Neurotoxicity of nitroxyl: Insights into HNO and NO biochemical imbalance

Sandra J. Hewett, Michael G. Espey, Tracy F. Uliasz, David A. Wink

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Nitroxyl anion (NO-), and/or its conjugate acid, HNO, may be formed in the cellular milieu by several routes under both physiological and pathophysiological conditions. Since experimental evidence suggests that certain reactive nitrogen oxide species can contribute significantly to cerebral ischemic injury, we investigated the neurotoxic potential of HNO/NO- using Angeli's salt (AS), a spontaneous HNO/NO--generating compound. Exposure to AS resulted in a time- and concentration-dependent increase in neural cell death that progressed markedly following the initial exposure. Coadministration of the donor with Tempol (1 mM), a one-electron oxidant that converts NO- to NO, prevented its toxic effect, as did the concomitant addition of Fe(III)TPPS. Media containing various chelators, catalase, Cu/Zn superoxide dismutase, or carboxy-PTIO did not ameliorate AS-mediated neurotoxicity, ruling out the involvement of transition metal complexes, H2O2, O2-, and NO, respectively. A concentration-dependent increase in supernatant protein 3-nitrotyrosine immunoreactivity was observed when cultures were exposed to AS under aerobic conditions, an effect lost in the absence of oxygen. A bell-shaped curve for augmented AS-mediated nitration was observed with increasing Fe(III)TPPS concentration, which contrasted with its linear effect on abating cytotoxicity. Finally, addition of glutamate receptor antagonists, MK-801 (10 μM) and CNQX (30 μM) to the cultures abrogated toxicity when given during, but not following, AS exposure; as did pretreatment with the exocytosis inhibitor, tetanus toxin (300 ng/ml). Taken together, our data suggest that under aerobic conditions, AS toxicity is initiated via HNO/NO- but progresses via secondary excitotoxicity.

Original languageEnglish (US)
Pages (from-to)1478-1488
Number of pages11
JournalFree Radical Biology and Medicine
Volume39
Issue number11
DOIs
StatePublished - Dec 1 2005

Keywords

  • Cell death
  • Excitotoxicity
  • Free radicals
  • Neurotoxicity
  • Nitric oxide
  • Nitroxyl
  • Protein nitration

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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