Oleoylethanolamide treatment reduces neurobehavioral deficits and brain pathology in a mouse model of Gulf War Illness

Abstract

There are nearly 250,000 Gulf War (GW) veterans who suffer from Gulf War Illness (GWI), a multi-symptom condition that remains untreatable. The main objective was to determine if targeting peroxisomal function could be of therapeutic value in GWI. We performed a pilot study that showed accumulation of very long chain fatty acids (VLCFA), which are metabolized in peroxisomes, in plasma from veterans with GWI. We then examined if targeting peroxisomal β-oxidation with oleoylethanolamide (OEA) restores these lipids to the normal levels and mitigates neuroinflammation and neurobehavioral deficits in a well-established mouse model of GWI. In GWI mice, treatment with OEA corresponded with cognitive benefits and reduced fatigue and disinhibition-like behavior in GWI mice. Biochemical and molecular analysis of the brain tissue showed reduced astroglia and microglia staining, decreased levels of chemokines and cytokines, and decreased NFκB phosphorylation. Treatment with OEA reduced accumulation of peroxisome specific VLCFA in the brains of GWI mice. These studies further support the translational value of targeting peroxisomes. We expect that OEA may be a potential therapy for treating neurobehavioral symptoms and the underlying lipid dysfunction and neuroinflammation associated with GWI. Oleoylethanolamide is available as a dietary supplement, making it appealing for human translational studies.

Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status

“…Plasma from this cohort was analyzed following a randomized block group design with experimenters performing the sample preparation, lipid extraction, qualitative and quantitative mass spectrometry analyses blinded to participants' group membership and other group characteristics. The extraction procedure and nano-LC/MS conditions were previously published by our laboratory (Joshi et al, 2018). Plasma (10 µL) was spiked with 5 µl of a mix of SPLASH LipidoMIX stable isotope and Cer/Sph Mixture I (Avanti, Polar Lipids, Inc.) diluted 1:10 in SPLASH internal standard (IS) mix.…”

The Innate Immune System and Inflammatory Priming: Potential Mechanistic Factors in Mood Disorders and Gulf War Illness

“…At 3 months post-exposure the animals showed an increase in the amount of time spent immobile in a forced swim test, a finding suggested to mirror increases in fatigue and depression commonly observed in GWI patients. Additionally, the mice in this study were found to display disinhibition behavior as measured by an increased amount of time in the open arms of an elevated plus maze ( 46 ). While the reason for differences in elevated plus maze behavior between the studies by Carreras and colleagues and Joshi et al.…”

Innate immune signaling and sex differences contribute to neurocognitive impairment, neuroinflammation, and mitochondrial rewiring in a mouse model of Gulf War illness

“…Using an established murine model of GWI 22,29,24 , we demonstrated that GWIC-exposed female However, the majority of GWI rodent model studies have used male mice only, using tests including the Barnes maze 24,29,7,39 , forced swim test 39,40 , and OFT 38,35,26 to reveal cognitive impairment, fatigue, and anxiety-related behavior. We tested both female and male GWICexposed mice using the OLT, NORT, and PST, which has been used in GWI rat models to show impairment in male animals with demonstrated hippocampal inflammation 27,42,43,44 .…”