title: Inhibition of poly(ADP-ribose) polymerase: reduction of ischemic injury and attenuation of N-methyl-D-aspartate-induced neurotransmitter dysregulation.
abstract: OBJECTIVE
  The nuclear enzyme poly(ADP-ribose) polymerase (PARP) may play a role in DNA repair. However, in cerebral ischemia, excessive 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 ischemia and (2) the degree of neurotransmitter dysregulation induced by local cortical perfusion of N-methyl-D-aspartate (NMDA).
  
  
  METHODS
  In experiment 1, rats were subjected to transient ischemia for 90 minutes by occlusion of the middle cerebral artery. After 22.5 hours of reperfusion, lesions were quantified by tetrazolium staining. Untreated rats were compared with those treated with the PARP inhibitor 3-aminobenzamide (10 mg/kg). In experiment 2, rats were implanted with microdialysis probes in the cortex, and 1 mmol/L NMDA was perfused for 2 hours. Extracellular concentrations of neurotransmitter and neuromodulator amino acids were measured. Untreated rats were compared with those given 10 mg/kg 3-aminobenzamide.
  
  
  RESULTS
  In experiment 1, PARP inhibition significantly reduced lesion volumes: 204+/-43 mm3 (untreated) versus 90+/-24 mm3 (treated). Neuroprotection was primarily manifested in the cortex. In experiment 2, NMDA perfusion resulted in large elevations of glutamate, taurine, and the lipid component phosphoethanolamine. Levels of the NMDA site modulator D-serine were reduced, and glycine levels appeared unchanged. 3-Aminobenzamide significantly attenuated the elevations in glutamate and phosphoethanolamine but had no effects on D-serine and glycine.
  
  
  CONCLUSIONS
  Inhibition of PARP reduced injury after transient focal ischemia in rats and attenuated NMDA-induced glutamate efflux and overall neurotransmitter dysregulation. The deleterious effects of excessive PARP activation may be related in part to amplification of excitotoxicity, possibly by cellular energy depletion and additional transmitter release and/or reduced reuptake.
authors.affiliation: Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown 02129, USA. eng@cipr.mgh.harvard.edu
authors.forename: E H
authors.initials: EH
authors.lastname: Lo
authors.forename: P
authors.initials: P
authors.lastname: Bosque-Hamilton
authors.forename: W
authors.initials: W
authors.lastname: Meng
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D017551:Microdialysis; D016202:N-Methylaspartate / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D010477:Perfusion; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016202:N-Methylaspartate; C025160:3-aminobenzamide