ENHANCED POLY(ADP-RIBOSYL)ATION AFTER FOCAL ISCHEMIA IN RAT-BRAIN

Nitric oxide from neuronal cells plays detrimental roles in glutamate neurotoxicity and in focal brain ischemia. Nitric oxide directly damag es DNA, and breaks in the DNA strands activate poly(ADP-ribose) polyme rase (PARP), which brings poly(ADP-ribosyl)ation of the nuclear protei ns. The excessive activation of PARP is thought to cause depletion of ATP and the energy failure resulting in cell death. To clarify the inv olvement of poly(ADP-ribosyl)ation in ischemic insult, we examined pol y(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 occlus ion model in rats. Poly(ADP ribosyl)ation was widely and markedly dete cted 2 hours after the ischemic insult in the cerebral cortex and stri atum in which infarction developed 24 hours later. The enhanced immuno reactivity 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 insul t decreased infarction volume in a dose-dependent manner along with th e immunohistochemical reduction of poly(ADP-ribosyl)ation. Pretreatmen t with 7-nitroindazole (25 mg/kg, intraperitoneally), a selective neur onal nitric oxide synthetase inhibitor, partially reduced poly(ADP-rib osyl)ation. These data suggest the involvement of poly(ADP-ribosyl)ati on in the development of cerebral infarction.