Enhanced Poly(ADP-ribosyl)ation after Focal Ischemia in Rat Brain
Enhanced Poly(ADP-ribosyl)ation after Focal Ischemia in Rat Brain
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DOI：
10.1097/00004647-199809000-00008
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发表时间：
1998-09
影响因子：
6.3
通讯作者：
T. Tokime;K. Nozaki;T. Sugino;Haruhiko Kikuchi;N. Hashimoto;K. Ueda
中科院分区：
文献类型：
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作者：
T. Tokime;K. Nozaki;T. Sugino;Haruhiko Kikuchi;N. Hashimoto;K. Ueda
神经元细胞的一氧化氮在谷氨酸神经毒性和局灶性脑缺血中起有害作用。一氧化氮直接损伤DNA，DNA链的断裂激活聚（ADP-核糖）聚合酶（PARP），这导致核蛋白的聚（ADP-核糖基）化。PARP的过度激活被认为会导致ATP的耗尽和能量衰竭，从而导致细胞死亡。为了阐明多聚腺苷二磷酸核糖基化在缺血损伤中的作用，我们用免疫组织化学方法检测了多聚腺苷二磷酸核糖基化，并采用大鼠大脑中动脉永久性闭塞模型研究了3-氨基苯甲酰胺（PARP抑制剂）对局灶性脑缺血的保护作用。缺血后2小时，在大脑皮层和纹状体广泛而显著地检测到聚腺苷二磷酸核糖基化，24小时后发生梗死。增强的多聚腺苷二磷酸核糖免疫反应性逐渐减弱，16小时后，未检测到免疫反应性。脑室内注射3-氨基苯甲酰胺（1 - 30 mg/kg）在缺血损伤前30分钟以剂量依赖性方式减少梗死体积，同时沿着免疫组织化学减少聚（ADP-核糖基）化。用选择性神经元型一氧化氮合成酶抑制剂7-硝基吲唑（25 mg/kg，腹膜内）预处理，部分减少聚（ADP-核糖基）化。这些数据表明，参与的多聚（ADP-核糖基）化在脑梗死的发展。
Nitric oxide from neuronal cells plays detrimental roles in glutamate neurotoxicity and in focal brain ischemia. Nitric oxide directly damages DNA, and breaks in the DNA strands activate poly(ADP-ribose) polymerase (PARP), which brings poly(ADP-ribosyl)ation of the nuclear proteins. The excessive activation of PARP is thought to cause depletion of ATP and the energy failure resulting in cell death. To clarify the involvement of poly(ADP-ribosyl)ation in ischemic insult, we examined poly(ADP ribosyl)ation by immunohistochemical methods and the protective effect of 3-aminobenzamide, which is a PARP inhibitor, on focal brain ischemia using an intraluminal permanent middle cerebral artery occlusion model in rats. Poly(ADP ribosyl)ation was widely and markedly detected 2 hours after the ischemic insult in the cerebral cortex and striatum in which infarction developed 24 hours later. The enhanced immunoreactivity of poly(ADP-ribose) gradually decreased, and 16 hours later, no immunoreactivity was detected. Intraventricular administration of 3-aminobenzamide (1 to 30 mg/kg) 30 minutes before the ischemic insult decreased infarction volume in a dose-dependent manner along with the immunohistochemical reduction of poly(ADP-ribosyl)ation. Pretreatment with 7-nitroindazole (25 mg/kg, intraperitoneally), a selective neuronal nitric oxide synthetase inhibitor, partially reduced poly(ADP-ribosyl)ation. These data suggest the involvement of poly(ADP-ribosyl)ation in the development of cerebral infarction.