Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuatescerebral damage in focal ischemia

Poly(ADP-ribose) polymerase (PARP) is thought to play a physio-logical role in maintaining genomic integrity and in the repair of DNA strand breaks. H owever, the activation of PARP by free radical-damaged DNA plays a pivotal role in mediating ischemia-reperfusion injury. The excessive activation of PARP causes a rapid depletion of intracellular energy leading to cell death . The present study examined the effect of post-ischemic pharmacological in hibition of PARP in a rat focal cerebral ischemia model. In Long-Evans rats , focal cerebral ischemia was produced by cauterization of the right distal middle cerebral artery (MCA) with bilateral temporary common carotid arter y (CCA) occlusion for 90 min. A PARP inhibitor, 3,4-dihydro-5-[4-(1-piperid inyl)butoxy]-1(2H)-isoquinolinone (DPQ; IC50 = 1 mu M/1) was injected i,p. 30 min after the onset of MCA occlusion (control: 10, 20, 40 and 80 mg/kg; n = 7 each). Twenty-four hours later, the total infarct volume was measured . Regional blood flow in the right parietal cortex decreased to approximate ly 20% of the baseline following MCA occlusion in all groups. PARP inhibiti on lead to a significant decrease in damaged volume in all treated groups w ith the largest reduction in the 40 mg/kg,group (111.5 +/- 24.8 mm(3) mean +/- SD, p < 0.01), compared to the control group (193.5 +/- 28.6 mm(3)). We also found there was a significant increase of poly(ADP-ribose) immunoreac tivity in the ischemic region, as compared to the contralateral side, with DPQ treatment diminishing poly(ADP-ribose) production. These findings indic ate that DPQ exerts its neuroprotective effects in vivo by PARP inhibition and that PARP inhibitors may be effective for treating ischemic stroke, eve n when the treatment is initiated after the onset of ischemia. (C) 1999 Els evier Science B.V. All rights reserved.