Discovery of treatment for nerve agents targeting a new metabolic pathway
Loading...
Links to Files
Author/Creator ORCID
Date
2020-07-27
Type of Work
Department
Program
Citation of Original Publication
Glaros, Trevor; Dhummakupt, Elizabeth S.; Rizzo, Gabrielle M.; McBride, Ethan; Carmany, Daniel O.; Wright, Linnzi K. M.; Forster, Jeffry S.; Renner, Julie A.; Moretz, Ruth W.; Dorsey, Russell; Marten, Mark R.; Huso, Walker; Doan, Alexander; Dorsey, Carrie D.; Phillips, Christopher; Benton, Bernard; Mach, Phillip M.; Discovery of treatment for nerve agents targeting a new metabolic pathway; Archives of Toxicology volume 94, pages3249–3264(2020); https://link.springer.com/article/10.1007/s00204-020-02820-4
Rights
This item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
Attribution 4.0 International (CC BY 4.0)
Attribution 4.0 International (CC BY 4.0)
Subjects
Abstract
The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX. Proteomic and metabolomic profiling resulted in the identification of several enzymes and metabolic precursors involved in glycolysis and the TCA cycle. All lines of experimental evidence indicated that there was a blockade of the TCA cycle at isocitrate dehydrogenase 2, which converts isocitrate to α-ketoglutarate. Using a primary beating cardiomyocyte cell model, we were able to determine that the supplementation of α-ketoglutarate subsequently rescued cells from the acute effects of VX poisoning. This study highlights the broad impacts that VX has and how understanding these mechanisms could result in new therapeutics such as α-ketoglutarate.