Neuroprotective effects of AEOL 10150 against organophosphate toxicity

AEOL 10150 对有机磷毒性的神经保护作用

基本信息

批准号：
8921304
负责人：
MANISHA N PATEL
金额：
$ 92.83万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8921304
关键词：
3-nitrotyrosine 4 hydroxynonenal Adverse event Animals Antioxidants Biochemical Biological Availability Blood - brain barrier anatomy Cessation of life Chemical Exposure Chemical Warfare Agents Chemicals Chlorine Clinical Trials Data Deoxyguanosine Development Dose Drug Kinetics Electroencephalography Excision Experimental Models Frequencies Gliosis Glutathione Disulfide Goals Health Human Hydrogen Peroxide Impaired cognition Incidence Individual Injectable Insecticides Iran Iraq Laboratories Lead Lipids Literature Measures Medical Military Personnel Modeling Monitor Mustard Mustard Gas Neuraxis Neuronal Injury Neurons Organophosphates Oxidative Stress Permeability Peroxonitrite Pesticides Pharmacodynamics Phase Phosgene Pilocarpine Pilot Projects Population Principal Investigator Property Radiation Rattus Receptor Signaling Reduced Glutathione Regimen Research Project Grants Safety Sarin Seizures Soman Subcutaneous Injections Subway Superoxides Techniques Testing Therapeutic Tokyo Toxic effect Treatment Efficacy United States National Institutes of Health War Work analytical tool base chemical threat cholinergic efficacy testing fluoro jade indexing lung injury mitochondrial dysfunction nerve agent neuron loss neuroprotection novel perhydroxyl radical prevent programs response toxic organophosphate insecticide exposure 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. Controlling seizure activity and downstream consequences is critical for neuroprotection and survival after organophosphate (OP) exposure. The goal of this research project is to develop a novel and efficacious neuroprotective countermeasure against OP nerve 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 a model OP and a primary nerve agent. Based on our preliminary results and prior work using a surrogate nerve agent, catalytic removal of reactive species by AEOL10150 is predicted to blunt oxidative stress and thereby prevent downstream changes such as neuronal loss and cognitive dysfunction. Specific goals of the project are to characterize oxidative stress as a target in two OP models, determine pharmacokinetics, bioavailability, and neuroprotective efficacy of AEOL10150 in these models 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。控制癫痫发作活性和下游后果对于有机磷酸盐（OP）暴露后神经保护和存活至关重要。该研究项目的目的是开发一种针对神经毒剂的新颖有效的神经保护对策。 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是否是针对模型OP和主要神经剂的神经保护性医学对策。基于我们的初步结果和使用替代神经剂的先前工作，预测AEOL10150对反应性物种的催化去除被预测会钝化氧化应激，从而防止神经元丧失和认知功能障碍等下游变化。该项目的具体目标是将氧化应激作为两个OP模型中的靶标表征为目标，即确定AEOL10150在这些模型中使用多种生化，药理和分析工具和技术的药代动力学，生物利用度和神经保护功效。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。