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：
8338425
负责人：
MANISHA N PATEL
金额：
$ 36.78万
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8338425
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.

描述（由申请人提供）：化学战特工对平民和军事人员都是威胁，迫切需要快速发展医疗对策。特别是，需要神经保护疗法来抵消化学战剂的中枢神经系统影响。 NIH抵抗计划开发医学对策的最新努力已将AEOL10150确定为铅化合物，从而挽救了由芥末和氯引起的肺损伤。该项目的目的是确定AEOL10150是否是针对替代神经和原发性神经剂的神经保护医学对策。基于我们的初步结果和先前的工作，预计将AEOL10150催化反应性物种会钝化氧化应激，从而防止下游变化，例如代谢功能障碍，神经胶质病和神经元丧失。该项目的具体目标是确定大鼠AEOL10150的药代动力学特征（特定目标1），并使用多种生物化学，药理工具和技术和技术和技术和技术评估AEOL10150对Pilocarpine诱导的神经毒性的神经保护功效（特定目标2）。这些研究可以帮助将AEOL10150识别为对化学战剂的多功能医学对策。