Protein S confers neuronal protection during ischemic/hypoxic injury in mice
Protein S confers neuronal protection during ischemic/hypoxic injury in mice
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DOI：
10.1161/01.cir.0000058460.34453.5a
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发表时间：
2003-04-08
期刊：
影响因子：
37.8
通讯作者：
Zlokovic, BV
中科院分区：
文献类型：
--
作者：
Liu, D;Guo, H;Zlokovic, BV
背景蛋白S是一种抗血栓因子，也具有促有丝分裂活性。因此，我们假设，蛋白S可以控制脑血管血栓形成中风和保护脑组织缺血性injuries.Methods和结果，我们研究了蛋白S在小鼠体内模型中风和体外模型的神经元缺氧/复氧损伤。动物接受纯化的人血浆衍生的蛋白S或载体静脉注射后10分钟开始大脑中动脉闭塞，然后再灌注。0.2至2 mg/kg的蛋白S显著改善了运动神经功能缺损3.8至3.2倍，并分别减少了45%至54%和45%至62%的梗死和水肿体积。2 mg/kg的蛋白S改善缺血后脑血流量21%至26%，并分别减少脑纤维蛋白沉积和中性粒细胞浸润40%和53%。使用蛋白S未观察到脑内出血。蛋白S以时间和剂量依赖性方式保护缺血神经元和培养神经元免受缺氧/复氧诱导的凋亡。重组人蛋白S产生保护作用，从缺氧引起的损伤类似的血浆衍生的蛋白S在体内和vitro. Conclusions蛋白S是一个重要的神经保护剂在缺血性脑损伤与直接影响神经元和抗血栓形成的效果。因此，蛋白S可能是一类新的临床中风药物的原型，具有直接的神经元保护作用和全身抗血栓形成和血栓形成活性。
Background-Protein S is an antithrombotic factor that also exhibits mitogenic activity. Thus, we hypothesized that protein S may control cerebrovascular thrombosis in stroke and protect brain tissue from ischemic injury.Methods and Results-We studied protein S in a murine in vivo model of stroke and an in vitro model of neuronal hypoxia/reoxygenation injury. Animals received purified human plasma-derived protein S or vehicle intravenously 10 minutes after initiation of middle cerebral artery occlusion followed by reperfusion. Protein S at 0.2 to 2 mg/kg significantly improved the motor neurological deficit by 3.8- to 3.2-fold and reduced infarction and edema volumes by 45% to 54% and 45% to 62%, respectively. Protein S at 2 mg/ kg improved postischemic cerebral blood flow by 21% to 26% and reduced brain fibrin deposition and infiltration with neutrophils by 40% and 53%, respectively. Intracerebral bleeding was not observed with protein S. Protein S protected ischemic neurons in vivo and cultured neurons from hypoxia/reoxygenation-induced apoptosis in a time- and dose-dependent manner. Recombinant human protein S exerted protective effects from hypoxia-induced damage similar to the plasma-derived protein S both in vivo and in vitro.Conclusions-Protein S is a significant neuroprotectant during ischemic brain injury with direct effects on neurons and antithrombotic effects. Thus, protein S could be a prototype of a new class of agents for clinical stroke with combined direct neuronal protective effects and systemic antithrombotic and antiinflammatory activities.