Targeting Lipid Metabolism as a Therapeutic Approach for Gulf War Illness

Upon returning from the 1991 Gulf War (GW), veterans from this conflict exhibited a persistent multisymptomatic illness which is now defined as Gulf War Illness (GWI). There is ample evidence that the presentation of GWI is associated with exposure to an anti-nerve agent pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), that were used as prophylactic measures by veterans during the war. The prevalence of GWI is about 30% in US veterans and 15% in UK veterans who were deployed during this conflict. Clinical presentation of GWI is heterogenous, and veterans with this condition display a wide range of symptoms such as memory impairment, fatigue, gastrointestinal disorder and chronic pain. Current treatment strategies for GWI are limited and provide only symptomatic relief. Due to the multifactorial nature of this illness, quest for appropriate treatment strategies is difficult and further complicated by the fact that many of the GW veterans are also facing age-related chronic health problems. I utilized a mouse model of GWI previously developed using combined exposure to PB and PER (GWI mice) which exhibits neurobehavioral features that are similar to the symptoms reported by GWI veterans. This model displays glia activation and neuroinflammation, pathological features that are reported in other GWI rodent models, representing a common chronic outcome associated with GW chemical exposure. The main objectives of this thesis are to find effective therapies against GWI that target the underlying pathology of GWI. Many clinical and imaging studies have suggested a possible central nervous system (CNS) involvement in GWI. However, even after two decades, there is no approved medication for treating the CNS pathology of GWI. Much of our previous work suggests dysregulation of lipid homeostasis and metabolism. These results pointed to both mitochondrial and peroxisomal abnormalities in GWI mice as well as in veterans with GWI. As part of my thesis work, I explored whether targeting mitochondrial and peroxisomal function can reduce abnormal brain lipid accumulation and improve chronic neurobehavioral deficits and the accompanying neuropathology in a mouse model of GW chemical exposure. I examined oleoylethanolamide, which targets peroxisome function via activation of peroxisome proliferator-activated receptors (PPAR) and also decreases inflammation. I examined another strategy using two different treatment regimens, nicotinamide riboside and a ketogenic diet, both of which target different aspects of mitochondrial bioenergetics. In addition to peroxisome and mitochondria dysfunction, recent evidence suggests that the symptoms of GWI resemble those of patients with autoimmune disorders, but it is unknown how GW chemicals could have caused immune dysfunction in GWI. Therefore, I focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), which is previously shown to form adducts with endogenous proteins. I observed the presence of 3-PBA modified lysine on protein peptides in GWI mice acutely post-exposure and also detected autoantibodies against 3-PBA-albumin conjugates in plasma of GWI mice and in veterans with GWI at chronic post-exposure timepoints. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI. I hope that the work described in this thesis provides novel avenues for the development of objective biomarkers and therapies for GWI.