Discovery of treatment for nerve agents targeting a new metabolic pathway
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 27, 2020
- Source ID
- 10.1007/s00204-020-02820-4
Entities
People
- Alexander Doan
- Bernard Benton
- Carrie D. Dorsey
- Christopher Phillips
- Daniel O. Carmany
- Elizabeth S Dhummakupt
- Ethan M. McBride
- Gabrielle M. Rizzo
- Jeffry S. Forster
- Julie A. Renner
- Linnzi K. M. Wright
- Mark R. Marten
- Phillip M Mach
- Russell Dorsey
- Ruth W. Moretz
- Trevor Glaros
- Walker Huso
Organizations
- Defense Threat Reduction Agency