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首页> 外文期刊>Neuroscience: An International Journal under the Editorial Direction of IBRO >PROTEASE ACTIVATED RECEPTOR-1 MEDIATES CYTOTOXICITY DURING ISCHEMIA USING IN VIVO AND IN VITRO MODELS
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PROTEASE ACTIVATED RECEPTOR-1 MEDIATES CYTOTOXICITY DURING ISCHEMIA USING IN VIVO AND IN VITRO MODELS

机译：激活的蛋白酶-1受体介导体内和体外模型在缺血过程中介导细胞毒性

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Protease activated receptors (PARs) populate neurons and astrocytes in the brain. The serine protease thrombin, which activates PAR-1 during the first hours after stroke, appears to be associated with the cytotoxicity. Thrombin antagonists and PAR-1 inhibitors have been correlated with reduced cell death and behavioral protection after stroke, but no data yet support a mechanistic link between PAR-1 action and benefit. We sought to establish the essential role of PAR-1 in mediating ischemic damage. Using a short hairpin mRNA packaged with green fluorescent protein in a lentivirus vector, we knocked downPAR-1 in the medial caudate nucleus prior to rat middle cerebral artery occlusion (MCAo) and in rat neurons prior to oxygen-glucose deprivation. We also compared aged PAR-1 knockout mice with aged PAR-3, PAR-4 mice and young wild-type mice in a standard MCAo model. Silencing PAR-1 significantly reduced neurological deficits, reduced endothelial barrier leakage, and decreased neuronal degeneration in vivo during MCAo. PAR-1 knock-down in the ischemic medial caudate allowed cells to survive the ischemic injury; infected cells were negative for terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) and c-Fos injury markers. Primary cultured neurons infected with PAR-1 short hairpin ribonucleic acid (shRNA) showed increased neuroprotection during hypoxic/aglycemic conditions with or without added thrombin. The aged PAR-1 knockout mice showed decreased infarction and vascular disruption compared to aged controls or young wild types. We demonstrated an essential role for PAR-1 during ischemia. Silencing or removing PAR-1 significantly protected neurons and astrocytes. Further development of agents that act at PAR-1 or its downstream pathways could yield powerful stroke therapy. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
机译：蛋白酶激活受体（PARs）填充大脑中的神经元和星形胶质细胞。丝氨酸蛋白酶凝血酶在中风后的头几个小时内激活PAR-1，似乎与细胞毒性有关。凝血酶拮抗剂和PAR-1抑制剂与中风后细胞死亡减少和行为保护相关，但尚无数据支持PAR-1作用与获益之间的机制联系。我们试图建立PAR-1在介导缺血损伤中的重要作用。在慢病毒载体中使用包装有绿色荧光蛋白的短发夹mRNA，我们敲低了大鼠大脑中动脉闭塞（MCAo）之前的尾状尾内侧核中的PAR-1，并且剥夺了氧葡萄糖剥夺之前的大鼠神经元中的PAR-1。我们还在标准MCAo模型中将老年PAR-1敲除小鼠与老年PAR-3，PAR-4小鼠和年轻的野生型小鼠进行了比较。沉默PAR-1可显着减少MCAo体内的神经系统缺陷，减少内皮屏障渗漏并减少神经元变性。在缺血性尾状尾中的PAR-1敲低可使细胞在缺血性损伤中幸存下来。感染的细胞对末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）和c-Fos损伤标记物阴性。在缺氧/血糖水平较低的条件下（添加或不添加凝血酶），感染PAR-1短发夹状核糖核酸（shRNA）的原代培养神经元表现出增强的神经保护作用。与衰老的对照组或年轻的野生型相比，衰老的PAR-1基因敲除小鼠显示出减少的梗塞和血管破坏。我们证明了PAR-1在缺血过程中的重要作用。沉默或去除PAR-1可显着保护神经元和星形胶质细胞。作用于PAR-1或其下游途径的药物的进一步开发可能会产生强大的中风疗法。 （C）2014年IBRO。由Elsevier Ltd.出版。保留所有权利。

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