Brandon Dickey

Introduction. An estimated 25%-32% of 700,000 U.S. Warfighters of the 1991 Gulf War continue to experience multiple unexplained health problems including fatigue, headaches, cognitive dysfunction, musculoskeletal pain, respiratory, gastrointestinal and dermatologic complaints^{1, 2}. It is proposed that multiple deployment-related exposures, pesticides, combustion products, and solvents are common etiologies². Consensus committees define Gulf War Illness (GWI) as the presence of chronic symptoms experienced for at least 6 months³. Methods. In a disease rat model, having received exposure to GWI-related chemicals and stress, oxidative stress-response, antioxidant, mitochondrial respiration chain, and inflammatory gene expression levels were measured with reverse transcription polymerase chain reaction (RT-PCR) protocol⁴. Additionally, through the use of confocal microscopy and dual immunofluorescence, neuronal nuclei+neurons were examined in the hippocampus for the expression of nuclear Nrf2 (master regulator of antioxidant response)⁴. Finally, the analyses of sections using ED-1 antibody for CD68 measured the presence of activated microglia in the hippocampus⁵. In a treatment rat model, having received therapeutic curcumin, RT-PCR analyzed antioxidant gene expression, and genes related to mitochondrial electron transport chain complexes I-V⁶. Additionally, immunohistochemical staining for GFAP was used for visualizing the occurrence of astrocyte hypertrophy post treatment to GWI rats⁶. Finally, a clinical, randomized, double-blind, placebo, control study of 46 veterans from the Gulf War received CoQ10 100 mg per day, 300 mg per day, or an identical-appearing placebo for 3.5 ± 0.5 months⁷. General self-rated health, physical function and 20 common GWI symptoms were measured. Results. In diseased animals with GWI-related chemicals and stress, genes related to oxidative stress, antioxidant, mitochondrial respiration chain, and inflammation demonstrated significantly elevated expression levels⁴. Additionally, the nuclear translocation of Nrf2 was increased, and sections using ED-1 antibody for CD68 confirmed the presence of activated microglia in the hippocampus⁵. Concerning treatment, curcumin reduced astrocyte hypertrophy, demonstrating the ability of curcumin to suppress the low-level neuroinflammation⁶. Additionally, curcumin enhanced multiple genes encoding proteins mediating antioxidant activity, and normalized the expression of genes encoding multiple proteins relevant to the mitochondrial ETC⁶. Finally, the treatment with Q100 versus placebo was favorable for all except sleep problems⁷. Conclusions. The current evidence regarding chronic oxidative stress, induction of genes involved in ROS, and mitochondrial dysfunction establish only one major target of the many mechanisms involved in the pathophysiology of GWI. The research targeted at countering these chronic pathological mechanisms shows promise and requires more clinical trials with larger sample sizes.

1. White RF, Steele L, Ocallaghan JP, et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex. 2016;74:449-475. doi:10.1016/j.cortex.2015.08.022.
2. National Academies of Sciences, Engineering, and Medicine. 2018. Gulf War and health, volume 11: Generational health effects of serving in the Gulf War. Washington, DC: The National Academies Press. doi: https://doi-org.ezproxy.library.tamu.edu/10.17226/25162.
3. Gulf War and Health: Treatment for Chronic Multisymptom Illness. Military Medicine. 2017;182(1):1449-1450. doi:10.7205/milmed-d-16-00325.
4. Shetty GA, Hattiangady B, Upadhya D, et al. Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness. Frontiers in Molecular Neuroscience. 2017;10. doi:10.3389/fnmol.2017.00182.
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6. Kodali M, Hattiangady B, Shetty G, Bates A, Shuai B, Shetty A. Curcumin treatment leads to better cognitive and mood function in a model of Gulf War Illness with enhanced neurogenesis, and alleviation of inflammation and mitochondrial dysfunction in the hippocampus. Brain, Behavior, and Immunity. 2018;69:499-514. doi:10.1016/j.bbi.2018.01.009
7. Golomb BA, Allison M, Koperski S, Koslik HJ, Devaraj S, Ritchie JB. Coenzyme Q10 Benefits Symptoms in Gulf War Veterans: Results of a Randomized Double-Blind Study. Neural Computation. 2014;26(11):2594-2651. doi:10.1162/neco_a_00659.