1. Discovery of treatment for nerve agents targeting a new metabolic pathway
- Author
-
Alexander Doan, Daniel O. Carmany, Jeffry S. Forster, Phillip M. Mach, Elizabeth S. Dhummakupt, Gabrielle M. Rizzo, Julie A. Renner, Trevor Glaros, Ruth W Moretz, Linnzi K Wright, Carrie D. Dorsey, Mark R. Marten, Bernard J. Benton, Russell Dorsey, Walker Huso, Ethan M. McBride, and Christopher Phillips
- Subjects
0301 basic medicine ,Proteomics ,Proteome ,Health, Toxicology and Mutagenesis ,Guinea Pigs ,Toxicology ,Organ Toxicity and Mechanisms ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Metabolomics ,a-Ketoglutarate ,medicine ,Animals ,Glycolysis ,Chemical Warfare Agents ,Nerve agent ,VX poisoning ,chemistry.chemical_classification ,Cardiomyocytes ,Poisoning ,General Medicine ,Acetylcholinesterase ,Cell biology ,Citric acid cycle ,Metabolic pathway ,030104 developmental biology ,Enzyme ,chemistry ,Mechanism of action ,medicine.symptom ,Nerve Agents ,030217 neurology & neurosurgery ,Metabolic Networks and Pathways ,medicine.drug - 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. Electronic supplementary material The online version of this article (10.1007/s00204-020-02820-4) contains supplementary material, which is available to authorized users.
- Published
- 2020