Mitochondria-Targeted Therapy for Gulf War Illness

The overarching challenge in this project is to develop a treatment strategy based upon the understanding of the pathobiological changes associated with Gulf War Illness (GWI), with a goal of eliminating the adverse health consequences associated with GWI and revolutionizing treatment. The area of emphasis will be chronic debilitating fatigue. GWI is characterized by a dysregulated biological system indicated by a range of neurological and neuromuscular disorders including cognitive impairment, chronic fatigue syndrome, and chronic pain. GWI has been estimated to have affected about one-third of the 700,000 U.S. Veterans deployed to the Persian Gulf during the 1990-91 war. Mitochondria form the powerhouse of cell. The studies so far in GWI show that there is a decline in the function of mitochondria in these patients. We therefore plan to use two small molecules, Metformin and MitoQ, to increase mitochondrial function and reduce inflammation and chronic fatigue. We will use a well-standardized mouse model of GWI by exposing the animals to pyridostigmine bromide (PB) and permethrin (PER). PB and PER were extensively used in the Gulf War and animals chronically exposed to these agents exhibit cognitive impairment, anxiety-like behaviors, myalgia, oxidative stress, and markers of inflammation, all symptoms of GWI. In this project, our goal is to unequivocally establish mitochondrial functional alterations in the mouse model and demonstrate that the two agents (MitoQ and Metformin) that improve mitochondrial function (directly or indirectly) can alone or in combination reduce or ameliorate the GWI signs, specifically chronic fatigue and chronic inflammation. The results of the studies will have a translational impact in the treatment of GWI, and in general, disorders associated with chronic fatigue syndrome. We expect that by the end of this 3-year project we will complete the preclinical study to determine the effectiveness of MitoQ and metformin treatment in GWI.