Neurosteroid Treatment for OP Intoxication

描述（由申请人提供）：该项目的总体目标是开发一种新型的广谱神经类固醇疗法，以减轻因急性暴露于神经毒剂和有机磷（OP）农药而引起的发病率和死亡率，这些毒剂和有机磷（OP）农药是军事和平民的可靠威胁剂。暴露于神经毒剂或OP中毒可导致持续癫痫发作、癫痫持续状态（SE）和永久性脑损伤。目前用于神经中毒的抗惊厥对策（苯二氮卓类药物）不能充分保护大脑免受SE的影响，SE是持续30分钟或更长时间的癫痫发作活动，具有显著的神经元损伤和死亡率。我们认为，与苯二氮卓类药物相比，增强相位和突触外强直性抑制的神经类固醇和选择性药物可以更有效地预防持续性SE，预防不可逆脑损伤，并延长治疗窗口期。这种新的治疗策略是基于神经类固醇的新分子机制和涉及SE的细胞变化，这是一种常见的神经毒剂的神经毒性。神经类固醇是对抗胆碱能药物引起的癫痫发作的最有效的抗惊厥药物。由于OP神经毒剂通过胆碱能过度激活引起持续癫痫发作和脑损伤，因此提出神经类固醇比苯二氮卓类药物更有效地治疗OP神经中毒。我们有初步证据表明，在匹罗卡品和DFP模型中，晚期暴露后神经类固醇治疗可以迅速控制SE，并在SE后起到神经保护作用，这表明神经类固醇治疗的疗效很有希望。本项目旨在探讨合成神经类固醇加那洛酮及其类似物作为神经毒剂和OP农药中毒的“广谱”医学对策的有效性和安全性。这是我们r21的逻辑扩展，用于进一步的功效验证，先导优化和IND应用。主要重点是生成有关主要候选药物的有效性和安全性的必要数据，并在5年内提交IND申请。为了开发出比地西泮更有效的神经类固醇，我们将解决三个具体目标：（目标1）：确定加那洛龙对DFP和梭曼诱导的SE和脑损伤的疗效；（目标2）：开发加那洛酮类似物，改善处方药代动力学和对DFP和soman诱导的SE和脑损伤的疗效；（目标3）：确定加那洛酮或其先导类似物的临床前安全性和毒性，并根据FDA动物规则途径提交IND临床开发。该项目将按照渐进式的“进行/不进行”里程碑计划实施，其中包括关键研究成功的定量标准，重点是三个主要结果衡量指标：(i)抗惊厥疗效；（ii）神经保护剂的功效；（三）预防神经退行性变。该项目的结果将确定一种有效的解毒剂，以治疗OP中毒，并加强对紧急情况的准备。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a novel, broad-spectrum neurosteroid therapy that will mitigate the morbidity and mortality caused by acute exposure to nerve agents and organophosphate (OP) pesticides, which are credible threat agents for military and civilian populations. Exposure to nerve agents or OP poisoning can result in persistent seizures, status epilepticus (SE), and permanent brain injury. Current anticonvulsant countermeasures (benzodiazepines) for nerve intoxication do not sufficiently protect the brain from SE, a prolonged seizure activity lasting 30 min or longer with significant neuronal injury and mortality. We propose that neurosteroids and selective drugs that enhance phasic and extrasynaptic tonic inhibition produce more effective protection against persistent SE than benzodiazepines, prevent irreversible brain injury, and extend the therapeutic window. This novel therapeutic strategy is based on the emerging molecular mechanisms of neurosteroids and also cellular changes involved in SE, a common neurotoxicity by nerve agents. Neurosteroids are the most powerful anticonvulsants against seizures induced by cholinergic agents. Since OP nerve agents cause persistent seizures and brain damage through cholinergic hyperactivation, it is proposed that neurosteroids are more effective anticonvulsants for OP nerve intoxication than benzodiazepines. We have pilot evidence that late post-exposure neurosteroid therapy can rapidly control SE and be neuroprotective after SE in pilocarpine and DFP models, suggesting the promising efficacy of neurosteroid therapy. The objective of this project is to investigate the efficacy and safety of the synthetic neurosteroid ganaxolone and its analogs as 'broad-spectrum' medical countermeasures for nerve agent and OP pesticide intoxication. This is a logical extension of our R21s for further efficacy validation, lead optimization, and IND application. The primary emphasis is to generate requisite data on the efficacy and safety of the lead candidate and submit an IND application within a 5 year period. To develop neurosteroids as superior countermeasures than diazepam, we will address three specific aims: (Aim 1): Determine the efficacy of ganaxolone against DFP- and soman-induced SE and brain damage; (Aim 2): Develop ganaxolone analogs with improved formulation pharmacokinetics and efficacy against DFP- and soman-induced SE and brain damage; and (Aim 3): Determine the preclinical safety and toxicity of ganaxolone or its lead analog and submit an IND for clinical development under the FDA Animal Rule Pathway. The project will be implemented as per the progressive "go/no-go" milestones plan, which includes quantitative criteria for the success of key studies focusing on three primary outcome measures: (i) anticonvulsant efficacy; (ii) neuroprotectant efficacy; and (iii) prevention of neurodegeneration. The outcome from this project will identify an effective antidote for OP intoxication and enhance readiness for emergencies.