Novel anticonvulsant and neuroprotective therapies for TETS and OP intoxication

加州大学戴维斯分校对抗卓越中心的统一目标是确定改进的医疗对策，以治疗急性中毒与诱发癫痫的化学威胁剂。研究将集中在有机磷（OP）胆碱酯酶抑制剂二异丙基氟磷酸（DFP）和gaba抑制剂三亚甲基二硫四胺（TETS）上，这两种药物可能包括诱发癫痫发作的化学威胁的机制谱，目的是确定具有广谱疗效的治疗方法。该中心的具体目标是：(1)确定急性发作和致死率的改进治疗方法；(2)确定缓解急性中毒患者癫痫引起的脑损伤的治疗策略。这将通过重新定位已上市药物和药物组合来实现，用于治疗由化学威胁剂引发的癫痫发作，同时根据强有力的初步疗效数据评估新的解毒剂。用于抗惊厥和神经保护功效测试的分子包括从接近IND研究准备的化合物到早期化学探针。在所有情况下，这些抗癫痫药物的翻译工作都得到了创新诊断工作的支持，这些诊断工作采用了新兴的体内成像技术和分析化学来监测病理效应、靶标接合和治疗效果。中心研究的其他成果将使中和社区受益，包括：(1)用于快速筛选化合物的高含量体外/离体平台，以确定抗惊厥和神经保护潜力以及机制相关的新药物靶点；(2) DFP和tets诱导癫痫发作的体内模型，用于研究癫痫尿源性暴露引发的神经系统后遗症的发病机制和治疗性救援；(3)创新的体内成像模式，用于无创的神经损伤纵向监测和对候选治疗方案的反应；(4)集中代谢组学分析鉴定癫痫发作损害的生物标志物；(5)用于检测生物和环境基质中TETS的创新免疫测定法。一个高度整合的跨学科(药理学，药物化学，神经毒理学，分析化学，行为神经科学，影像学，具有药物发现和转化研究经验的细胞/分子神经科学研究团队将进行合作和协同工作，以实现中心的目标，即确定可在化学紧急情况下随时部署的改进医疗对策，以阻止癫痫发作并减轻由TETS和OPs引发的癫痫发作的神经系统后遗症。

The unifying goal of the UC Davis CounterACT Center of Excellence is to identify improved medical countermeasures for treating acute intoxication with seizure-inducing chemical threat agents. Research will focus on the organophosphorus (OP) cholinesterase inhibitor diisopropylfluorophosphate (DFP) and the GABA-inhibiting agent tramethylenedisulfotetramine (TETS), which arguably encompass the mechanistic spectrum of seizure inducing chemical threats, with the goal of identifying therapeutic approaches with broad-spectrum efficacy. The specific objectives of the Center are to: (1) identify improved treatments for acute seizures and lethality; and (2) identify therapeutic strategies for mitigating seizure-induced brain damage in patients that survive acute intoxication. This will be accomplished by repositioning marketed drugs and drug combinations for treatment of seizures triggered by chemical threat agents, in parallel with evaluation of new antidotes based on strong preliminary efficacy data. The molecules to be tested for anticonvulsant and neuroprotective efficacy range from compounds approaching readiness for IND enabling studies to early stage chemical probes. In all cases, these efforts in translation of anti-seizure agents are supported by innovative work on diagnostics employing emerging in vivo imaging technologies and analytical chemistry for monitoring pathological effects as well as target engagement and therapeutic efficacy. Additional outcomes from Center research that will benefit the CounterACT community include: (1) a high content in vitro/ex vivo platform for rapid screening of compounds to identify anticonvulsant and neuroprotective potential as well as mechanistically relevant novel drug targets; (2) in vivo models of DFP and TETS-induce seizures for studying neuropathic mechanisms and therapeutic rescue of neurologic sequelae triggered by seizurogenic exposures; (3) innovative in vivo imaging modalities for non-invasive longitudinal monitoring of neurologic damage and response to therapeutic candidates; (4) focused metabolomic profiling to identify biomarkers of seizure damage; and (5) innovative immunoassays for the detection of TETS in biological and environmental matrices. A highly integrated, interdisciplinary (pharmacology, medicinal chemistry, neurotoxicology, analytical chemistry, behavioral neuroscience, imaging, cellular/molecular neuroscience) research team with experience in drug discovery and translational research will work cooperatively and synergistically to achieve the Center's goal of identifying improved medical countermeasures that can be readily deployed during a chemical emergency to stop seizures and mitigate the neurological sequelae of seizures triggered by TETS and OPs.