GPI 6150 prevents H2O2 cytotoxicity by inhibiting poly(ADP-ribose) polymerase

Jie Zhang, Susan Lautar, Shirley Huang, Cynthia Ramsey, Anissa Cheung, Jia He Li

Research output: Contribution to journalArticle

Abstract

GPI 6150 (1,11b-dihydro-[2H]benzopyrano[4,3,2-de]isoquinolin-3-one) is a novel inhibitor of poly(ADP-ribose) polymerase (PARP). It has demonstrated efficacy in rodent models of focal cerebral ischemia, traumatic brain injury, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine damage to dopaminergic neurons, regional myocardial ischemia, streptozotocin-induced diabetes, septic shock, and arthritis. Here we report the structure of GPI 6150, its enzymatic characteristics, and biochemical property in cytoprotection. As a competitive PARP inhibitor (K(i) = 60 nM), GPI 6150 protected the P388D1 cells against hydrogen peroxide cytotoxicity, by preventing PARP activation and the depletion of NAD+, the substrate for PARP. To address the concerns of potential side effects of PARP inhibition, we tested GPI 6150 and found it had no effect on the repair and expression of a plasmid DNA damaged by N-methyl-N'-nitro-N-nitrosoguanidine. Neither did it affect dehydrogenases with NAD co-enzyme. GPI 6150 was much less potent to inhibit mono-ADP-ribosyltransferase. There was no selectivity for GPI 6150 between PARP isozymes. These attributes render GPI 6150 a useful tool to probe the functions of PARP. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)590-598
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume278
Issue number3
DOIs
StatePublished - Nov 30 2000
Externally publishedYes

Keywords

  • NAD depletion
  • Reactive oxygen species damage
  • Small molecule PARP inhibitor
  • Specificity of GPI 6150

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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