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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Death / drug effects
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Cerebral Infarction / etiology
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Cerebral Infarction / pathology
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Cerebral Infarction / prevention & control*
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Coumarins / pharmacology*
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Enzyme Inhibitors / pharmacology*
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Ischemia / complications
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L-Lactate Dehydrogenase / metabolism
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Male
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Mice
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Mitochondria / drug effects
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Mitochondria / metabolism
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Neuroglia / drug effects*
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Neuroglia / pathology
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Neurons / drug effects
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Neurons / enzymology
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Neurons / pathology
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Neurons / ultrastructure
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Nitrates / toxicity*
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Poly(ADP-ribose) Polymerase Inhibitors*
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Rats
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Tumor Cells, Cultured
Substances
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Coumarins
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Enzyme Inhibitors
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Nitrates
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Poly(ADP-ribose) Polymerase Inhibitors
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5-iodo-6-amino-1,2-benzopyrone
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peroxynitric acid
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L-Lactate Dehydrogenase