Neurosteroids as a standard medical countermeasure for OP poisoning

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Acute organophosphorous poisoning is a military and civilian threat that causes a complex cascade of lethal central and peripheral nervous system toxicities. Identifying new and improved therapeutics to treat and/or prevent central nervous system (CNS) injuries resulting from exposure to chemical threats is a mission for the NIH Countermeasures Against Chemical Threats (CounterACT) program. This grant proposal seeks support for research on the identification of a small molecule lead candidate compound to block status epilepticus (SE) seizures caused by chemical warfare agent exposure. The objective of this proposal is to test the anticonvulsant efficacy of synthetic neuroactive steroids as an adjunct to standard medical countermeasures for soman-induced SE in a delayed treatment rodent model. Our studies will result in synthetically feasible compounds that are biologically active with specificity, affinity, potency, efficacy and target selectivity towards extrasynaptic α4β3δ subunit containing γ-aminobutyric acid-A receptors (GABAARs) for counteracting CNS toxicities arising from OP nerve agent exposure. We propose to demonstrate in vivo proof-of-concept efficacy data of one lead optimization compound ready for advanced therapeutic development plus a suitable backup molecule. The impact of the proposed research will be to understand if pharmacological targeting of extrasynaptic GABAARs is a strategy for designing effective medical countermeasures to chemical weapons exposure.