PROTECTIVE EFFECTS OF 5-IODO-6-AMINO-1,2-BENZOPYRONE, AN INHIBITOR OFPOLY(ADP-RIBOSE) SYNTHETASE AGAINST PEROXYNITRITE-INDUCED GLIAL DAMAGE AND STROKE DEVELOPMENT

Peroxynitrite triggers DNA single-strand breakage, which activates the nuclear enzyme poly(ADP-ribose) synthetase (PARS). Activation of PARS depletes its substrate, NAD(+), slowing the rate of glycolysis, elect ron transport, and ATP formation, resulting in cell necrosis. Here, we demonstrate that inhibition of PARS with the novel, potent PARS inhib itor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) protects against peroxyni trite-induced cell death (as measured by measurement of mitochondrial respiration and release of lactate dehydrogenase) in C6 glioma cells i n vitro, and in a murine stroke model in vivo. Inhibition of PARS with INH2BP may represent a novel approach for the experimental therapy of stroke. (C) 1998 Elsevier Science B.V. All rights reserved.