于缺血性中风的治疗方法，即丝氨酸蛋白酶组织型纤溶酶原激活剂（tPA）。在硝酮自旋捕捉剂/自由基清除剂NXY - 059的中风临床试验失败后，许多文章提出了一个问题：我们做的事情对吗？动物研究在确定中风治疗新药物方面真的具有转化价值吗？这篇综述总结了纤溶酶原激活剂在溶栓治疗中的现状。除了治疗价值外，tPA还存在潜在的副作用，这些副作用会加重中风损伤并抵消闭塞动脉再灌注带来的益处。因此，本文还讨论了一些联合治疗方案（单独使用超声或与微球/纳米气泡联合使用、机械分解血栓、活化蛋白C（APC）、纤溶酶原激活剂抑制剂 - 1（PAI - 1）、神经丝氨酸蛋白酶和胞磷胆碱），这些方案可以抵消tPA的毒性副作用并提高疗效。去氨普酶是一种源自吸血蝙蝠圆叶吸血蝠唾液的纤溶酶原激活剂，它通过在血脑屏障（BBB）界面竞争性结合低密度脂蛋白相关受体（LPR），拮抗血管tPA诱导的神经毒性，从而减少tPA进入脑实质。tPA还可以激活基质金属蛋白酶（MMPs），这是一个由24种哺乳动物酶组成的内肽酶家族，主要催化细胞外基质（ECM）的周转和降解。MMPs在中风后的早期与血脑屏障破坏和神经元损伤有关，但在中风后的后期修复阶段也有助于血管重塑、血管生成、神经发生和轴突再生。tPA直接或通过激活MMP - 9，可能通过血管内皮生长因子（VEGF）促进神经血管修复，从而对中风后的恢复产生有益影响。然而，任何针对MMPs的治疗方案都必须考虑它们的多效性以及可能取决于治疗时间与脑损伤阶段关系的有益或有害影响的可能性。
