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.
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.
Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
M
M
Endres
G S
GS
Scott
A L
AL
Salzman
E
E
Kun
M A
MA
Moskowitz
C
C
Szabó
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003374:Coumarins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007511:Ischemia / Q000150:complications; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D009566:Nitrates / Q000633:toxicity*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D014407:Tumor Cells, Cultured
D003374:Coumarins; D004791:Enzyme Inhibitors; D009566:Nitrates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C071383:5-iodo-6-amino-1,2-benzopyrone; C039642:peroxynitric acid; D007770:L-Lactate Dehydrogenase