Stress Hormone Enhancement of OP-Induced Neuroinflammation as an Animal Model of GWI: The Role of Toll-Like Receptors and Plasticity
Abstract
Gulf War illness (GWI) is a multi-symptom disorder with features similar to "sickness behavior" (e.g., fatigue, depression, cognitive impairments, gastrointestinal problems). While these symptoms usually abate over time as normal function returns, individuals with GWI experience recurring bouts of severe symptoms. The exposures and conditions in theater that caused GWI remain unknown, but several chemicals and environmental conditions have been identified. We have combined GW chemical exposures with stress hormone administration in a mouse model to simulate the physiological conditions of the war theater. The use of a valid animal model to investigate the nature of GWI is invaluable, as cellular mechanisms can be evaluated and invasive procedures conducted that would not be possible in ill Veterans. We found in our previous Congressionally Directed Medical Research Programs project that exposure to some types of insecticides and nerve gases from the GW caused an increase in brain inflammation that was markedly exacerbated by the presence of high stress levels, producing "sickness behavior." These results and additional more recent evidence have led us to the current application for funding that proposes: (1) extending our mouse model to other agents encountered in the GW theater; (2) identifying nerve cell mechanisms that cause the stress to greatly enhance the brain inflammation; (3) defining the persistence of the inflammation effects on several types of brain function; and (4) testing new therapeutic approaches with a high likelihood of success. Thus, there are two major thrusts of this research plan. First, we will determine whether other GW chemical exposures can produce the brain inflammation, and we will study the cellular mechanisms that sensitize the brain to stress. Second, throughout the project we will be testing new potential treatments. We will use an approved drug that has previously been shown in animal studies to block the high levels of brain inflammation, and we will also test a more specific experimental compound that may block the cellular sensitization process. We will also examine the effects of other drugs that have trophic effects on brain function and are hypothesized to reverse the long-term central nervous system symptoms of GWI. One of these latter drugs is also Food and Drug Administration-approved and in use for other purposes. We also believe that the new treatment approach of the combination of a drug to block the brain inflammation and one to enhance brain function offers new promise in successfully providing relief from this cluster of GWI symptoms. If this project is successful, clinical use of these approved drugs can be implemented quickly, while development of more specific pharmaceuticals based on this information can be instituted. Thus, the project can advance treatment for GWI in new directions on the basis of experimental evidence and increase the hopes for providing effective relief for ill GWI Veterans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610556
Entities
People
- Stephen Lasley
Organizations
- United States Army
- University of Illinois at Chicago