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.

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
Research Project--Cooperative Agreements (U01)
Project #
5U01NS083422-02
Application #
8732717
Study Section
Special Emphasis Panel (ZRG1-MDCN-J (50))
Program Officer
Jett, David A
Project Start
2013-09-15
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
$848,415
Indirect Cost
$133,267
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Pearson-Smith, Jennifer N; Patel, Manisha (2017) Metabolic Dysfunction and Oxidative Stress in Epilepsy. Int J Mol Sci 18:
McElroy, Pallavi B; Liang, Li-Ping; Day, Brian J et al. (2017) Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation. Exp Neurol 298:13-22
Heischmann, Svenja; Quinn, Kevin; Cruickshank-Quinn, Charmion et al. (2016) Exploratory Metabolomics Profiling in the Kainic Acid Rat Model Reveals Depletion of 25-Hydroxyvitamin D3 during Epileptogenesis. Sci Rep 6:31424
Pearson, Jennifer N; Patel, Manisha (2016) The role of oxidative stress in organophosphate and nerve agent toxicity. Ann N Y Acad Sci 1378:17-24
Liang, Li-Ping; Patel, Manisha (2016) Plasma cysteine/cystine redox couple disruption in animal models of temporal lobe epilepsy. Redox Biol 9:45-49
Patel, Manisha (2016) Targeting Oxidative Stress in Central Nervous System Disorders. Trends Pharmacol Sci 37:768-78
Pearson, Jennifer N; Rowley, Shane; Liang, Li-Ping et al. (2015) Reactive oxygen species mediate cognitive deficits in experimental temporal lobe epilepsy. Neurobiol Dis 82:289-297
Rowley, Shane; Liang, Li-Ping; Fulton, Ruth et al. (2015) Mitochondrial respiration deficits driven by reactive oxygen species in experimental temporal lobe epilepsy. Neurobiol Dis 75:151-8
Bhuyan, Pallavi; Patel, Dipan C; Wilcox, Karen S et al. (2015) Oxidative stress in murine Theiler's virus-induced temporal lobe epilepsy. Exp Neurol 271:329-34

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