Depending on the level of exposure, symptoms range from dizziness, headache, and hyperventilation to loss of consciousness, hemodynamic compromise, arrhythmias, seizures, apnea, cardiac arrest and finally death, which can occur rapidly with high concentrations of cyanide. The acute clinical effects of cyanide are a direct function of cellular pseudohypoxia and acidosis due to the inability of cells to extract oxygen for respiration. However, this does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.Ĭyanide causes rapid toxicity upon exposure, in large part due to the inhibition of cytochrome c oxidase-dependent cellular respiration, although other mechanisms are also likely involved owing to its reactive nature. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: a patent application has been submitted for the use of glyoxylate as a cyanide antidote. All other relevant data, including the raw metabolomics data that were used to perform the pathway analysis, are within the paper and its Supporting Information files.įunding: This work was supported by National Institutes of Health ( grant U54NS079201 to RTP and CAM. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: The microarray data used for the gene expression analysis of zebrafish embryos and larvae exposed to cyanide have been deposited in the ArrayExpress database at EMBL-EBI under accession number E-MTAB-6311, and can be accessed at the following link. Received: JanuAccepted: FebruPublished: June 7, 2018Ĭopyright: © 2018 Sips et al. Tanguay, Oregon State University, UNITED STATES (2018) Identification of specific metabolic pathways as druggable targets regulating the sensitivity to cyanide poisoning. Together, our results indicate that the resistance of zebrafish embryos to cyanide toxicity during early development is related to an altered regulation of cellular metabolism, which we propose may be exploited as a potential target for the development of novel antidotes against cyanide poisoning.Ĭitation: Sips PY, Shi X, Musso G, Nath AK, Zhao Y, Nielson J, et al. Modulators of the pyruvate dehydrogenase complex, as well as the small molecule sodium glyoxylate, consistently protected against cyanide toxicity in 7 dpf zebrafish larvae. In cyanide-sensitive 7 dpf larvae, we identified several such compounds that offer significant protection against cyanide toxicity. Metabolomics measurements demonstrated significant age-dependent differences in energy metabolism during cyanide exposure which prompted us to test modulators of the tricarboxylic acid cycle and related metabolic processes as potential antidotes. Unbiased analysis of gene expression in response to several hours of ultimately lethal doses of cyanide in both 1 and 7 dpf zebrafish revealed modest changes in iron-related proteins associated with the age-dependent cyanide resistance. We found that zebrafish embryos in the first 3 days post fertilization (dpf) are highly resistant to cyanide, becoming progressively more sensitive thereafter. We have created a pipeline that combines high-throughput screening in zebrafish with subsequent validation in two mammalian small animal models as well as a porcine large animal model. As a result, there are ongoing efforts to exploit different animal models to identify novel countermeasures. Cyanide is a potent toxic agent, and the few available antidotes are not amenable to rapid deployment in mass exposures.
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