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

Utsav Joshi,Sarah Oberlin,Michael Mullan,Laila Abdullah,Benoit Mouzon,Joseph Ojo,Carlyn Lungmus,James E Evans,Tanja Emmerich,Nicole Saltiel,Heather Langlois,Nancy Klimas,Daniel Paris,Chao Jin,Ross Joseph,Kimberly Sullivan,Fiona Crawford

doi:10.1038/s41598-018-31242-7

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.

Highlights

There are nearly 250,000 Gulf War (GW) veterans who suffer from Gulf War Illness (GWI), a multisymptom condition that remains untreatable
In a pilot cross-sectional study of age- and gender-matched healthy GW veterans (n = 10) and those with GWI (n = 12), we examined pristanic acid, very long chain fatty acids (VLCFA), and several free fatty acids (FFA)
In order to determine if NFκB-mediated pro-inflammatory pathways could be inhibited by OEA in the brains of GWI mice, we examined the ratios of the phosphorylated p65 (p-65) to total p65 protein, which is a subunit of NFκB, phosphorylated STAT3 (p-STAT3) and several pro-inflammatory cytokines

Summary

Introduction

There are nearly 250,000 Gulf War (GW) veterans who suffer from Gulf War Illness (GWI), a multisymptom condition that remains untreatable. Evidence for CNS involvement in GWI comes from animal modeling studies that used chemicals that were widely used by military personnel during the GW conflict[3] These studies showed neurobehavioral deficits such as depression and cognitive problems corresponding with chronic brain astroglia and microglia activation, appearing at chronic post-exposure periods[3,4,5,6,7,8,9]. Extensive characterization of these GWI mouse models using proteomic, lipidomics, and metabolomics technologies suggests the presence of inflammation and impaired lipid metabolism[6,8].

Objectives

Methods

Results

Discussion

Conclusion