Evaluation of Neuroprotective Effects of AEOL10150 against Chemical Threat Agents

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。特别地，需要神经保护疗法来抵消化学战剂的中枢神经系统效应。NIH CounterAct计划最近开发医疗对策的努力已经将AEOL10150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是否是针对替代和主要神经毒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，预测AEOL 10150催化去除活性物质可以钝化氧化应激，从而防止下游变化，如代谢功能障碍，神经胶质增生和神经元丢失。该项目的具体目标是确定AEOL 10150在大鼠中的药代动力学特征（具体目标1），并使用各种生化、药理学和分析工具和技术评价AEOL 10150对大鼠中毛果芸香碱诱导的神经毒性的神经保护功效（具体目标2）。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. 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.