A review of pre-clinical models for Gulf War Illness

Gulf War Illness (GWI) is a chronic multisymptomatic disorder that afflicts over 1/3rd of the 1991 GW veterans. It spans multiple bodily systems and presents itself as a syndrome exhibiting diverse symptoms including fatigue, depression, mood, and memory and concentration deficits, musculoskeletal pain and gastrointestinal distress in GW veterans. The etiology of GWI is complex and many factors, including chemical, physiological, and environmental stressors present in the GW arena, have been implicated for its development. It has been over 30 years since the end of the GW but, GWI has been persistent in suffering veterans who are also dealing with paucity of effective treatments. The multifactorial aspect of GWI along with genetic heterogeneity and lack of available data surrounding war-time exposures have proved to be challenging in developing pre-clinical models of GWI. Despite this, over a dozen GWI animal models exist in the literature. In this article, following a brief discussion of GW history, GWI definitions, and probable causes for its pathogenesis, we will expand upon various experimental models used in GWI laboratory research. These animal models will be discussed in the context of their attempts at mimicking GW-related exposures with regards to the variations in chemical combinations, doses, and frequency of exposures. We will discuss their advantages and limitations in modeling GWI followed by a discussion of behavioral and molecular findings in these models. The mechanistic data obtained from these preclinical studies have offered multiple molecular pathways including chronic inflammation, mitochondrial dysfunction, oxidative stress, lipid disturbances, calcium homeostatic alterations, changes in gut microbiota, and epigenetic modifications, amongst others for explaining GWI development and its persistence. Finally, these findings have also informed us on novel druggable targets in GWI. While, it has been difficult to conceive a single pre-clinical model that could express all the GWI signs and exhibit biological complexity reflective of the clinical presentation in GWI, animal models have been critical for identifying molecular underpinnings of GWI and evaluating treatment strategies for GWI.