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用于治疗急性中毒的改进医学对策，这些药物可导致癫痫发作。研究将集中在有机磷(OP)胆碱酯酶抑制剂二异丙基氟磷酸盐(DFP)和GABA抑制剂曲亚甲基二磺酸毒鼠强(TETS)，这两种药物可以说涵盖了诱发癫痫的化学威胁的机制谱，目的是确定具有广泛疗效的治疗方法。该中心的具体目标是：(1)确定改进的急性癫痫发作和致命性治疗方法；(2)确定减轻急性中毒幸存者癫痫所致脑损伤的治疗策略。这将通过重新定位用于治疗化学威胁剂引发的癫痫发作的市场药物和药物组合来实现，同时根据强大的初步疗效数据评估新的解毒剂。接受抗惊厥和神经保护功效测试的分子范围从接近准备进行IND研究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的诊断工作的支持，这些工作利用新兴的活体成像技术和分析化学来监测病理效应以及靶标参与和治疗效果。中心研究将使中和社区受益的其他成果包括：(1)高含量体外/体外化合物筛选平台，以快速筛选化合物，以确定抗惊厥和神经保护的潜力以及机制上相关的新型药物靶点；(2)DFP和TETS诱导癫痫的体内模型，用于研究癫痫发作的神经病理机制和治疗抢救；(3)创新的体内成像方法，非侵入性地纵向监测神经损伤和候选治疗药物的反应；(4)重点代谢组学分析，以确定癫痫损害的生物标志物；(5)创新的免疫分析方法，用于检测生物和环境基质中的TETS。一个具有药物发现和转化研究经验的高度整合的跨学科(药理学、药物化学、神经毒理学、分析化学、行为神经科学、成像、细胞/分子神经科学)研究团队将通力合作，协同工作，以实现该中心的目标，即确定可以在化学紧急情况下轻松部署的改进的医疗对策，以阻止癫痫发作，并减轻TETS和OP引发的癫痫发作的神经后遗症。

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.