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Toxicological Sciences 58, 127-134 (2000)
Copyright © 2000 by the Society of Toxicology

Neurotoxicology

Various Nitric Oxide Donors Protect Chick Embryonic Neurons from Cyanide-Induced Apoptosis

Mads Skak Jensen*,1, Niels Chresten Berg Nyborg{dagger} and Erling Sonnich Thomsen*

* Department of Analytical and Pharmaceutical Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark; and {dagger} Safety Pharmacology, Drug Safety, Health Care, Research and Development, Preclinical Development, Novo Nordisk A/S, Denmark

The discovery of numerous biochemical effects of cyanide not directly related to the inhibition of the respiratory chain, including the involvement of apoptosis, has challenged the basis of traditional antidote treatment, which primarily depends on nitrite-induced conversion of hemoglobin into methemoglobin, releasing the blockade of cytochrome c oxidase by high-affinity binding of cyanide as cyanmethemoglobin. The fact that amyl nitrite has antidotal effects not related to methemoglobin formation has unfolded new mechanism of actions of nitrites including release of nitric oxide (NO). In this study, we characterized the effect of various NO donor compounds on cyanide-induced cell death in cultured chick embryonic neurons. Apoptosis was induced by treating the neuronal cultures with 1 mM NaCN for 1 h, followed by a cyanide-free incubation period of 23 h. Using this treatment protocol, we showed that cyanide-induced apoptosis was blocked in the presence of the different NO donors sodium nitroprusside, S-nitrosoglutathione, S-nitroso-N-acetylpenicillamin, nitroglycerin, 3-morpholinosydnonimine, and diethylamine nitric oxide, indicating independence of the redox-related species of NO released. The effect was confirmed to be mediated by NO, since exhausted NO donors did not afford protection, and the mechanism likely involved chemical modification of thiol groups, since the effect was completely reversed by dithiothreitol. Furthermore, NMDA antagonists protected against cyanide-induced cell death, whereas inhibitors of nitric oxide synthase increased cyanide-induced apoptotic damage, indicating a protective effect of endogenously generated NO, at least in cell cultures.

Key Words: apoptosis; cyanide; nitric oxide; neurons; neuroprotection.


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