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，导致一系列复杂的致命 中枢和外周神经系统毒性。确定新的和改进的治疗方法和/或 预防暴露在化学威胁下的中枢神经系统(CNS)损伤是 美国国立卫生研究院化学威胁对策(中)计划。这项拨款提案寻求支持 用于鉴定阻断癫痫持续状态(SE)的小分子候选化合物 由化学战剂暴露引起的癫痫发作。这项提案的目标是测试 作为标准医学对策辅助的合成神经活性类固醇的抗惊厥效果 在延迟治疗的啮齿动物模型中治疗梭曼诱发的SE。我们的研究将得出综合可行的结论 具有生物活性的化合物，具有特异性、亲和力、效力、有效性和靶向选择性 含α-氨基丁酸-A受体的突触外β4-δ3γ亚单位对中枢神经系统的拮抗作用 OP神经毒剂暴露引起的毒性。我们建议在体内证明概念验证的有效性 一种先导优化化合物的数据为先进的治疗开发做好准备，外加适当的备份 分子。这项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策的策略 曝光。

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.