UC Davis CounterACT Center of Excellence: Developing Therapeutic Strategies for Mitigating the Chronic Neurological Consequences of Acute Organophosphate Intoxication

项目摘要--总体 新的加州大学戴维斯分校卓越对抗中心的主要目标是识别和开发新的 作为现场标准护理(SOC)治疗的辅助治疗策略 急性有机磷(OP)中毒将减轻长期的、不利的 神经后果。该中心的首要假设是，治疗策略 减少脑部炎症，保护血脑屏障(BBB)功能，和/或使神经元正常化 在改善长期神经预后方面，兴奋性将比单独使用SOC更有效。现代医学 对策可以降低有机磷农药中毒患者的死亡率，但它们不能提供预防 急性OP中毒相关的长期神经后遗症，除非在 暴露几分钟，如果发生意外、自杀或与恐怖分子有关的事件，这是不太可能的情况 曝光。这些局限性突显了改进医疗对策的迫切需要。《中心》 由三个研究项目组成：项目1将评估减少 神经炎症；项目2将评估保护血脑屏障功能的策略；项目3将测试 使神经元兴奋性正常化的药理学和电生理学策略。三大科学核心 支持项目：分析和药物化学核心将支持生物标记物检测、药物 化学、配方和PK研究；神经成像核心将在体内提供临床前和高含量 统计核心将为实验设计和数据分析提供支持。研究性教育 核心将提供对策研究方面的培训，行政核心将作为中心的 负责和管理新兴科学和科学家试点项目计划。该中心将使用两个 急性OP中毒的临床前模型：二异丙基氟磷酸盐急性中毒大鼠模型 (DFP)和急性梭曼中毒大鼠模型，概括了急性(胆碱能)危象和状态 癫痫)和慢性(进行性神经病理、自发性反复发作和认知 损害)在急性有机磷农药中毒的人身上观察到的效果。我们在第一个项目阶段的目标是： (1)基于对慢性不良反应发病机制的研究，确定新的治疗靶点 急性有机磷农药中毒的神经影响。(2)开发治疗候选药物，当单独或在 联合作为SOC的辅助治疗可预防或减轻慢性神经毒性。候选治疗药物包括 新型小分子可溶性环氧化物水解酶抑制物(SEH)、纤溶酶原激活物抑制物-1(PAI-1)或 Calain；Kca通道激活剂；以及美国食品和药物管理局批准的疗法(IL-1β阻滞剂、离子通道调节剂和深 脑刺激)。(3)确定生物标志物(血液中的分子，以及脑电生理学， 神经影像和行为指标)，可转化为临床用于预测发展 暴露个体中的SRS和认知功能障碍。

Project Summary – Overall The primary objective of the new UC Davis CounterACT Center of Excellence is to identify and develop novel therapeutic strategies that when administered as an adjunct to in-field standard of care (SOC) treatments for acute organophosphate (OP) intoxication will mitigate the onset and/or severity of long-term, adverse neurological consequences. The overarching hypothesis of the Center is that therapeutic strategies that reduce inflammation in the brain, protect blood-brain barrier (BBB) function, and/or normalize neuronal excitability will be more effective than SOC alone in improving long-term neurological outcomes. Current medical countermeasures can reduce mortality in OP-intoxicated individuals, but they do not provide protection against the long-term neurological sequelae associated with acute OP intoxication unless they are administered within minutes of exposure, which is an unlikely scenario in the event of accidental, suicidal or terrorist-related exposures. These limitations underscore the urgent need for improved medical countermeasures. The Center consists of three Research Projects: Project 1 will evaluate novel therapeutic candidates that reduce neuroinflammation; Project 2 will assess strategies for protecting BBB function; and Project 3 will test pharmacologic and electrophysiologic strategies for normalizing neuronal excitability. Three Scientific Cores support the Projects: the Analytical and Medicinal Chemistry Core will support biomarker detection, medicinal chemistry, formulation and PK studies; the Neuroimaging Core will provide preclinical in vivo and high-content imaging; and the Statistics Core will support experimental design and data analyses. A Research Education Core will provide training in countermeasure research, and an Administrative Core will function as the Center’s hub and administer the Emerging Science and Scientists Pilot Project Program. The Center will use two preclinical models of acute OP intoxication: the rat model of acute intoxication with diisopropylfluorophosphate (DFP) and the rat model of acute soman intoxication, which recapitulate the acute (cholinergic crisis and status epilepticus) and chronic (progressive neuropathology, spontaneous recurrent seizures (SRS) and cognitive impairment) effects observed in humans acutely intoxicated with OPs. Our goals in this 1st project period are to: (1) Identify novel therapeutic targets based on mechanistic studies of the pathogenesis of chronic, adverse neurological effects of acute OP intoxication. (2) Develop therapeutic candidates that when given singly or in combination as adjunct therapy to SOC prevent or mitigate chronic neurotoxicity. Therapeutic candidates include novel small molecule inhibitors of soluble epoxide hydrolase (sEH), plasminogen activator inhibitor-1 (PAI-1), or calpain; KCA channel activators; and FDA-approved therapies (IL-1β blocker, ion channel modulators and deep brain stimulation). (3) Identify biomarkers (blood-borne molecules, as well as brain electrophysiology, neuroimaging and behavioral indices) that can be translated to clinical use for predicting the development of SRS and cognitive dysfunction in exposed individuals.