Neurotoxicity after cyanide exposure is generally believed to result from inhibition of cytochrome oxidase and subsequent histotoxic anoxia. However, the relationship between histotoxic anoxia and the symptoms produced by cyanide is poorly defined. Our preliminary studies indicate cyanide elevates neuronal cytosolic free calcium and this parallels the appearance of many of the symptoms of cyanide toxicity. We hypothesize that cyanide produces a rapid rise in neuronal cytosolic free calcium which activates a series of biochemical events culminating in the characteristic signs, symptoms and lesions of cyanide poisoning. Proposed experiments are designed to determine the source of the increased cytosolic calcium and to correlate changes in calcium homeostasis with the energy status of a cyanide-induced accumulation of intracellular calcium to release of neurotransmitters in cyanide intoxicated mice and in the PC12 cell line. Finally, the role of calcium in lipid peroxidation will be examined as an explanation for cyanide-induced neuronal lesions. The proposed studies represents a new approach to the investigation of cyanide toxicity and will yield important information on the biochemical mechanism(s) of cyanide induced neurotoxicity.
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