For over 25 years now, 250,000 Veterans from the 1990-1991 Gulf War (GW) still suffer from a chronic and debilitating multisymptom illness, called Gulf War Illness (GWI). Research studies conducted over the last decade provide compelling evidence that GWI may have been caused by exposure to chemicals, such as an anti-nerve agent pyridostigmine bromide (PB) and different types of pesticides (GW agents). These studies also show that brain structures that are involved in processing and storing memory, as well as brain pathways involved in controlling pain and fatigue, are altered in GW Veterans with this condition. Even now, nearly 25 years later, Veterans with GWI continue to experience these heterogeneous symptoms and this illness remains difficult to treat given the complex underlying biology of GWI. We have recently shown that fat (lipid) disturbances may also be a feature of GWI, present in both animal models of GWI and in blood from Veterans suffering from this condition. We found that these lipids were associated with the sub-cellular compartments (peroxisomes) that break down fats and transfer them to mitochondria (body’s powerhouse) for complete oxidation as an alternative energy source. We therefore tested a naturally occurring lipid, oleoylethanolamide (OEA), that targets peroxisomes to determine if such a strategy could be useful for treating GWI in a well-validated mouse model of GWI. Based on the promising outcomes of preliminary studies, the work described here is aimed at conducting additional preclinical studies to identify safe and efficacious doses of OEA, which can be tested in clinical trials of Veterans with GWI.

Understanding biological causes of GWI, which involve brain abnormalities, cannot be directly studied in humans since access to the brain tissue is only possible post-mortem due to ethical and practical constraints. Therefore, animal studies are critical in identifying disease mechanisms and facilitating preclinical testing of therapies. Tremendous advances in understanding GWI have been made through modeling GW chemical exposures in rodents. These studies show chronic immune cell proliferation, suggesting inflammation in the brain after acute exposure to GW chemicals. In addition, as described above, our team has identified that several major classes of lipids are affected in GWI, both in the brain and the blood of GWI mice, as well in blood from Veterans with GWI. Our in-depth evaluation suggested that these lipid disturbances may be indicative of peroxisomal dysfunction, so we examined OEA in order to normalize fat metabolism and utilization. Our studies show that oral administration of OEA for 6 months improves learning and memory and reduces fatigue-like behavior in treated GWI compared to untreated GWI mice. These studies also show that OEA treatment restores lipid metabolism in the brain and reduces immune cell activation and other markers associated with inflammation in the brains of GWI mice. There was no overt toxicity as quantified by weight change, and no physical signs of distress were observed in mice. Based on these studies, we propose in-depth experimentations to assess safety and efficacy of several doses of OEA in order to identify human equivalent doses, which can be administered to Veterans with GWI.

As part of the proposed preclinical work for translating OEA into the clinical realm, we plan to orally administer several doses of OEA, and only those doses that do not show toxicity will be examined further for additional pharmacological studies to evaluate how OEA moves through the systemic circulation and reaches the brain. After oral administration of OEA, we will sample blood and tissue at various timepoints in order to determine how OEA is metabolized and distributed throughout the body. At these timepoints, we will examine how OEA treatment affects lipid profiles and activation of nuclear factor kappa-B (NFkappaB) (as a marker of inflammation) to provide an indication of how OEA is working during a 24-hour period. We will establish steady-state dosing, which will be tested further to examine efficacy of OEA in treating GWI-related features in our well-established and validated mouse model of GWI. We expect these studies will allow us to generate enough preclinical support to file an Investigational New Drug application with the Food and Drug Administration (FDA). As OEA is already available as a natural weight loss supplement, we expect that the path to clinic will be easier since it will not require the usual scrutiny from the FDA.