Pathophysiological basis and promise of experimental therapies for Gulf War Illness, a chronic neuropsychiatric syndrome in veterans

Kodali, Maheedhar; Jankay, Tanvi; Shetty, Ashok K.; Reddy, Doodipala Samba

doi:10.1007/s00213-023-06319-5

Cited by 8 publications

(7 citation statements)

References 209 publications

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“…Reliable blood biomarkers need to be discovered for GWI [ 90 ]. GWI pathogenesis may involve neuroinflammation, oxidative stress, and neuronal damage leading to disruption of neuronal function [ 92 , 101 ]. These alterations often are associated with a leaky gut, leading to increasing neuroinflammatory responses in affected individuals [ 102 ].…”

Section: Gulf War Illness (Gwi)mentioning

confidence: 99%

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cohen,

Mathew,

Dourvetakis

et al. 2024

Cells

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Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood–brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

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Section: Gulf War Illness (Gwi)mentioning

confidence: 99%

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cohen,

Mathew,

Dourvetakis

et al. 2024

Cells

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“…For example, Gulf War illness (GWI) is a chronic neuropsychiatric disorder characterized by neurocognitive deficits arising from OXS, neuroinflammation, and neuronal damage. Currently, no effective treatment of GWI is known [ 45 ]. However, in a GWI experimental model, NR-mediated SIRT1 activation restored brain MT bioenergetics dysfunction (following astroglia activation) and reduced neuroinflammation.…”

Section: Effects Of Nicotinamide Riboside On Several Organs and Systemsmentioning

confidence: 99%

Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives

Biță

Scorei²,

Ciocîlteu

et al. 2023

Molecules

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Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). As a dietary supplement, NR appears to be well tolerated, having better pharmacodynamics and greater potency. Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Recently, work related to prebiotic chemistry discovered that NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself. This review provides a comprehensive summary (through Q1 of 2023) of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.

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“…These DFP-exposed rats exhibit neuronal injury and neurologic morbidities similar to those reported by GW veterans, and this model has been used to identify mechanisms and therapeutics for GWI treatment ( Phillips et al, 2019 ; Zhu et al, 2020 ; Ribeiro et al, 2021 ). Preclinical research has implicated several mechanisms for GWI persistence, including chronic neuroinflammation, gut dysbiosis, neuronal calcium imbalances, and epigenetic alterations ( Dickey et al, 2021 ; Ribeiro and Deshpande, 2021 ; Kodali et al, 2023 ). Epigenetics studies chemical modifications to the genome that do not alter the DNA sequence but can influence how genes are expressed ( Jaenisch and Bird, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

“…Research into treatments for GWI has taken a mechanisms-based approach by choosing/repurposing drugs that could target the underlying pathologic mechanisms to alleviate GWI symptoms ( Dickey et al, 2021 ; Ribeiro and Deshpande, 2021 ; Kodali et al, 2023 ). One such pathologic mechanism that has come to the forefront for GWI is the alterations in the brain-derived neurotrophic factor (BDNF) ( Carreras et al, 2018 ; Kimono et al, 2020 ; Ribeiro et al, 2020 , 2021 ; Brown et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Ketamine Produces Antidepressant Effects by Inhibiting Histone Deacetylases and Upregulating Hippocampal Brain-Derived Neurotrophic Factor Levels in a Diisopropyl Fluorophosphate–Based Rat Model of Gulf War Illness

Ribeiro-Davis,

Al Saeedy,

Jahr

et al. 2023

J Pharmacol Exp Ther

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Approximately one-third of Gulf War veterans suffer from Gulf War Illness (GWI), which encompasses mood disorders and depressive symptoms. Deployment-related exposure to organophosphate compounds has been associated with GWI development. Epigenetic modifications have been reported in GWI veterans. We previously showed that epigenetic histone dysregulations were associated with decreased brain-derived neurotrophic factor (BDNF) expression in a GWI rat model. GWI has no effective therapies. Ketamine (KET) has recently been approved by the Food and Drug Administration for therapy-resistant depression. Interestingly, BDNF upregulation underlies KET’s antidepressant effect in GWI-related depression. Here, we investigated whether KET’s effect on histone mechanisms signals BDNF upregulations in GWI. Male Sprague-Dawley rats were injected once daily with diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c., 5 days). At 6 months following DFP exposure, KET (10 mg/kg, i.p.) was injected, and brains were dissected 24 hours later. Western blotting was used for protein expression, and epigenetic studies used chromatin immunoprecipitation methods. Dil staining was conducted for assessing dendritic spines. Our results indicated that an antidepressant dose of KET inhibited the upregulation of histone deacetylase (HDAC) enzymes in DFP rats. Furthermore, KET restored acetylated histone occupancy at the Bdnf promoter IV and induced BDNF protein expression in DFP rats. Finally, KET treatment also increased the spine density and altered the spine diversity with increased T-type and decreased S-type spines in DFP rats. Given these findings, we propose that KET’s actions involve the inhibition of HDAC expression, upregulation of BDNF, and dendritic modifications that together ameliorates the pathologic synaptic plasticity and exerts an antidepressant effect in DFP rats. SIGNIFICANCE STATEMENT This study offers evidence supporting the involvement of epigenetic histone pathways in the antidepressant effects of ketamine (KET) in a rat model of Gulf War Illness (GWI)-like depression. This effect is achieved through the modulation of histone acetylation at the Bdnf promoter, resulting in elevated brain-derived neurotrophic factor expression and subsequent dendritic remodeling in the hippocampus. These findings underscore the rationale for considering KET as a potential candidate for clinical trials aimed at managing GWI-related depression.

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Pathophysiological basis and promise of experimental therapies for Gulf War Illness, a chronic neuropsychiatric syndrome in veterans

Cited by 8 publications

References 209 publications

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives

Ketamine Produces Antidepressant Effects by Inhibiting Histone Deacetylases and Upregulating Hippocampal Brain-Derived Neurotrophic Factor Levels in a Diisopropyl Fluorophosphate–Based Rat Model of Gulf War Illness

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