Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity

Science. 1994 Feb 4;263(5147):687-9. doi: 10.1126/science.8080500.

Abstract

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.

Publication types

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

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Brain / cytology
  • Brain / drug effects
  • Brain / enzymology
  • Cell Death / drug effects
  • Cell Line
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / enzymology
  • DNA Damage
  • Enzyme Activation
  • Humans
  • N-Methylaspartate / toxicity*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / enzymology
  • Nitric Oxide / toxicity*
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Benzamides
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Nitric Oxide
  • N-Methylaspartate
  • benzamide
  • Poly(ADP-ribose) Polymerases