Protective effects of 5-iodo-6-amino-1,2-benzopyrone, an inhibitor of poly(ADP-ribose) synthetase against peroxynitrite-induced glial damage and stroke development

Eur J Pharmacol. 1998 Jun 26;351(3):377-82. doi: 10.1016/s0014-2999(98)00381-1.

Abstract

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, electron transport, and ATP formation, resulting in cell necrosis. Here, we demonstrate that inhibition of PARS with the novel, potent PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) protects against peroxynitrite-induced cell death (as measured by measurement of mitochondrial respiration and release of lactate dehydrogenase) in C6 glioma cells in 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cerebral Infarction / etiology
  • Cerebral Infarction / pathology
  • Cerebral Infarction / prevention & control*
  • Coumarins / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Ischemia / complications
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neuroglia / drug effects*
  • Neuroglia / pathology
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / pathology
  • Neurons / ultrastructure
  • Nitrates / toxicity*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Rats
  • Tumor Cells, Cultured

Substances

  • Coumarins
  • Enzyme Inhibitors
  • Nitrates
  • Poly(ADP-ribose) Polymerase Inhibitors
  • 5-iodo-6-amino-1,2-benzopyrone
  • peroxynitric acid
  • L-Lactate Dehydrogenase