Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment

Kozlova, Elena; Carabelli, Bruno; Bishay, Anthony E.; Li, Rui; Denys, Maximillian E.; Macbeth, John; Piamthai, Varadh; Crawford, Meli’sa; McCole, Declan F.; Nieden, Nicole I. zur; Hsiao, Ansel; Currás-Collazo, Margarita

doi:10.1016/j.lfs.2021.120153

Cited by 9 publications

(14 citation statements)

References 118 publications

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“…Within the cortex, structural changes such as reduced neurogenesis, neurodegeneration and inflammation in the hippocampus may underlie object memory dysfunction (NORT) and associative learning deficits (PAT) [108] and have been previously shown to occur after GW agent exposure [11,91]. Therefore, as a follow up to this study demonstrating differential phenotypes for GW2 and GW1, we compared neuroinflammatory transcriptional signatures, and brain IL-6 levels as well as plasma endotoxin and the gut microbiome community structure to find molecular/pathological correlates that may specifically drive the GW2 cognitive and fatigue phenotype [1].…”

Section: Discussionmentioning

confidence: 99%

“…Aims: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1].…”

mentioning

confidence: 90%

“…1). After mice were anesthetized and sacrificed at PT199, tissues were harvested and analyzed as shown in the accompanying article [1].…”

Section: Gw Agent Exposure Paradigmmentioning

confidence: 99%

“…Our results indicate that GW1 and GW2 did not display a common phenotype, indicating that the PB dose may dictate the occurrence and characteristics of GWI phenotypes. Tissues from these animals were used to determine neuromolecular signatures and other biomarkers associated with these GW phenotypes described in the accompanying article in this issue [1]. Our comprehensive mouse model provides an integrated substrate for diagnosis of multiple symptoms established and emerging in GWI, for examination of underlying pathophysiology as well as for testing potential targets for therapeutic benefit.…”

Section: Introductionmentioning

confidence: 99%

“…

Aims: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1].Main methods: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O.

…”

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confidence: 99%

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Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness

et al. 2022

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

“…1). After mice were anesthetized and sacrificed at PT199, tissues were harvested and analyzed as shown in the accompanying article [1].…”

Section: Gw Agent Exposure Paradigmmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…

…”

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confidence: 99%

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Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness

et al. 2022

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Acute Exposure to Pyridostigmine Bromide Disrupts Cholinergic Myenteric Neuroimmune Function in Mice

et al. 2023

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Gulf War Illness (GWI) results from chemical exposure during the Gulf War, with notable impacts on gastrointestinal motility. Due to the limited demographic impacted by this ailment, an in‐depth investigation of the GWI has yielded little regarding the underlying pathophysiological mechanisms. Here, the hypothesis that exposure to pyridostigmine bromide (PB) results in severe enteric neuro‐inflammation, that cascades to disruptions in colonic motility, is tested. The analyses are performed on male C57BL/6 mice that are treated with physiologically similar doses of PB given to GW veterans. When colonic motility is assessed, GWI colons have significantly reduced forces in response to acetylcholine or electrical field stimulation. GWI is also accompanied by high levels of pro‐inflammatory cytokines and chemokines, associated with increased numbers of CD40+ pro‐inflammatory macrophages within the myenteric plexus. Enteric neurons responsible for mediating colonic motility reside within the myenteric plexus, and PB exposure reduced their numbers. Significant smooth muscle hypertrophy is also observed due to increased inflammation. Together, the results show that PB exposure caused functional and anatomical dysfunction, promoting impaired motility within the colon. Achieving a greater understanding of the mechanisms of GWI will allow more refinement in therapeutic options that improve veterans’ quality of life.

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Experimental Models of Gulf War Illness, a Chronic Neuropsychiatric Disorder in Veterans

Reddy

Singh

et al. 2023

Current Protocols

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Gulf War illness (GWI) is a chronic multifaceted condition with debilitating pain and fatigue, as well as sleep, behavioral, and cognitive impairments in war veterans. Currently, there is no effective treatment or cure for GWI; therefore, there is a critical need to develop experimental models to help better understand its mechanisms and interventions related to GWI-associated neuropsychiatric disorders. Chemical neurotoxicity appears to be one cause of GWI, and its symptoms manifest as disruptions in neuronal function. However, the mechanisms underlying such incapacitating neurologic and psychiatric symptoms are poorly understood. The etiology of GWI is complex, and many factors including chemical exposure, psychological trauma, and environmental stressors have been associated with its development. Attempts have been made to create GWI-like symptomatic models, including through chronic induction in mice and rats. Here, we present a brief protocol of GWI in rats and mice, which exhibit robust neuropsychiatric signs and neuropathologic changes reminiscent of GWI. This article provides a guide to working protocols, application of therapeutic drugs, outcomes, troubleshooting, and data analysis. Our broad profiling of GWI-like symptoms in rodents reveals features of progressive morphologic and long-lasting neuropsychiatric features. Together, the GWI model in rodents shows striking consistency in recapitulating major hallmark features of GWI in veterans. These models help identify mechanisms and interventions for GWI.

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Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment

Cited by 9 publications

References 118 publications

Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness

Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness

Acute Exposure to Pyridostigmine Bromide Disrupts Cholinergic Myenteric Neuroimmune Function in Mice

Experimental Models of Gulf War Illness, a Chronic Neuropsychiatric Disorder in Veterans

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