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.

U01NS083422

2013-09-15

2020-08-31