Abstract

We studied the effects of several PARP inhibitors (including 3, 4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ), thieno [2,3-C]-isoquinolinon-5-one (TIQ-A) and others) against oxygen plus glucose deprivation (OGD)-induced neuronal death in primary cultures of i) mixed murine cortical cells or ii) organotypic rat hippocampal slices. We also evaluated the neuroprotective effects of systemic administration of PARP inhibitors after iii) transient or iv) permanent occlusion of the middle cerebral artery (MCA) in rats or v) after transient bilateral carotid occlusion in gerbils.Cortical cells exposed to OGD released lactate dehydrogenase into the medium and displayed ultrastructural features of necrotic cell death, with neither caspase-3 activation nor morphological features of apoptosis at any time point after OGD. In contrast, in the CA1 subregion of organotypic hippocampal slices, OGD caused apoptotic neuronal death (evaluated using fluorescence and electron microscopic approaches) and a marked increase in caspase-3 activity. PARP-inhibitors (DPQ, TIQ-A and others) reduced neuronal death in mixed cortical cells but not in organotypic slice cultures.The administration of TIQ-A (3 and 10 mg/Kg, i.p.) and DPQ (10 mg/Kg, i.p.) reduced the infarct volume caused by transient (2h) MCA occlusion in rats. TIQ-A (but not DPQ) significantly reduced the infarct volume also when administered after permanent MCAO. PARP inhibitors were unable to reduce CA1 hippocampal pyramidal cell loss in gerbils exposed to transient (5 min) forebrain ischemia.Our results show that TIQ-A, a novel and potent PARP-1 inhibitor, may have neuroprotective effects against focal but not global forebrain ischemia. References: 1.Moroni F, Meli E, Peruginelli F, Chiarugi A et al: Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia. Cell Death Differ, 2001; 8: 921-932 2.Chiarugi A, Meli E, Picca R et al: Novel isoquinolinone-derived inhibitors of poly(ADP-ribose) polymerase-1: pharmacological characterization and neuroprotective effects in an in vitro model of cerebral ischemia. Submitted to JPET

Keywords: Brain Ischemia, Stroke, TIQ-A, DPQ