Neuroprotective effects of AEOL 10150 against organophosphate toxicity

描述(由申请人提供)：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学对策。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。本研究的目标是开发一种新颖有效的神经保护对策来对抗OP神经毒剂。美国国立卫生研究院对抗计划最近努力开发医学对策，已确定AEOL10150是一种先导化合物，可以抢救由芥末和氯引起的肺损伤。该项目的目标是确定AEOL10150是否是针对模型OP和初级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使用替代神经毒剂的工作，预计AEOL10150对活性物质的催化去除可以钝化氧化应激，从而防止下游变化，如神经元丢失和认知功能障碍。该项目的具体目标是将氧化应激描述为两种OP模型中的靶标，在这些模型中使用各种生化、药理和分析工具和技术确定AEOL10150的药代动力学、生物利用度和神经保护效果。这些研究有助于确定AEOL10150是一种针对化学战剂的多功能医学对策。

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.