Neuroprotective effects of AEOL 10150 against organophosphate toxicity

说明（申请方提供）：化学战剂对平民和军事人员都是一种威胁，迫切需要迅速发展医疗对策。控制癫痫发作活动和下游后果对于有机磷（OP）暴露后的神经保护和生存至关重要。本研究的目的是开发一种新的有效的神经保护对策，对OP神经毒剂。NIH CounterACT计划最近开发医疗对策的努力已经将AEOL 10150确定为挽救芥子气和氯引起的肺损伤的先导化合物。本项目的目标是确定AEOL10150是否是针对OP模型和主要神经毒剂的神经保护性医疗对策。基于我们的初步结果和使用替代神经毒剂的先前工作，预测AEOL 10150对反应性物质的催化去除可钝化氧化应激，从而防止下游变化，如神经元损失和认知功能障碍。该项目的具体目标是在两种OP模型中表征氧化应激作为靶标，使用各种生化，药理学和分析工具和技术确定AEOL 10150在这些模型中的药代动力学，生物利用度和神经保护功效。这些研究可以帮助确定AEOL 10150作为一种多功能的医学对抗化学战剂。

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.