Novel anticonvulsant and neuroprotective therapies for TETS and OP intoxication

针对 TETS 和 OP 中毒的新型抗惊厥药和神经保护疗法

• 批准号: 9142832
• 负责人: Pamela J Lein
• 金额: $ 13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142832
• 关键词: Acute; Analytical Chemistry; Anticonvulsants; Antidotes; Behavioral; Biological; Biological Markers; Brain Injuries; Chemicals; Cholinesterase Inhibitors; Communities; Data; Detection; Development; Diagnostic; Drug Combinations; Drug Targeting; Emergency Situation; Evaluation; Goals; Imaging technology; Immunoassay; In Vitro; Injury; Interdisciplinary Study; Intoxication; Isoflurophate; Medical; Molecular; Monitor; Neurologic; Neuropathy; Neuropharmacology; Neurosciences; Neurosciences Research; Outcome; Patients; Pharmaceutical Chemistry; Pharmacology; Readiness; Research; Research Project Grants; Seizures; Staging; Testing; Therapeutic; Translational Research; Translations; Treatment Efficacy; United States National Institutes of Health; Work; base; behavioral pharmacology; chemical release; chemical threat; drug discovery; drug market; experience; gamma-Aminobutyric Acid; imaging modality; improved; in vivo Model; in vivo imaging; innovation; metabolomics; molecular/cellular imaging; mortality; neuroimaging; neuropathology; neurotoxicology; novel; prevent; response; screening; tetramethylenedisulfotetramine; treatment strategy

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.

加州大学戴维斯分校 CounterACT 卓越中心的统一目标是确定改进的医疗对策，用于治疗诱发癫痫的化学威胁剂引起的急性中毒。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 抑制剂四亚甲基二磺四胺 (TETS) 上，它们可以说涵盖了诱发化学威胁的癫痫发作的机制范围，目的是确定具有广谱功效的治疗方法。该中心的具体目标是：(1) 确定急性癫痫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发作引起的脑损伤的治疗策略。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售药物和药物组合来实现，同时根据强有力的初步疗效数据评估新的解毒剂。待测试抗惊厥和神经保护功效的分子范围从接近可用于 IND 的化合物到早期化学探针的研究。在所有情况下，这些抗癫痫药物转化的努力都得到了诊断方面的创新工作的支持，这些工作采用新兴的体内成像技术和分析化学来监测病理效应以及目标参与和治疗效果。中心研究的其他成果将有利于 CounterACT 社区，包括：(1) 高含量的体外/离体平台，用于快速筛选化合物，以确定抗惊厥和神经保护潜力以及机制相关的新药物靶标； (2) DFP 和 TETS 诱导癫痫发作的体内模型，用于研究神经病理机制和由癫痫暴露引发的神经系统后遗症的治疗性救援； (3) 创新的体内成像方式，用于无创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，以确定癫痫损伤的生物标志物； (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、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）的研究团队，在药物发现和转化研究方面拥有丰富的经验，他们将通力合作、协同努力，以实现该中心的目标，即确定改进的医学在化学紧急情况下可以轻松部署的对策，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。