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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS072099-02
Application #
8338425
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (55))
Program Officer
Yeung, David
Project Start
2011-09-30
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$367,761
Indirect Cost
$117,761
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Ryan, Kristen; Liang, Li-Ping; Rivard, Christopher et al. (2014) Temporal and spatial increase of reactive nitrogen species in the kainate model of temporal lobe epilepsy. Neurobiol Dis 64:8-15
Pearson, Jennifer N; Schulz, Kalynn M; Patel, Manisha (2014) Specific alterations in the performance of learning and memory tasks in models of chemoconvulsant-induced status epilepticus. Epilepsy Res 108:1032-40
Brooks-Kayal, Amy R; Bath, Kevin G; Berg, Anne T et al. (2013) Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia 54 Suppl 4:44-60
Rowley, Shane; Patel, Manisha (2013) Mitochondrial involvement and oxidative stress in temporal lobe epilepsy. Free Radic Biol Med 62:121-31