GPI 6150 prevents H2O2 cytotoxicity by inhibiting poly(ADP-ribose) polymerase

GPI 6150 (1,11b-dihydro-[2H]benzopyrano[4,3,2-de]isoquinolin-3-one) is a no vel inhibitor of poly(ADP-ribose) polymerase (PARP). It has demonstrated ef ficacy in rodent models of focal cerebral ischemia, traumatic brain injury, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine damage to dopaminergic neuron s, regional myocardial ischemia, streptozotocin-induced diabetes, septic sh ock, and arthritis. Here we report the structure of GPI 6150, its enzymatic characteristics, and biochemical property in cytoprotection. As a competit ive PARP inhibitor (K-i = 60 nM), GPI 6150 protected the P388D1 cells again st hydrogen peroxide cytotoxicity, by preventing PARP activation and the de pletion of NAD(+), the substrate for PARP. To address the concerns of poten tial side effects of PARP inhibition, we tested GPI 6150 and found it had n o effect on the repair and expression of a plasmid DNA damaged by N-methyl- N'-nitro-N-nitrosoguanidine. Neither did it affect dehydrogenases with NAD co-enzyme. GPI 6150 was much less potent to inhibit mono-ADP-ribosyltransfe rase. There was no selectivity for GPI 6150 between PARP isozymes. These at tributes render GPI 6150 a useful tool to probe the functions of PARP. (C) 2000 Academic Press.