Two distinct mechanisms of nitric oxide-mediated neuronal cell death show thiol dependency.
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.
Gow
A J
AJ
Stokes Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania 19104, USA.
Chen
Q
Q
Gole
M
M
Themistocleous
M
M
Lee
V M
VM
Ischiropoulos
H
H
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009336:Necrosis; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009566:Nitrates / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D006834:Hydrazines; D009566:Nitrates; D020030:Nitric Oxide Donors; D016877:Oxidants; C112653:PAPA NONOate; D013438:Sulfhydryl Compounds; C039642:peroxynitric acid; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D006152:Cyclic GMP; D000111:Acetylcysteine