Preclinical Validation of (+)-Epicatechin for the Treatment of Gulf War Illness
Abstract
Scientific Objective and Rationale: Gulf War Illness (GWI) afflicts ~30% of the Veterans who served in the first Persian Gulf War. GWI prominently impacts the nervous and skeletal muscle systems leading to cognitive deficits, muscle pain, weakness, exercise intolerance, and fatigue. The cause is currently unknown, but exposure to environmental factors is suspect. Veterans apparently consumed and were exposed to several chemical agents intended to protect them from nerve gas and insects. Some of these agents may compromise the bioenergetics status of cells by impairing their ability to make the required fuel (ATP) that allows for proper organ function. Department of Veterans Affairs (VA) investigators have developed a rat model where animals are exposed to such agents as well as mild forms of physical stress. The model has been used to characterize changes in rat behavior, learning, memory, and voluntary exercise as well as for changes in their nervous system. However, no studies have examined the effects of such treatment on skeletal muscle structure and function including bioenergetics. It has been recently proposed that impaired muscle bioenergetics (in addition to brain) may also explain GWI symptoms, in particular, fatigue. Flavonoids are a class of natural compounds found in cacao plants (and their products, i.e., chocolate) that are known for their safety profile, lack of toxicity, and health benefits. We have extensively characterized the stimulatory effects of the flavanol (+)-epicatechin (+Epi) on cell bioenergetics. +Epi restores and/or stimulates multiple indicators of brain and muscle cell structure leading to major improvements in function that translate into reduced indicators of brain and muscle fatigue. In animal models of disease, treatment also restores multiple markers of tissue damage back to normal. These results suggest greater levels of efficacy and possible reduced risks if given for extended periods of time. We recently completed a Food and Drug Administration (FDA)-approved clinical study on the use of +Epi with initial results yielding an initial profile of the compound in blood with no evidence of adverse effects or toxicity. Given the above-presented information, we propose to: “Validate using an established animal model of GWI, the capacity of +Epi to restore brain and skeletal muscle bioenergetics and reduce markers of damage leading to improved function.” We will examine two objectives as follows: Objective 1: To examine in an animal model of GWI, changes in brain and skeletal muscle bioenergetics, structure and function as well as markers of tissue damage. For these purposes, we will use an established model of GWI in rats and extensively characterize changes in organ structure, function, and tissue damage. Objective 2: To examine the capacity of +Epi to reverse GWI-related changes in brain and skeletal muscle bioenergetics, structure, and function as well as markers of tissue damage. Once an animal model of GWI is well characterized (as per Objective 1 above), we will implement different modalities of +Epi treatment so as to examine its capacity to reverse detrimental changes seen in brain and skeletal muscle structure and function, while also reducing indicators of tissue damage. Applicability of the Research: Currently, there is no directed treatment for GWI. We expect that the potential use of +Epi in the treatment of GWI will benefit all patients regardless of their age or comorbidities. We expect that eventually the use of +Epi in the clinical setting will be identified as the first targeted treatment for GWI that can be used safely for extended periods of time. On the basis of the preliminary data collected so far, the expected benefits are to notably improve the fatigue syndrome associated with the disease and other important symptoms such as impaired memory. So far, the expected risks are seen as minimal as this class of compounds has been proven to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910419
Entities
People
- Francisco Villarreal
Organizations
- United States Army
- University of California, San Diego