Mechanisms of Cyanide-Induced Neurotoxicity and Purine Dysregulation

PROJECT SUMMARY Cyanide is a rapid-acting asphyxiant that prevents cells from utilizing oxygen to produce ATP. This depletion causes detrimental effects on organs with high ATP demand; thus, cyanide is particularly toxic to the nervous system. People exposed to a single high dose of cyanide can develop a Parkinson-like syndrome. Cyanide inhibition of cytochrome c oxidase is well-established, but this mechanism does not completely explain cyanide’s neurotoxic effects. To fill the knowledge gap in cyanide’s mechanisms of neurotoxicity, we combined mass spectrometry-based metabolite profiling with in vivo models of cyanide exposure to elucidate the metabolite disturbances downstream of cyanide exposure. We profiled metabolites in zebrafish, rabbit, and swine models of lethal cyanide exposure. The plasma concentration of several concordant metabolites in the purine catabolic products were markedly increased in response to cyanide in these three animal models. Purine metabolites are normally recovered via the salvage pathway to regenerate ATP. But, they can regulate neuronal cell function and survival, with abnormalities in purine metabolism associated with the pathophysiology of trauma to the brain and nervous system. Moreover, inborn errors of purine metabolism highlight the significance of purines in human health. These human genetic findings strongly link defects in purine metabolism to neurological manifestations. Thus, our data demonstrating a link between dysregulation of purine metabolism and cyanide creates a new entry point to elucidate the mechanisms of cyanide toxicity and are the subject of this application to PAR-24- 030, which “supports basic research to identify and validate molecular mechanisms of acute toxicity to chemical agents with primary or secondary effects on the nervous system”. As described in this proposal, we discovered defects in a key regulatory point in purine metabolism; in addition, we developed two new tools to interrogate the effects of cyanide on neurotoxicity. The proposed work addresses a critical knowledge gap in molecular mechanisms of cyanide toxicity, in addition to providing new tools to investigate the effect(s) of cyanide and potentially other neurotoxicants on the nervous system. Understanding these mechanisms may lead to the identification of new biomarkers of cyanide toxicity and/or novel therapeutic targets to mitigate cyanide-induced toxicity.