Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase

摘要: Poly(ADP-ribose)polymerase (PARP, EC 2.4.2.30), an abundant nuclear protein activated by DNA nicks, mediates cell death in vitro nicotinamide adenine dinucleotide (NAD) depletion after exposure to nitric oxide. The authors examined whether genetic deletion of PARP (PARP null mice) or its pharmacologic inhibition 3-aminobenzamide (3-AB) attenuates tissue injury transient cerebral ischemia. Twenty-two hours reperfusion following 2 filamentous middle artery occlusion, ischemic was decreased PARP-/- and PARP+/- mice compared with PARP+/+ litter mates, also attenuated 129/SV wild-type 3-AB treatment controls. Infarct sparing accompanied functional recovery 3-AB-treated mice. Increased poly(ADP-ribose) immunostaining observed nuclei 5 minutes reduced treatment. Levels NAD--the substrate PARP--were were 35% contralateral levels at 24 hours. decreases animals. cleavage caspase-3 (CPP-32) has been proposed as important step apoptotic death. Markers apoptosis, such oligonucleosomal damage, total fragmentation, the density terminal deoxynucleotidyl transferase dUTP nick-end-labelled (TUNEL +) cells, however, did not differ brain animals versus controls, although there differences number TUNEL-stained cells reflecting decrease infarct size. Thus, activates contributes most likely NAD energy failure, have excluded a role for earlier later stages Inhibitors activation could provide potential therapy acute stroke.