Jacob Gibbs

Introduction: Gulf War illness (GWI), is a chronic multisymptomatic illness with destructive cognitive impairments.¹ An estimated 1/3 of veterans of the Gulf War are affected by GWI.² GWI encompasses chronic pain, weakness, headache, fatigue, cognitive deficits, alterations in mood, and numerous multi-system complaints.² Possible factors contributing to GWI include consuming the prophylactic drug pyridostigmine bromide, and applying N,N-Diethyl-meta-toluamide (DEET) on the skin and permethrin on uniforms and tents, exposures to low-level sarin, combustion products, burning oil wells, mustard gas, vaccines, and depleted uranium.¹ Exposure to GWI-related AChE inhibitors likely caused increased neuronal cholinergic signaling leading to neuronal hyperactivation and increased oxidative stress.¹ Increased oxidative stress promotes HMGB1 leakage and the occurrence of proinflammatory microglia.¹ Proinflammatory microglia present activated NLRP3 inflammasomes which increase the release of proinflammatory cytokines and promotes a chronic inflammatory state.¹ NLRP3 inflammasomes are intracellular multiple-protein complexes, triggered by damage-associated molecular patterns released by damaged cells or reactive oxygen species, which activate caspase-1 in microglia.⁵ Activated Caspase-1 cleave pro-IL-1β  and pro-IL-18 into mature cytokines (IL-1β, IL-18).⁶ Chronic elevation of IL-1β and IL-18 exacerbates neuroinflammation and causes severe damage to brain tissue over time.⁶ IL-1β recruits inflammatory response cells by inducing the expression of adhesion molecules.⁶ IL-18 promote Th1 cell activation and enhance the activity of CD8+ T cells and natural killer cells by upregulation of FasL.⁶  Methods: Neuroinflammation was measured in GWI veterans, using a (PET) study using [11C]PBR28, which binds to an inflammatory protein upregulated in activated microglia.⁴ Melatonin was chosen as a possible treatment for GWI in an animal model because of its ability to reduce oxidative stress and neuroinflammation.¹ Rats with chronic GWI were treated with melatonin (5, 10, 20, 40, or 80 mg/kg) for eight weeks and behavioral tests were conducted after the treatment regimen.  Results: GWI patients demonstrated elevated levels of inflammation in the brain.⁴ Melatonin treatment in rats with chronic GWI lowered the number of NLRP3 inflammasomes and activated microglia in the hippocampus.¹ Melatonin also modulated oxidative stress and increased mitochondrial function. Modulation of neuroinflammation in GWI rats enhanced hippocampal neurogenesis, reduced synapse loss, and improved hippocampus-dependent cognitive function.¹ The effects of melatonin were dose dependent.¹  Conclusion: Melatonin treatment in an animal model of chronic GWI reduced oxidative stress and chronic neuroinflammation, increased hippocampal neurogenesis, and reduced synapse loss, leading to improved cognitive and mood function. Since GWI patients also display chronic neuroinflammation associated with cognitive and mood impairments, melatonin could be a potential treatment for GWI. However, clinical trials in veterans with GWI are needed to validate this assumption.

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