Two distinct mechanisms of nitric oxide-mediated neuronal cell death show thiol dependency

Andrew J. Gow, Qiping Chen, Madhura Gole, Marios Themistocleous, Virginia M Y Lee, Harry Ischiropoulos

Research output: Contribution to journalArticle

31 Citations (Scopus)


To better understand the mechanism(s) underlying nitric oxide (·NO)- mediated toxicity, in the presence and absence of concomitant oxidant exposure, postmitotic terminally differentiated NT2N cells, which are incapable of producing ·NO, were exposed to PAPA-NONOate (PAPA/NO) and 3- morpholinosydnonimine (SIN-1). Exposure to SIN-1, which generated peroxynitrite in the range of 25-750 nM/min, produced a concentration- and time-dependent delayed cell death. In contrast, a critical threshold concentration (>440 nM/min) was required for.NO to produce significant cell injury. Examination of cells by electron microscopy shows a largely necrotic injury after peroxynitrite exposure but mainly apoptotic-like morphology after ·NO exposure. Cellular levels of reduced thiols correlated with cell death, and pretreatment with N-acetylcysteine (NAC) fully protected from cell death in either PAPA/NO or SIN-1 exposure. NAC given within the first 3 h posttreatment further delayed cell death and increased the intracellular thiol level in SIN-1 but not ·NO-exposed cells. Cell injury from ·NO was independent of cGMP, caspases, and superoxide or peroxynitrite formation. Overall, exposure of non-·NO-producing cells to ·NO or peroxynitrite results in delayed cell death, which, although occurring by different mechanisms, appears to be mediated by the loss of intracellular redox balance.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Issue number6 47-6
Publication statusPublished - 2000
Externally publishedYes



  • Apoptosis
  • Necrosis
  • Nitrosative stress
  • Oxidative stress
  • Peroxynitrite

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology
  • Physiology (medical)

Cite this

Gow, A. J., Chen, Q., Gole, M., Themistocleous, M., Lee, V. M. Y., & Ischiropoulos, H. (2000). Two distinct mechanisms of nitric oxide-mediated neuronal cell death show thiol dependency. American Journal of Physiology - Cell Physiology, 278(6 47-6).