Novel Anticonvulsant and Neuroprotective Therapies for TETS and OP Intoxication

针对 TETS 和 OP 中毒的新型抗惊厥和神经保护疗法

基本信息

批准号：
10204117
负责人：
Pamela J Lein
金额：
$ 364.92万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204117
关键词：
AMPA Receptors Acute Address Adolescent Advanced Development Allopregnanolone Analytical Chemistry Animals Anticonvulsants Antidotes Atropine Biological Markers Brain Injuries Cessation of life Chemicals Cholinesterase Inhibitors Chronic Brain Injury Cognitive deficits Convulsants Convulsions Dantrolene Data Data Analyses Detection Development Diazepam Dose Drug Screening Epilepsy Epoxide hydrolase Experimental Designs Exposure to Face Female Formulation General Population Goals Human In Vitro Individual Infrastructure Interdisciplinary Study Intoxication Investigational Drugs Isoflurophate Lead Life Medical Memory Loss Microglia Midazolam Modeling Monitor Mood Disorders Morbidity - disease rate Neurologic Neurologic Deficit Neuropharmacology Neuroprotective Agents Organophosphates Outcome PTGS2 gene Paraoxon Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Picrotoxin Pre-Clinical Model Readiness Recurrence Research Research Project Grants Rodent Safety Scientist Seizures Soman Status Epilepticus Survivors Testing Therapeutic Toxic effect Toxicology Training Support Treatment Efficacy United States Food and Drug Administration aged antibody detection authority base chemical disaster chemical threat cyclooxygenase 2 data management drug development drug discovery drug market education research efficacy study imaging approach improved in vitro Model in vivo evaluation in vivo imaging inhibitor/antagonist innovation male medical countermeasure meetings mortality neuroimaging neuroinflammation neuron loss neuropathology neurosteroids next generation nonhuman primate novel novel therapeutics operation pharmacokinetics and pharmacodynamics positive allosteric modulator prevent receptor research and development safety study screening side effect small molecule standard of care statistics tetramethylenedisulfotetramine therapeutic candidate therapeutic target translational neuroscience

项目摘要

The primary objective of the UC Davis CounterACT Center of Excellence is to identify and advance improved medical countermeasures for rapidly terminating seizures and mitigating the delayed neurologic consequences following acute intoxication with convulsant chemical threat agents. The Center comprises three research projects: Project 1 discovers therapeutic candidates via in vitro mechanistic screens, which are tested for in vivo antiseizure and neuroprotective efficacy by Projects 2 and 3, respectively. The projects rely on three scientific cores to support drug analysis and biomarker detection (Core A), medicinal chemistry and pharmacological testing (Core B), and experimental design and data analysis (Core C). A Research Education Core supports training in countermeasure research, and an Administrative Core oversees and coordinates scientific and administrative operations. The Center focuses on the GABAA receptor antagonist tetramethylenedisulfotetramine (TETS) and the organophosphate cholinesterase inhibitor diisopropylfluorophosphate (DFP), which can trigger convulsions that progress to life threatening status epilepticus (SE). Survivors face significant, long-term morbidity, including mild-to-severe memory loss, affective disorders and recurrent seizures. Current medical countermeasures can reduce mortality in exposed individuals, but they do so with significant side effects and are maximally effective only if administered within minutes of exposure. These limitations underscore the urgent need for improved medical countermeasures. In the first project period, we developed innovative in vitro platforms for mechanism-based screening to identify candidate antiseizure and neuroprotective therapeutics, and novel preclinical models that recapitulate acute seizure activity and neurological deficits observed in humans following acute intoxication with TETS or OPs. Using these models, we discovered: (1) allopregnanolone, a GABAA receptor positive allosteric modulator, was a superior countermeasure for TETS-induced SE, and (2) combining standard-of-care with allopregnanolone and a low dose of perampanel, a potent AMPA receptor antagonist, was more effective than standard-of-care alone in terminating DFP-induced SE. We also discovered that neuropathology was mitigated by post-exposure treatment with dantrolene, a Ca2+ channel stabilizer, or a novel small molecule dual inhibitor of soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2). Our goals in this second project period are to: (1) advance our antiseizure lead allopregnanolone; (2) continue development of allopregnanolone and perampanel; (3) identify adjunct neuroprotective leads, focusing initially on the dual sEH-COX-2 inhibitor and dantrolene; and (4) conduct mechanistic studies to discover new therapeutic candidates. Our milestones for the second project period are to: (i) produce data and a regulatory strategy to advance allopregnanolone for treatment of GABAAR antagonist-induced seizures; (ii) determine whether combination treatment with allopregnanolone and perampanel warrants development as a lead “universal antidote”; and (iii) identify lead neuroprotective treatments for improving long-term outcomes.

加州大学戴维斯分校 CounterACT 卓越中心的主要目标是确定并推进改进的快速终止癫痫发作并减轻迟发性神经系统后果的医疗对策该中心包括三项研究。项目：项目 1 通过体外机械筛选发现治疗候选药物，并进行体内测试项目 2 和 3 分别具有抗癫痫和神经保护功效。支持药物分析和生物标志物检测（核心 A）、药物化学和药理学的核心测试（核心 B）以及实验设计和数据分析（核心 C）支持研究教育核心。对策研究培训，行政核心负责监督和协调科学和技术该中心专注于 GABAA 受体拮抗剂四亚甲基二磺四胺。（TETS）和有机磷酸酯胆碱酯酶抑制剂二异丙基氟磷酸盐（DFP），可触发惊厥发展为危及生命的癫痫持续状态 (SE) 幸存者面临着严重的长期威胁。发病率，包括轻度至重度记忆丧失、情感障碍和复发性癫痫发作。对策可以降低暴露个体的死亡率，但这样做会带来显着的副作用只有在暴露后几分钟内给药才能发挥最大效果，这些都强调了紧迫的局限性。需要改进的医疗对策在第一个项目期间，我们开发了创新的体外技术。基于机制的筛选平台，以确定候选抗癫痫和神经保护疗法，以及重现人类观察到的急性癫痫发作活动和神经功能缺损的新型临床前模型在 TETS 或 OP 急性中毒后，我们发现：(1) allopregnanolone，一种 GABAA 受体正变构调节剂，是 TETS 诱导的 SE 的优越对策，并且 (2) 将标准护理与四氢孕酮和低剂量吡仑帕奈（一种有效的 AMPA 受体）相结合我们还发现，拮抗剂在终止 DFP 诱导的 SE 方面比单独使用标准护理更有效。神经病理学可通过丹曲林、Ca2+通道稳定剂或新型小分子可溶性环氧化物水解酶 (sEH) 和环氧合酶-2 (COX-2) 双重抑制剂。第二个项目期的目标是：(1) 推进我们的抗惊厥先导药物四氢孕酮；(2) 继续推进开发四氢孕酮和吡仑帕奈；(3) 确定辅助神经保护药物，首先重点关注 sEH-COX-2 双重抑制剂和丹曲林；(4) 进行机制研究以发现新的我们第二个项目期的里程碑是：（i）产生数据和监管。推进四氢孕酮治疗 GABAAR 拮抗剂引起的癫痫发作的策略；(ii) 确定四氢孕酮和吡仑帕奈的联合治疗是否值得作为先导药物进行开发 “通用解毒剂”；以及（iii）确定改善长期结果的主要神经保护治疗方法。

项目成果

期刊论文数量（52）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment-resistant status epilepticus.

DOI：
10.1111/epi.13999
发表时间：
2018-10
期刊：
Epilepsia
影响因子：
5.6
作者：
Zolkowska D;Wu CY;Rogawski MA
通讯作者：
Rogawski MA

A Microfluidic Platform to Study Astrocyte Adhesion on Nanoporous Gold Thin Films.

DOI：
10.3390/nano8070452
发表时间：
2018-06-21
期刊：
Nanomaterials (Basel, Switzerland)
影响因子：
0
作者：
Hampe AE;Li Z;Sethi S;Lein PJ;Seker E
通讯作者：
Seker E

Perampanel, a potent AMPA receptor antagonist, protects against tetramethylenedisulfotetramine-induced seizures and lethality in mice: comparison with diazepam.

DOI：
10.1007/s00204-021-03053-9
发表时间：
2021-07
期刊：
Archives of toxicology
影响因子：
6.1
作者：
Zolkowska D;Dhir A;Rogawski MA
通讯作者：
Rogawski MA

Importance of membrane selection in the development of immunochromatographic assays for low-molecular weight compounds.

膜选择在低分子量化合物免疫层析测定开发中的重要性。

DOI：
10.1016/j.aca.2012.10.052
发表时间：
2012
期刊：
Analytica chimica acta
影响因子：
6.2
作者：
Lee,Ji-Ye;Kim,YoungAh;Kim,MiYeon;Lee,YongTae;Hammock,BruceD;Lee,Hye-Sung
通讯作者：
Lee,Hye-Sung

Novel image analysis tool for rapid screening of cell morphology in preclinical animal models of disease.

用于快速筛选临床前动物疾病模型中细胞形态的新型图像分析工具。

DOI：
10.1016/j.heliyon.2023.e13449
发表时间：
2023-02
期刊：
HELIYON
影响因子：
4
作者：
Guignet, Michelle;Schmuck, Martin;Harvey, Danielle J.;Nguyen, Danh;Bruun, Donald;Echeverri, Angela;Gurkoff, Gene;Lein, Pamela J.
通讯作者：
Lein, Pamela J.