Mitigation of Neurological Damage Following Seizures

减轻癫痫发作后的神经损伤

• 批准号: 10204125
• 负责人: Pamela J Lein
• 金额: $ 101.66万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204125
• 关键词: AMPA Receptors; Acute; Address; Adolescent; Advanced Development; Affective; Allopregnanolone; Animals; Anti-Inflammatory Agents; Anticonvulsants; Antihypertensive Agents; Anxiety; Atropine; Attenuated; Behavior assessment; Behavioral; Benzodiazepines; Biochemical; Brain; Brain Injuries; Chemicals; Cholinergic Receptors; Cholinesterase Inhibitors; Clinical; Cognition; Cognitive; Cognitive deficits; Collaborations; Convulsants; Dantrolene; Data; Development; Diazepam; Dose; Electroencephalography; Electrographic Status Epilepticus; Epilepsy; Epoxide hydrolase; FDA approved; Face; Female; Goals; Histology; Human; Hypotension; Imaging Device; Inflammation Mediators; Intoxication; Intramuscular; Isoflurophate; Lead; Life; Magnetic Resonance Imaging; Measures; Medical; Medical Research; Memory Loss; Midazolam; Minocycline; Modeling; Monitor; Mood Disorders; Morbidity - disease rate; Motor; Mus; Nerve Degeneration; Nervous System Trauma; Neurologic Deficit; Neurons; Neuroprotective Agents; Neuropsychology; Organophosphates; Outcome; PTGS2 gene; Paraoxon; Peripheral; Pharmaceutical Preparations; Picrotoxin; Positron-Emission Tomography; Potassium Channel; Pre-Clinical Model; Proteins; Rattus; Recurrence; Research Institute; Research Personnel; Rest; Rodent Model; Safety; Sedation procedure; Seizures; Sodium; Soman; Status Epilepticus; Structure; Survivors; Synapses; Testing; Therapeutic; Time; aged; analog; base; chemical threat; cyclooxygenase 2; functional outcomes; improved; in vitro Model; in vivo imaging; inhibitor/antagonist; male; medical countermeasure; medication safety; mouse model; neuroinflammation; neuropathology; neuroprotection; new therapeutic target; novel; novel marker; positive allosteric modulator; prevent; receptor; sedative; side effect; small molecule; standard of care; tetramethylenedisulfotetramine; therapeutic development; treatment optimization; voltage

Project Summary – Project 3 Convulsant chemical threat agents, such as the GABAA receptor blocker tetramethylenedisulfotetramine (TETS) and the organophosphate (OP) cholinesterase inhibitor diisopropylfluorophosphate (DFP), can trigger seizures 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 (epilepsy). Current medical counter- measures fail to sufficiently protect against these neurological deficits. It is hypothesized that neuroprotection will be enhanced by: (1) improving seizure control, and (2) combining antiseizure treatment with agents that mitigate neuroinflammation and/or Ca2+ dysregulation. During the first project period, we developed a mouse model of TETS-induced SE and refined a rat model of DFP-induced SE for use in neuroprotection studies. Using these preclinical models, Projects 1 and 2 showed that allopregnanolone, a positive allosteric modulator of GABAA receptors, was a superior countermeasure for TETS-induced SE, particularly when administered at delayed times. Allopregnanolone alone or in combination with midazolam did not terminate DFP-induced SE, but the combined intramuscular administration of midazolam, allopregnanolone and a low dose of perampanel, a potent AMPA receptor antagonist, was highly effective in terminating DFP-induced behavioral and electrographic SE without causing significant sedation. We also discovered in a screen of candidate neuro- protectants that post-exposure treatment with dantrolene, a Ca2+ channel stabilizer, reduced neurodegeneration, and that a novel small molecule dual inhibitor of soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX- 2) attenuated microglial activation. Core A found that sEH inhibitors (sEHI) also normalized the hypotension associated with high-dose diazepam or midazolam. In the second project period, we will quantify the effects of antiseizure and neuroprotective treatments on neurodegenerative, neuroinflammatory and functional outcomes using in vivo imaging to longitudinally monitor brain damage with corroborative histology, 24 h video electroencephalography to quantify recurrent seizures, and behavioral assessments of cognitive, affective and motor function. Our goals are to: (1) obtain neuroprotection data to support the advance of our antiseizure lead allopregnanolone; (2) obtain proof-of-concept neuroprotective efficacy data for perampanel alone or in combination with allopregnanolone; and (3) identify neuroprotectant leads, with an initial focus on our most promising candidate compounds: sEHI, the dual sEH-COX-2 inhibitor and dantrolene. We will continue testing additional antiseizure candidates identified by Project 2 and novel neuroprotective treatments identified in Project 1 using in vitro models. Superior neuroprotective treatments identified in this project will be tested by Project 2 to assess whether they interact with antiseizure treatments. Results from this project will support transition of allopregnanolone to advanced development and assess whether perampanel, other candidate antiseizure treatments, or candidate neuroprotective treatments, should become development leads.

项目总结 – 项目 3 惊厥性化学威胁剂，例如 GABAA 受体阻滞剂四亚甲基二磺四胺 (TETS) 和有机磷酸酯 (OP) 胆碱酯酶抑制剂二异丙基氟磷酸盐 (DFP)，可引发癫痫发作 进展为危及生命的癫痫持续状态 (SE)。幸存者面临严重的长期发病率，包括 轻度至重度记忆丧失、情感障碍和反复发作（癫痫）。目前医疗反 措施未能充分预防这些神经缺陷。据推测，神经保护作用 将通过以下方式得到增强：(1) 改善癫痫发作控制，以及 (2) 将抗癫痫治疗与药物相结合 减轻神经炎症和/或 Ca2+ 失调。在第一个项目期间，我们开发了一款鼠标 TETS 诱导的 SE 模型，并改进了 DFP 诱导的 SE 的大鼠模型，用于神经保护研究。使用 这些临床前模型，项目 1 和 2 表明，allopregnanolone，一种正变构调节剂 GABAA 受体是 TETS 诱导的 SE 的优越对策，特别是在 延迟的时间。单独使用别孕酮或与咪达唑仑联合使用并不能终止 DFP 诱导的 SE， 但联合肌内注射咪达唑仑、别孕酮和低剂量吡仑帕奈， 一种有效的 AMPA 受体拮抗剂，在终止 DFP 诱导的行为和行为方面非常有效 电图 SE 不会引起明显的镇静作用。我们还在候选神经筛选中发现 暴露后使用丹曲林（一种 Ca2+ 通道稳定剂）进行治疗的保护剂，可减少神经变性， 一种新型小分子可溶性环氧化物水解酶（sEH）和环氧合酶-2（COX- 2）小胶质细胞活化减弱。 Core A 发现 sEH 抑制剂 (sEHI) 还可使低血压正常化 与大剂量地西泮或咪达唑仑相关。在第二个项目期间，我们将量化 针对神经退行性、神经炎症和功能结果的抗癫痫和神经保护治疗 使用体内成像纵向监测脑损伤并提供确凿的组织学、24 小时视频 脑电图量化复发性癫痫发作，以及认知、情感和行为评估 运动功能。我们的目标是：(1) 获得神经保护数据以支持我们的抗癫痫药物的进展 别孕酮； (2) 获得单独使用吡仑帕奈或联合使用吡仑帕奈的概念验证神经保护功效数据 与四异孕酮组合； (3) 确定神经保护剂线索，首先关注我们最关心的问题 有前途的候选化合物：sEHI、双重 sEH-COX-2 抑制剂和丹曲林。我们将继续测试 项目 2 确定的其他抗癫痫候选药物以及项目中确定的新型神经保护治疗方法 1 使用体外模型。本项目确定的优质神经保护疗法将由项目 2 进行测试 评估它们是否与抗癫痫治疗相互作用。该项目的结果将支持过渡 四氢孕酮促进开发并评估吡仑帕奈和其他候选抗癫痫药物是否有效 治疗或候选神经保护治疗应该成为发展的主导。