Project 1: Reduction of Pro-Inflammatory Signaling

项目概要 – 项目 1 惊厥性化学威胁剂，例如有机磷酸酯 (OP)、二异丙基氟磷酸酯 (DFP) 和 Soman 可能引发癫痫发作，进而发展为危及生命的癫痫持续状态 (SE)。幸存者面临着重大的、 长期发病率，包括自发性复发性癫痫发作（SRS）和轻度至重度记忆丧失。当前 医疗对策无法充分预防这些长期神经功能缺陷。项目1将 使用成熟的急性 DFP 中毒大鼠模型来检验以下假设： 当作为标准护理的辅助手段施用时，炎症的消退将减轻长期的不利影响 急性 OP 中毒的神经系统后果。该假设的科学前提包括 实验证据表明：(1) 急性 OP 中毒会在多种疾病中引发强烈的神经炎症反应 持续长达 6 个月的大脑区域； (2) 促炎症信号传导与 非 OP 模型中的癫痫发生和认知功能障碍。我们将把最初的努力集中在脂质介质上 炎症。我们对 DFP 急性中毒大鼠脑脂质组的分析表明了两种潜在的可能性 治疗方法：抑制环氧合酶-2 (COX-2) 以阻止前列腺素的形成，以及 抑制酶溶性环氧化物水解酶（sEH）以稳定抗炎脂质介质。一个小 加州大学戴维斯分校开发的 sEH 分子抑制剂 (sEHI) 已被证明可以显着减弱 SRS 毛果芸香碱诱发癫痫的临床前模型，改善阿尔茨海默病临床前模型的认知功能 疾病（AD），并减少 AD、中风和帕金森病模型的病理。我们的初步数据 表明 sEHI 还可以减轻大鼠 DFP 模型中的神经炎症并终止 SRS。我们的目标是： (1) 表征急性 DFP 后雄性和雌性大鼠神经炎症的时空特征 中毒，以确定治疗靶点，确定治疗窗口，并开发可翻译的 预测 SRS 和/或认知功能障碍的炎症生物标志物。 (2) 神经保护作用评价 sEHI 和其他针对雄性和雌性大鼠失调炎症介质的化合物的功效 DFP 严重中毒。 (3) 确定治疗先导药物的安全性及其保护功效 对抗急性索曼中毒大鼠模型中的不良神经后果。如果成功，项目 1 将确定新的治疗先导药物，当用作辅助治疗时可改善长期神经系统结果 护理标准，以及识别个体发生 SRS 和/或的风险增加的生物标志物 急性OP中毒后的认知缺陷。

Project Summary – Project 1 Convulsant chemical threat agents, such as the organophosphates (OPs) diisopropylfluorophosphate (DFP) and soman, can trigger seizures that progress to life-threatening status epilepticus (SE). Survivors face significant, long-term morbidity, including spontaneous recurrent seizures (SRS) and mild-to-severe memory loss. Current medical countermeasures fail to sufficiently protect against these long-term neurological deficits. Project 1 will use a well-established rat model of acute DFP intoxication to test the hypothesis that therapies that promote resolution of inflammation when administered as adjuncts to standard of care will mitigate the long-term, adverse neurological consequences of acute OP intoxication. The scientific premise for this hypothesis includes experimental evidence that: (1) acute OP intoxication triggers a robust neuroinflammatory response in multiple brain regions that persists for up to 6 months; and (2) pro-inflammatory signaling is causally linked to epileptogenesis and cognitive dysfunction in non-OP models. We will focus our initial efforts on lipid mediators of inflammation. Our analyses of the brain lipidome in rats acutely intoxicated with DFP suggests two potential therapeutic approaches: inhibiting cyclooxygenase-2 (COX-2) to block the formation of prostaglandins, and inhibiting the enzyme soluble epoxide hydrolase (sEH) to stabilize anti-inflammatory lipid mediators. A small molecule inhibitor of sEH (sEHI) developed at UC Davis has been shown to significantly attenuate SRS in preclinical models of pilocarpine-induced epilepsy, improve cognitive function in preclinical models of Alzheimer’s disease (AD), and reduce pathology in models of AD, stroke and Parkinson’s disease. Our preliminary data suggest that sEHI also mitigates neuroinflammation and terminates SRS in the rat DFP model. Our goals are to: (1) Characterize the spatiotemporal profile of neuroinflammation in male and female rats following acute DFP intoxication in order to identify therapeutic targets, determine therapeutic windows, and develop translatable biomarkers of inflammation that predict SRS and/or cognitive dysfunction. (2) Evaluate the neuroprotective efficacy of sEHI and other compounds that target dysregulated inflammatory mediators in male and female rats acutely intoxicated with DFP. (3) Determine the safety of therapeutic lead(s) and their efficacy in protecting against adverse neurological consequences in a rat model of acute soman intoxication. If successful, Project 1 will identify novel therapeutic lead(s) that improve long-term neurological outcomes when used as adjuncts to standard of care, as well as biomarkers that identify individuals at increased risk for developing SRS and/or cognitive deficits following acute OP intoxication.