Gulf War Illness: Mechanisms Underlying Brain Dysfunction and Promising Therapeutic Strategies

Abstract

Gulf War Illness (GWI), a chronic multisymptom health problem, afflicts ~30% of veterans served in the first GW. Impaired brain function is among the most significant symptoms of GWI, which is typified by persistent cognitive and mood impairments, concentration problems, headaches, chronic fatigue, and musculoskeletal pain. This review aims to discuss findings from animal prototypes and veterans with GWI on mechanisms underlying its pathophysiology and emerging therapeutic strategies for alleviating brain dysfunction in GWI. Animal model studies have linked brain impairments to incessantly elevated oxidative stress, chronic inflammation, inhibitory interneuron loss, altered lipid metabolism and peroxisomes, mitochondrial dysfunction, modified expression of genes relevant to cognitive function, and waned hippocampal neurogenesis. Furthermore, the involvement of systemic alterations such as the increased intensity of reactive oxygen species and proinflammatory cytokines in the blood, transformed gut microbiome, and activation of the adaptive immune response have received consideration. Investigations in veterans have suggested that brain dysfunction in GWI is linked to chronic activation of the executive control network, impaired functional connectivity, altered blood flow, persistent inflammation, and changes in miRNA levels. Lack of protective alleles from Class II HLA genes, the altered concentration of phospholipid species and proinflammatory factors in the circulating blood have also been suggested as other aiding factors. While some drugs or combination therapies have shown promise for alleviating symptoms in clinical trials, larger double-blind, placebo-controlled trials are needed to validate such findings. Based on improvements seen in animal models of GWI, several antioxidants and anti-inflammatory compounds are currently being tested in clinical trials. However, reliable blood biomarkers that facilitate an appropriate screening of veterans for brain pathology need to be discovered. A liquid biopsy approach involving analysis of brain-derived extracellular vesicles in the blood appears efficient for discerning the extent of neuropathology both before and during clinical trials.

Keywords: Chemical exposures; Coenzyme Q10; Cognitive dysfunction; Curcumin; DNA methylation; Depression; Microbiota; Mitochondrial dysfunction; Neuroinflammation; Oxidative Stress.

Fig. 1.

A schematic illustrating the potential mechanisms causing brain dysfunction in Gulf War Illness (GWI) as gleaned from animal model studies. Systemic changes caused by the exposure to GWI-related chemicals have been mostly correlated between animal models and GWI patients (solid red line). These include activation of the peripheral adaptive immune response and alterations in lipid metabolism, bioenergetics, peroxisomes, lysosomes, liver function, mitochondrial function, microbiome, and leaky gut. Animal model studies also suggested that such exposures could directly affect the brain of veterans (indicated by a dotted red line), which may result in neuronal hyperexcitability and altered synaptic plasticity. Furthermore, both direct and indirect effects of exposures likely underlie persistently increased oxidative stress and inflammation in the brain, which could lead to a leaky blood-brain barrier, reduced hippocampal neurogenesis, and cognitive and mood impairments.HMGB1, high mobility group box-1.

Fig. 2.

A flowchart illustrating the potential mechanisms underlying cognitive and mood dysfunction, fatigue, neuronal hyperexcitability, and neuroinflammation in Gulf War Illness (GWI) as observed from studies on the brain, cerebrospinal fluid, and the blood from veterans with GWI. CAMKII, calcium-calmodulin kinase II; GFAP, glial fibrillary acidic protein; HLA, human leukocyte antigen; MAP2, microtubule-associated protein-2; MBP, myelin basic protein; tau, microtubule-associated tau (T) proteins.

Fig. 3.

A schematic showing the major results of preclinical studies that examined the efficacy of compounds such as curcumin, monosodium luminol, oleoylethanolamide, and nicotinamide riboside in animal models of Gulf War Illness (GWI). CCR-2, C-C chemokine receptor type 2; MCP-1, monocyte chemoattractant protein-1; NAD+, nicotinamide adenine dinucleotide; NF-kB, nuclear factor kappa B; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha; VLCFA, very-long-chain fatty acid.

Fig. 4.

A flowchart depicting some of the clinical trials that showed promise for alleviating the symptoms of Gulf War Illness (GWI). These include cognitive behavioral therapy with exercise, Coenzyme Q10 treatment, Hubbard regimen of detoxification, and combination of methylphenidate and micronutrient formula for improving mitochondrial function. The significant effects are highlighted.