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.

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.

• Authors: M Endres, G S Scott, A L Salzman, E Kun, M A Moskowitz, C Szabó
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 351 Issue 3 Pg. 377-82 (Jun 26 1998) ISSN: 0014-2999 [Print] Netherlands
• PMID: 9721031 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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