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

Rogawski MA
Acta Neurol Scand Suppl. 2013;(197):9-18. doi: 10.1111/ane.12099.
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Devinsky O1, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA
Trends Neurosci. 2013 Mar;36(3):174-84. doi: 10.1016/j.tins.2012.11.008. Epub 2013 Jan 5.
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Zolkowska D1, Banks CN, Dhir A, Inceoglu B, Sanborn JR, McCoy MR, Bruun DA, Hammock BD, Lein PJ, Rogawski MA
J Pharmacol Exp Ther. 2012 May;341(2):435-46. doi: 10.1124/jpet.111.190579. Epub 2012 Feb 10.
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Coleman N1, Nguyen HM, Cao Z, Brown BM, Jenkins DP, Zolkowska D, Chen YJ, Tanaka BS, Goldin AL, Rogawski MA, Pessah IN, Wulff H
Neurotherapeutics. 2014 Sep 26. [Epub ahead of print]
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Cao Z, Hammock BD, McCoy M, Rogawski MA, Lein PJ, Pessah IN
Toxicol Sci. 2012 Dec;130(2):362-72.
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