Bryce Jensen

 Background: Gulf War Illness (GWI) is a chronic multisymptom illness characterized by cognitive impairments, musculoskeletal pains, fatigue, and gastrointestinal symptoms.^1,2 This illness affects approximately 30% of United States veterans of the First Persian Gulf War in 1990-1991, even over 30 years after the conflict.^1,2 Although there have been some breakthroughs in understanding the pathophysiology of the disease, there still are many questions surrounding the mechanisms behind the disease.¹ Studies suggest that exposure to a combination of different chemicals during deployment are likely the cause of the illness.^1,2 Current treatments target symptoms as there are no treatment strategies that cure GWI.² Pyridostigmine bromide (PB), an acetylcholinesterase inhibitor, was prophylactically given to soldiers due to concerns of chemical warfare.³ In animal model studies, the combination of PB and stress have been found to contribute to the cognitive dysfunctions seen in patients with GWI.⁴ Evaluation of the interaction between PB and stress may lead to new understandings of the pathophysiology of GWI.³

Objective: This narrative aims to explore mechanisms behind neurological complications associated with pyridostigmine bromide and stress in patients with Gulf War Illness.

Search Methods: An online search of articles published from 2017-2023 in the MEDLINE database was conducted using the following keywords: “pyridostigmine bromide”, “Gulf War Illness”, “GWI”, “stress”.

Results: Studies have shown changes in the central cholinergic system in animal models treated with PB and subjected to stress and immune challenge.⁴ Changes in central cholinergics differed in different parts of the brain.⁴ Acetylcholine levels were found to be decreased in the hippocampus following the lipopolysaccharide challenge and decreased in both the prefrontal cortex and hippocampus following an acute immobilization challenge.⁴ These findings coincided with impaired contextual and cue-based fear conditioning, which are memory-related tasks associated with the dorsal hippocampus and prefrontal cortex, respectively.⁴ Glutamatergic neurochemistry was also altered in animal models in a brain-region-specific pattern.⁵ Glutamate levels in the prefrontal cortex were decreased following immune challenge in PB-treated rats.⁵ Immobilization stress increased glutamate in the prefrontal cortex, and these levels did not recover in the post-stress period in PB-treated rats.⁵ Glutamate levels in the hippocampus were decreased following immune challenge in PB-treated rats.⁵ These decreases in glutamate levels in the hippocampus were reduced in PB-treated rats subjected to stress challenge.⁵ These rats also displayed no habituation in the glutamate response to immobilization stress.⁵

Conclusions: Studies have found alterations in central cholinergics and glutamatergic neurochemistry in animal models treated with PB and subjected to repeated restraint stress. These changes were different in the prefrontal cortex and hippocampus. The impaired ability of cholinergic systems in the brain to respond to inflammatory and stressful stimuli may be a contributing mechanism behind cognitive problems associated with GWI.⁴ As excitatory neurotransmitters are important for memory, changes in glutamatergic systems in the brain may be associated with the memory problems seen in patients with GWI.⁵ Treatment strategies can be developed to target factors in these pathways.

Works Cited:

1. Dickey B, Madhu LN, Shetty AK. Gulf War Illness: Mechanisms Underlying Brain Dysfunction and Promising Therapeutic Strategies. Pharmacol Ther. 2021;220:107716. doi:10.1016/j.pharmthera.2020.107716
2. Chatterjee S, Bose D, Seth R. Host gut microbiome and potential therapeutics in Gulf War Illness: A short review. Life Sci. 2021;280:119717. doi:10.1016/j.lfs.2021.119717
3. Macht, V. A., Woodruff, J. L., Grillo, C. A., Wood, C. S., Wilson, M. A., & Reagan, L. P. (2018). Pathophysiology in a model of Gulf War Illness: Contributions of pyridostigmine bromide and stress. Psychoneuroendocrinology, 96, 195-202. doi.org/10.1016/j.psyneuen.2018.07.015
4. Macht VA, Woodruff JL, Maissy ES, et al. Pyridostigmine bromide and stress interact to impact immune function, cholinergic neurochemistry and behavior in a rat model of Gulf War Illness. Brain Behav Immun. 2019;80:384-393. doi:10.1016/j.bbi.2019.04.015
5. Macht, V. A., Woodruff, J. L., Burzynski, H. E., Grillo, C. A., Reagan, L. P., & Fadel, J. R. (2020). Interactions between pyridostigmine bromide and stress on glutamatergic neurochemistry: Insights from a rat model of Gulf War Illness. Neurobiol Stress, 12, 100210. doi.org/10.1016/j.ynstr.2019.100210