Preclinical Approach to Mitochondrial Dysfunction in Gulf War Illness
Abstract
Gulf War Illness (GWI) refers to the complex, chronic symptoms that affect about one-third of Veterans of the Persian Gulf War (1990-1991). The symptoms of GWI include fatigue, muscle and joint pain, respiratory problems, cardiovascular disease, skin conditions, sleep disturbances, headaches, memory impairments, and anxiety. Unfortunately, these symptoms do not diminish with time, and treatments are lacking. It is thought that GWI originated from the exposure to chemicals [pyridostigmine bromide (PB), permethrin (PER), and DEET] designed to protect military personnel from nerve agents and from insects. While these drugs generally are considered safe at the doses administered, it is thought that their combination together with the stress encountered during the war contributed collectively and synergistically to generate the GWI. This chemical exposure hypothesis has been supported by data from animal models of GWI. We, and others, have shown that exposure of mice or rats to low concentrations of PB/PER/DEET together with mild stress for 1 month causes anxiety and memory impairments that are associated with pathological changes in the brain. Recent studies have indicated that GWI patients have damaged mitochondria, a cell organelle known to be very sensitive to environmental pollutants and whose major function is to produce energy for the cell. This is in line with fatigue being a major complain of patients with GWI. Moreover, Veterans with the disease suffer from post-exertional malaise, meaning that their cognitive and physical exhaustion is made worse by effort. In fact, exercise has been shown to magnify the pathology in GWI patients, but this important information has not been tested in animals yet. Drugs that target mitochondrial function should be therefore investigated for the treatment of GWI. One such drug, dichloroacetate (DCA), has been used clinically for decades to treat patients with rare congenital mitochondrial diseases. DCA has also been shown to be protective in animal models of neurodegenerative conditions in which mitochondrial dysfunction has been implicated, such as Huntington’s disease and amyotrophic lateral sclerosis. We propose to treat a well-characterized rat model of GWI based on the chemicals and stress mentioned above with DCA under basal conditions and with extra exercise challenge to test the hypothesis that (1) mitochondrial dysfunction is central to the pathology and symptoms of GWI, (2) exercise challenge worsens mitochondria dysfunction and its consequences, and (3) oral treatment with DCA will improve the symptoms and the pathology in GWI-model rats under basal conditions and with extra physical challenge. We will examine the effects of DCA on rats’ behavior with tests to measure anxiety, memory, and fatigue, and we will determine the effects of DCA treatment on pathological markers in blood and brain. We expect that the data collected in the course of the proposed studies will: (1) Advance our understanding of GWI pathobiology and will provide additional support to the idea that mitochondrial dysfunction drives the abnormalities in the brain and in the immune system in GWI and underlies the symptoms of Veterans with GWI. (2) Recognize the detrimental effects of physical exercise in GWI in the brain and immune system. We will test, for the first time in an animal model of GWI, the idea that exercise challenge aggravates the biological and behavioral abnormalities in GWI and that mitochondrial dysfunction underlies such effects. (3) Have the potential to unveil previously unrecognized changes in the brain and in the immune system that may provide additional therapeutic opportunities. (4) Demonstrate that targeting the mitochondrial function is an effective therapeutic strategy for treating GWI.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910549
Entities
People
- Isabel Carreras
Organizations
- Boston VA Research Institute
- United States Army