Evaluation of Neuroprotective Effects of AEOL10150 against Chemical Threat Agents

AEOL10150 针对化学威胁剂的神经保护作用评估

基本信息

批准号：
8215391
负责人：
MANISHA N PATEL
金额：
$ 36.82万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215391
关键词：
3-nitrotyrosine 4 hydroxynonenal Adverse event Animal Model Animals Antioxidants Astrocytes Atropine Biochemical Blood - brain barrier anatomy Brain Cell model Cessation of life Chemical Exposure Chemical Warfare Agents Chemicals Chlorine Clinical Trials Data Deoxyguanosine Development Diazepam Dose Drug Kinetics Electroencephalography Evaluation Excision Experimental Models Functional disorder Gliosis Glutathione Disulfide Goals Human Hydrogen Peroxide Incidence Individual Iran Iraq Laboratories Lead Lipids Literature Measures Medical Metabolic Metabolism Metalloporphyrins Military Personnel Mitochondria Monitor Mustard Mustard Gas Neuraxis Neuronal Injury Neurons Neuroprotective Agents Organophosphates Oxidative Stress Oxygen Consumption Permeability Peroxonitrite Pesticides Phase Pilocarpine Pilot Projects Plasma Population Property Radiation Rattus Reactive Oxygen Species Receptor Signaling Reduced Glutathione Regimen Research Project Grants Rodent Safety Sarin Seizures Self Administration Subcutaneous Injections Subway Superoxides Techniques Therapeutic Tokyo Treatment Efficacy United States National Institutes of Health War Work analytical tool base chlorine gas fluoro jade in vivo indexing lung injury mitochondrial dysfunction nerve agent neuron loss neuroprotection neurotoxicity novel perhydroxyl radical prevent programs toxicant

项目摘要

DESCRIPTION (provided by applicant): Chemical warfare agents are a threat to both the civilian population and military personnel and there is an urgent need for rapid development of medical countermeasures. In particular, there is a need for neuroprotective therapies to counteract the central nervous system effects of chemical warfare agents. Recent efforts by the NIH CounterAct program to develop medical countermeasures have identified AEOL10150 as a lead compound that rescues lung injury caused by mustard and chlorine. The goal of this project is to determine if AEOL10150 is a neuroprotective medical countermeasure against surrogate and primary nerve agents. Based on our preliminary results and prior work, catalytic removal of reactive species by AEOL10150 is predicted to blunt oxidative stress and thereby prevent downstream changes such as metabolic dysfunction, gliosis and neuronal loss. Specific goals of the project are to determine the pharmacokinetic profile of AEOL10150 in rats (Specific Aim 1) and evaluate the neuroprotective efficacy of AEOL10150 against pilocarpine-induced neurotoxicity in rats (Specific Aim 2) using a variety of biochemical, pharmacological and analytical tools and techniques. These studies can help identify AEOL10150 as a versatile medical countermeasure against chemical warfare agents. PUBLIC HEALTH RELEVANCE: Chemical warfare agents are an immense threat to both the civilian population and military personnel and there is an urgent need for rapid development of medical countermeasures against chemical warfare agents. In particular, there is a dire need for neuroprotective therapies to counteract the central nervous system effects of chemical warfare agents. The goal of this project is to determine if catalytic antioxidant compound is a neuroprotective medical countermeasure against a class of chemical threat agents.

描述（由申请人提供）：化学战剂对平民和军事人员都构成威胁，迫切需要快速开发医疗对策。特别是，需要神经保护疗法来抵消化学战剂对中枢神经系统的影响。 NIH CounterAct 计划最近致力于开发医疗对策，已确定 AEOL10150 是一种先导化合物，可以挽救芥末和氯引起的肺损伤。该项目的目标是确定 AEOL10150 是否是针对替代和原发神经毒剂的神经保护性医学对策。根据我们的初步结果和之前的工作，AEOL10150 催化去除活性物质预计可以减弱氧化应激，从而防止代谢功能障碍、神经胶质增生和神经元损失等下游变化。该项目的具体目标是确定 AEOL10150 在大鼠中的药代动力学特征（具体目标 1），并使用各种生化、药理学和分析工具评估 AEOL10150 对毛果芸香碱诱导的大鼠神经毒性的神经保护功效（具体目标 2）技术。这些研究有助于将 AEOL10150 确定为针对化学战剂的多功能医疗对策。公共卫生相关性：化学战剂对平民和军事人员都构成巨大威胁，迫切需要快速开发针对化学战剂的医疗对策。特别是，迫切需要神经保护疗法来抵消化学战剂对中枢神经系统的影响。该项目的目标是确定催化抗氧化剂化合物是否是针对一类化学威胁剂的神经保护性医疗对策。