Project 1: Prevention & Termination Of Seizures

The objective of this project is to find new and improved medical countermeasures for acute seizures caused by two broad classes of chemical threat agents: organophosphate (OP) anticholinesterase inhibitors and GABAA receptor antagonists. These countermeasures aim to improve the survival and long-term prognosis for those exposed to toxic levels of these chemicals by stopping or preventing seizures.

Two OP agents, soman (O-pinacolyl methylphosphonofluoridate) and DFP (diisopropylfluorophosphate), and one GABAA receptor antagonist, TETS (tetramethylenedisulfotetramine), were selected to represent the two broad classes of chemical threat agents. Soman is a nerve agent classified as a Schedule 1 substance under the Chemical Warfare Convention (CWC), meaning it can be used as or in the manufacture of a chemical weapon. DFP is less potent than the nerve agents identified in the CWC but has similar effects. TETS is a lethal toxin that has previously been used as a rodenticide. Though it is now banned everywhere in the world, lethal poisonings continue to occur frequently.

As a result of the research conducted in the project, the first animal model was developed to evaluate potential treatments for TETS poisoning. Potential therapies are compared with diazepam, the current standard of care for emergency treatment of seizures caused by chemical exposure, and with midazolam, the emerging standard. Potential therapies are further evaluated in project 2 (Mitigation of Neurological Damage) for their ability to prevent seizure-induced brain damage. Project 1 utilizes the chemistry capabilities of cores A (Analytical Chemistry) and B (Probe and Pharmaceutical Chemistry). 

Related Publications

Inceoglu B, Zolkowska D, Yoo HJ, Wagner KM, Yang J, Hackett E, Hwang SH, Lee KS, Rogawski MA, Morisseau C, Hammock BD
PLoS One 11;8(12):e80922. doi: 10.1371/journal.pone.0080922
PubMed PMID: 
PubMed PMCID: 
Vaitkevicius H, Ng M, Moura L, Rosenthal E, Westover MB, Rosand J, Rogawski MA, Reddy K, Cole AJ
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Encyclopedia of Toxicology, 3rd edition (Wexler P, ed.) Oxford, UK: Elsevier.