Mechanisms of Cyanide-Induced Neurotoxicity and Purine Dysregulation

Cyanide is a rapid-acting asphyxiant that prevents cells from utilizing oxygen to produce ATP. Thisdepletion causes detrimental effects on organs with high ATP demand; thus cyanide is particularly toxic to thenervous 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 explaincyanides neurotoxic effects. To fill the knowledge gap in cyanides mechanisms of neurotoxicity we combinedmass spectrometry-based metabolite profiling with in vivo models of cyanide exposure to elucidate the metabolitedisturbances downstream of cyanide exposure. We profiled metabolites in zebrafish rabbit and swine modelsof lethal cyanide exposure. The plasma concentration of several concordant metabolites in the purine catabolicproducts were markedly increased in response to cyanide in these three animal models. Purine metabolites arenormally recovered via the salvage pathway to regenerate ATP. But they can regulate neuronal cell functionand survival with abnormalities in purine metabolism associated with the pathophysiology of trauma to the brainand nervous system. Moreover inborn errors of purine metabolism highlight the significance of purines in humanhealth. 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 newentry 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 chemicalagents with primary or secondary effects on the nervous system. As described in this proposal we discovereddefects in a key regulatory point in purine metabolism; in addition we developed two new tools to interrogate theeffects of cyanide on neurotoxicity. The proposed work addresses a critical knowledge gap in molecularmechanisms of cyanide toxicity in addition to providing new tools to investigate the effect(s) of cyanide andpotentially other neurotoxicants on the nervous system. Understanding these mechanisms may lead to theidentification of new biomarkers of cyanide toxicity and/or novel therapeutic targets to mitigate cyanide-inducedtoxicity.