Evaluation of Neuroprotective Effects of AEOL10150 against Chemical Threat Agents

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。特别是，需要神经保护疗法来抵消化学战剂对中枢神经系统的影响。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是否是针对替代和主要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的工作，AEOL10150对活性物质的催化去除被预测可以钝化氧化应激，从而防止下游的变化，如代谢障碍、胶质增生和神经元丢失。该项目的具体目标是确定AEOL10150在大鼠体内的药代动力学特征(特定目标1)，并使用各种生化、药理和分析工具和技术评估AEOL10150对匹罗卡品诱导的大鼠神经毒性的神经保护作用(特定目标2)。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。 与公共卫生有关：化学战剂对平民和军事人员都是一个巨大的威胁，迫切需要迅速制定针对化学战剂的医学对策。特别是，迫切需要神经保护疗法来抵消化学战剂对中枢神经系统的影响。本项目的目标是确定催化抗氧化剂化合物是否是针对一类化学威胁物质的神经保护性医学对策。

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. 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. PUBLIC HEALTH RELEVANCE: Chemical warfare agents are an immense threat to both the civilian population and military personnel and there is an urgent need for rapid development of medical countermeasures against chemical warfare agents. In particular, there is a dire need for neuroprotective therapies to counteract the central nervous system effects of chemical warfare agents. The goal of this project is to determine if catalytic antioxidant compound is a neuroprotective medical countermeasure against a class of chemical threat agents.