Neurosteroids as a standard medical countermeasure for OP poisoning

急性有机磷中毒是一种军事和民用威胁，会导致一系列复杂的致命疾病， 中枢和外周神经系统毒性。鉴定新的和改进的治疗剂以治疗和/或 防止中枢神经系统（CNS）因暴露于化学威胁而受到伤害是化学品安全局的使命， 美国国立卫生研究院化学威胁对策（CounterACT）计划。这项拨款建议寻求支持 用于鉴定阻断癫痫持续状态（SE）的小分子先导候选化合物的研究 因接触化学战剂引起的癫痫发作。本提案的目的是测试 合成神经活性类固醇作为标准医疗对策的辅助抗惊厥效果 在延迟给药啮齿动物模型中梭曼诱导的SE。我们的研究将导致综合可行的 具有特异性、亲和力、效力、功效和靶向选择性的生物活性的化合物， 用于对抗CNS的含有γ-氨基丁酸-A受体（GABAARs）的突触外α4β3δ亚基 OP神经毒剂暴露引起的毒性。我们建议证明体内概念验证的功效 一种先导优化化合物的数据，可用于高级治疗开发，加上合适的备份 分子。拟议研究的影响将是了解药物靶向是否 突触外GABAARs是一种设计有效的化学武器医学对抗措施的策略 exposure.

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.