Saracatinib Mitigates OP nerve agent-induced Long-term Neurotoxicity

化学战神经毒剂（NA）越来越多地用于攻击世界各地的平民。过去的沙林毒气袭击 在东京，VX在马来西亚杀人袭击中的使用，最近在叙利亚对平民的沙林袭击，以及最严重的 最近在英国发生的Novichok（“新来者”）袭击再次表明了化学战对平民的真实的威胁 人口NA在恐怖分子手中对全球人类健康构成威胁，目前我们缺乏有效的 对幸存者的治疗。直到最近，预防NA暴露导致的急性死亡一直是最优先考虑的问题。的 关于沙林毒气袭击幸存者终身健康后果的报告开始出现， 迫使发现新的药物或新的治疗方法，以减轻急性 NA暴露。沙林暴露的受试者，虽然住院和接受传统治疗，在长期- 他们发展为癫痫和认知、运动和心理障碍。比如有机磷 (OP)，NA是胆碱酯酶抑制剂和有效的神经毒性。在动物模型中，急性NA或OP暴露 会导致长时间的癫痫和其他胆碱能症状。当前医疗对策药物 （阿托品、肟和地西泮）不能预防长期神经毒性和合并症， 因为持续的神经炎症和神经退化我们的首要假设是， 新型神经保护剂，saracatinib（SAR，也称为AZD 0305）和对策的组合 药物可以防止NA诱导的长期神经毒性并恢复脑功能。我们建议调查 一种新型Fyn/Src家族酪氨酸激酶抑制剂SAR在二异丙基 氟磷酸盐（DFP）和NA梭曼大鼠模型。SAR正在进行阿尔茨海默病和 几种类型的癌症患者最近，我们证明了Fyn/Src激酶在神经炎症中的作用， 在大鼠和小鼠模型中， 神经炎症，保护神经元和预防/改变癫痫发生。我们目前的实验也 揭示了大鼠癫痫发生、神经变性和行为功能障碍的相似机制 DFP模型由于SAR治疗后预防和/或显著改变癫痫发生，我们预测 SAR可以减轻DFP和梭曼诱导的长期神经毒性。在具体目标1和2中，我们将 研究SAR对大鼠DFP和梭曼的神经保护作用和对认知功能障碍的挽救作用 模型我们还将进行一系列的行为测试，并进行关键的促炎细胞因子（多重 测定）和硝基氧化应激测定。在某些动物身上我们会植入无线遥测装置来监测 脑电活动，以确认SAR对神经保护、抗癫痫和行为的影响。 救援我们的建议涉及到反ACT计划的使命[“促进和支持研究， 开发新的和改进的疗法，以减轻化学威胁对健康的影响”]，并可 为NA诱导的长期神经毒性提供了一种新的治疗方法。

Chemical warfare nerve agents (NA) are increasingly used to attack civilians worldwide. The past sarin attacks in Tokyo, VX usage in homicide attack in Malaysia, the recent sarin attacks in Syria on civilians, and the most recent Novichok ("newcomer") attack in England reiterate the real threat of chemical warfare NA to civilian population. NA in the hands of terrorists pose threat to human health globally and currently we lack effective treatment for survivors. Preventing acute death due to NA exposure had taken top priority until recently. The reports on the life-long health consequences of sarin attacks survivors are beginning to emerge, which compels the discovery of new drugs or new therapeutic approaches to mitigate the long-term effects of acute NA exposure. Sarin exposed subjects, though hospitalized and treated with conventional therapy, in the long- term they developed seizures and cognitive, motor, and psychological impairment. Like organophosphates (OP), NA are cholinesterase inhibitors and potent seizurogenic. In animal models, acute NA or OP exposure causes prolonged seizures and other cholinergic symptoms. The current medical countermeasure drugs (atropine, oxime, and diazepam) do not prevent the long-term neurotoxicity and comorbidity, which are largely due to persistent neuroinflammation and neurodegeneration. Our overarching hypothesis is that a combination of a novel neuroprotectant, saracatinib (SAR, also known as AZD0305), and countermeasure drugs can prevent NA-induced long-term neurotoxicity and restore brain function. We propose to investigate the long-term neuroprotective effects of a novel Fyn/Src family tyrosine kinase inhibitor, SAR in diisopropyl flurophosphate (DFP) and a NA soman rat models. SAR is in clinical trials for Alzheimer's disease and for several types of cancer patients. Recently we demonstrated the role of Fyn/Src kinase in neuroinflammation, neurodegeneration, and seizures onset in the rat and mouse models, and showed that SAR treatment dampened neuroinflammation, protected neurons and prevented/modified epileptogenesis. Our current experiments also revealed a similar mechanism of epileptogenesis, neurodegeneration, and behavioral dysfunction in the rat DFP model. Since the SAR post-treatment prevented and/or significantly modified epileptogenesis, we predict that SAR can mitigate DFP- and soman-induced long-term neurotoxicity. In specific aim 1 and 2, we will investigate the neuroprotective effect and rescue of cognitive dysfunction by SAR in the rat DFP and soman models. We will also perform a battery of behavioral tests and conduct key proinflammatory cytokines (multiplex assay) and nitro-oxidative stress assays. In some animals we will implant a wireless telemetry device to monitor brain electrical activity to confirm the impact of SAR on neuroprotection, anti-epileptogenicity, and behavioral rescue. Our proposal addresses the mission of the CounterACT program ["to foster and support research and development of new and improved therapeutics to mitigate the health effects of chemical threats"], and may yield a novel therapy for NA-induced long-term neurotoxicity.