Tokime T, Nozaki K, Sugino T, Kikuchi H, Hashimoto N, Ueda K
Department of Neurosurgery, Faculty of Medicine, Kyoto University, Japan.
J Cereb Blood Flow Metab. 1998 Sep;18(9):991-7. doi: 10.1097/00004647-199809000-00008.
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.
来自神经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），从而使核蛋白发生聚（ADP - 核糖基）化。PARP的过度激活被认为会导致ATP耗竭和能量衰竭，进而导致细胞死亡。为了阐明聚（ADP - 核糖基）化在缺血性损伤中的作用，我们采用免疫组织化学方法检测聚（ADP - 核糖基）化，并使用大鼠管腔内永久性大脑中动脉闭塞模型，研究PARP抑制剂3 - 氨基苯甲酰胺对局灶性脑缺血的保护作用。在缺血性损伤后2小时，在24小时后发生梗死的大脑皮层和纹状体中广泛且明显地检测到聚（ADP - 核糖基）化。聚（ADP - 核糖）增强的免疫反应性逐渐降低，16小时后未检测到免疫反应性。在缺血性损伤前30分钟脑室内注射3 - 氨基苯甲酰胺（1至30 mg/kg），梗死体积以剂量依赖方式减小，同时聚（ADP - 核糖基）化的免疫组织化学染色减弱。用选择性神经元一氧化氮合酶抑制剂7 - 硝基吲唑（25 mg/kg，腹腔注射）预处理可部分降低聚（ADP - 核糖基）化。这些数据表明聚（ADP - 核糖基）化参与了脑梗死的发生发展。
