Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity.
Poly(adenosine 5'-diphosphoribose) synthetase (PARS) is a nuclear enzyme which, when activated by DNA strand breaks, adds up to 100 adenosine 5'-diphosphoribose (ADP-ribose) units to nuclear proteins such as histones and PARS itself. This activation can lead to cell death through depletion of beta-nicotinamide adenine dinucleotide (the source of ADP-ribose) and adenosine triphosphate. Nitric oxide (NO) stimulated ADP-ribosylation of PARS in rat brain. Benzamide and other derivatives, which inhibit PARS, blocked N-methyl-D-aspartate- and NO-mediated neurotoxicity with relative potencies paralleling their ability to inhibit PARS. Thus, NO appeared to elicit neurotoxicity by activating PARS.
Zhang
J
J
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Dawson
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Dawson
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Snyder
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D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004249:DNA Damage; D004789:Enzyme Activation; D006801:Humans; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000633:toxicity*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009569:Nitric Oxide; D016202:N-Methylaspartate; C037689:benzamide; D011065:Poly(ADP-ribose) Polymerases