INHIBITION OF POLY(ADP-RIBOSE) POLYMERASE - REDUCTION OF ISCHEMIC-INJURY AND ATTENUATION OF N-METHYL-D-ASPARTATE-INDUCED NEUROTRANSMITTER DYSREGULATION

Background and Purpose-The nuclear enzyme poly(ADP-ribose) polymerase (PARP) may play a role in DNA repair. However, in cerebral ischemia, e xcessive PARP activation may lead to energy depletion and exacerbation of neuronal damage, We examined the effect of inhibiting PARP on (1) the degree of cerebral injury in a rat model of transient focal ischem ia and (2) the degree of neurotransmitter dysregulation induced by loc al cortical perfusion of N-methyl-D-aspartate (NMDA). Methods-In exper iment 1, rats were subjected to transient ischemia for 90 minutes by o cclusion of the middle cerebral artery. After 22.5 hours of reperfusio n, lesions were quantified by tetrazolium staining. Untreated rats wer e compared with those treated with the PARP inhibitor 3-aminobenzamide (10 mg/kg), In experiment 2, rats were implanted with microdialysis p robes in the cortex, and 1 mmol/L NMDA was perfused for 2 hours. Extra cellular concentrations of neurotransmitter and neuromodulator amino a cids were measured. Untreated rats were compared with those given 10 m g/kg 3-aminobenzamide. Results-In experiment 1, PARP inhibition signif icantly reduced lesion volumes: 204+/-43 mm(3) (untreated) 90 +/- 24 m m(3) (treated), Neuroprotection was primarily manifested in the cortex . In experiment 1, NMDA perfusion resulted in large elevations of glut amate, taurine, and the lipid component phosphoethanolamine. Levels of the NMDA site modulator D-serine were reduced, and glycine levels app eared unchanged. 3-Aminobenzamide significantly attenuated the elevati ons in glutamate and phosphoethanolamine but had no effects on D-serin e and glycine. Conclusions-Inhibition of PARP reduced injury after tra nsient focal ischemia in rats and attenuated NMDA-induced glutamate ef flux and overall neurotransmitter dysregulation. The deleterious effec ts of excessive PARP activation may be related in part to amplificatio n of excitotoxicity, possibly by cellular energy depletion and additio nal transmitter release and/or reduced reuptake.