Saracatinib Mitigates OP nerve agent-induced Long-term Neurotoxicity

Saracatinib 减轻 OP 神经毒剂引起的长期神经毒性

基本信息

批准号：
9916826
负责人：
Thimmasettappa Thippeswamy
金额：
$ 18.67万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916826
关键词：
Acute Address Adult Affect Aftercare Alzheimer&apos s Disease Animal Model Animals Antiepileptogenic Atropine Behavioral Biological Assay Biological Availability Brain Brain Diseases Brain Injuries Cancer Patient Cause of Death Cessation of life Chemical Agents Chemical Warfare Chemical Warfare Agents Cholinesterase Inhibitors Clinical Trials Cognitive Devices Diazepam Disease Dose Electroencephalography England Epilepsy Epileptogenesis Exposure to Female Fostering Functional disorder Genes Health Homicide Hospitals Hour Human Impaired cognition Impairment Implant Knockout Mice Life Long-Term Effects Malaysia Malignant Neoplasms Measures Microglia Midazolam Mission Modeling Monitor Motor Motor Seizures Mus NADPH Oxidase Nerve Degeneration Neurologic Neurons Neuroprotective Agents Nitrogen Oral Organophosphates Oxidative Stress Oximes Oxygen Pharmaceutical Preparations Phase II/III Clinical Trial Population Populations at Risk Production Publications Rattus Reporting Research Support Rest Role Sarin Seizures Serum Soman Sprague-Dawley Rats Status Epilepticus Survivors Symptoms Syria Telemetry Terrorism Testing Therapeutic Tokyo Tyrosine Kinase Inhibitor Wireless Technology behavior test blood-brain barrier permeabilization brain electrical activity cancer clinical trial cancer type chemical threat cholinergic comorbidity conventional therapy cytokine effective therapy experimental study forced swim test global health improved kainate male medical countermeasure morris water maze mouse model nerve agent neuroinflammation neuroprotection neurotoxicity novel novel therapeutic intervention novel therapeutics prevent programs psychologic research and development src-Family Kinases toxic organophosphate insecticide exposure translational approach

项目摘要

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.

化学战神经毒剂（NA）越来越多地用于攻击全球平民。过去的沙林攻击在东京，在马来西亚凶杀袭击中使用VX，最近在叙利亚袭击了平民的袭击，也是最多的最近在英格兰的Novichok（“新来者”）攻击重申了化学战NA对平民的真正威胁人口。 NA在恐怖分子的手中对全球人类健康构成威胁，目前我们缺乏有效幸存者的治疗。防止因NA暴露而导致的急性死亡一直处于重中之重，直到最近。这关于沙林袭击的终身健康后果的报告，幸存者开始出现，这是迫使发现新药或新的治疗方法来减轻急性的长期影响 NA暴露。沙林暴露于长期以来住院和接受常规治疗的受试者他们产生了癫痫发作和认知，运动和心理障碍。像有机磷酸盐（OP）Na是胆碱酯酶抑制剂和有效的蛋白酶成分。在动物模型中，急性NA或OP暴露引起长时间的癫痫发作和其他胆碱能症状。当前的医疗对策药物（Atropine，oxime和Wizepam）不能防止长期神经毒性和合并症，这在很大程度上是由于持续的神经炎症和神经变性。我们的总体假设是一种新型神经保护剂，萨拉卡替尼（SAR，也称为AZD0305）和对策的组合药物可以预防NA引起的长期神经毒性并恢复大脑功能。我们建议调查新型FYN/SRC家族酪氨酸激酶抑制剂的长期神经保护作用，二异丙基氟磷酸盐（DFP）和NA SOMAN大鼠模型。 SAR正在接受阿尔茨海默氏病的临床试验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，神经变性，大鼠和小鼠模型中的发作发作，并表明SAR治疗抑制了神经炎症，受保护的神经元并预防/修饰的癫痫发生。我们当前的实验揭示了大鼠癫痫生成，神经退行性和行为功能障碍的类似机制 DFP模型。由于SAR治疗后预防和/或显着修饰的癫痫发生，我们预测 SAR可以减轻DFP和SOMAN引起的长期神经毒性。在特定的目标1和2中，我们将研究大鼠DFP和SOMAN中SAR对认知功能障碍的神经保护作用和拯救型号。我们还将执行一系列行为测试并进行关键促炎细胞因子（多路复用测定）和硝基氧化应力测定。在某些动物中，我们将植入一个无线遥测设备来监视脑电活动以确认SAR对神经保护，抗癫痫发作和行为的影响救援。我们的建议涉及反对计划的使命[“促进和支持研究和开发新的和改进的治疗剂，以减轻化学威胁的健康影响”，并可能产生一种新的NA诱导的长期神经毒性的疗法。