Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia

An excessive activation of poly(ADP-ribose) polymerase (PARP) has been prop osed to play a key role in postischemic neuronal death. We examined the neu roprotective effects of the PARP inhibitors benzamide, 6(5H)-phenanthridino ne, and 3,4-dihydro-5-[4-1(1-piperidinyl)buthoxy]-1(2H)-isoquinolinone in t hree rodent models of cerebral ischemia. Increasing concentrations of the t hree PARP inhibitors attenuated neuronal injury induced by 60 min oxygen-gl ucose deprivation (OGD) in mixed cortical cell cultures, but were unable to reduce CA1 pyramidal cell loss in organotypic hippocampal slices exposed t o 30 min CGD or in gerbils following 5 min bilateral carotid occlusion. We then examined the necrotic and apoptotic features of OGD-induced neurodegen eration in cortical cells and hippocampal slices using biochemical and morp hological approaches. Cortical cells exposed to OGD released lactate dehydr ogenase into the medium and displayed ultrastructural features of necrotic cell death, whereas no caspase-3 activation nor morphological characteristi cs of apoptosis were observed at any time point after OGD. In contrast, a m arked increase in caspase-3 activity was observed in organotypic hippocampa l slices after OGD, together with fluorescence and electron microscope evid ence of apoptotic neuronal death in the CA1 subregion. Moreover, the caspas e inhibitor Z-VAD-FMK reduced OGD-induced CA1 pyramidal cell loss. These fi ndings suggest that PARP overactivation may be an important mechanism leadi ng to post-ischemic neurodegeneration of the necrotic but not of the apopto tic type.