Gulf War Illness: Mechanisms Underlying Brain Dysfunction and Promising Therapeutic Strategies

Dickey, B.R.; Madhu, Leelavathi N.; Shetty, Ashok K.

doi:10.1016/j.pharmthera.2020.107716

Cited by 39 publications

(38 citation statements)

References 241 publications

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“…Current literature suggests that both the innate and adaptive immune systems play a role in the chronic and persistent pathophysiology of GWI. While a role of innate immunity in GWI has been well-described and reviewed elsewhere, 31 , 32 this review will focus primarily on the role of adaptive cellular and humoral immune responses ( Figure 1 ) in the context of GW chemical exposure and discuss how such chemicals can promote long-lasting changes in the immune system. Discussions will also include how crosstalk between the brain’s innate immune system and the peripheral adaptive immune cells could contribute to the CNS pathology in GWI.…”

Section: Role Of Immune System In Gwimentioning

confidence: 99%

Adaptive Immune Responses Associated with the Central Nervous System Pathology of Gulf War Illness

et al. 2021

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Gulf War Illness is a multisymptomatic condition which affects 30% of veterans from the 1991 Gulf War. While there is evidence for a role of peripheral cellular and humoral adaptive immune responses in Gulf War Illness, a potential role of the adaptive immune system in the central nervous system pathology of this condition remains unknown. Furthermore, many of the clinical features of Gulf War Illness resembles those of autoimmune diseases, but the biological processes are likely different as the etiology of Gulf War Illness is linked to hazardous chemical exposures specific to the Gulf War theatre. This review discusses Gulf War chemical–induced maladaptive immune responses and a potential role of cellular and humoral immune responses that may be relevant to the central nervous system symptoms and pathology of Gulf War Illness. The discussion may stimulate investigations into adaptive immunity for developing novel therapies for Gulf War Illness.

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Section: Role Of Immune System In Gwimentioning

confidence: 99%

Adaptive Immune Responses Associated with the Central Nervous System Pathology of Gulf War Illness

et al. 2021

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“…Mitochondrial dysfunction was reported in muscle tissue of GWI patients and mitochondrial dysfunction was also replicated in animal models of GWI. [18,41] Therefore, we sought to determine how combined exposure to compounds implicated in GWI affects mitochondrial function in this in vitro paradigm. The Seahorse instrument was used to determine the combined effect of GWI mixture on mitochondrial function of immortalized neuron-like neuroblastoma cells amenable to high throughput screenings.…”

Section: Gwi Toxicant Mixture Activates P38/mapk and Psapk/jnk Apoptotic Signaling Following 8-h Incubationmentioning

confidence: 99%

Pyridostigmine bromide, chlorpyrifos, and DEET combined Gulf War exposure insult depresses mitochondrial function in neuroblastoma cells

Delic

Karp

Klein

et al. 2021

J Biochem & Molecular Tox

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Gulf War Illness (GWI) is defined by the Centers for Disease Control and Prevention (CDC) as a multi-symptom illness having at least one symptom from two of three factors, which include: fatigue, mood-cognition problems, and musculoskeletal disorders. The cluster of long-term symptoms is unique to military personnel from coalition countries including United States, Australia, and the United Kingdom that served in Operation Desert Storm from 1990 to 1991. Reporting of these symptoms is much lower among soldiers deployed in other parts of the world like Bosnia during the same time period. The exact cause of GWI is unknown, but combined exposure to N,N-diethyl-m-toluamide (DEET), organophosphates like chlorpyrifos (CPF), and pyridostigmine bromide (PB), has been hypothesized as a potential mechanism.Mitochondrial dysfunction is known to occur in most neurodegenerative diseases that share symptoms with GWI and has therefore been implicated in GWI. Although exposure to these and other toxicants continues to be investigated as potential causes of GWI, their combined impact on mitochondrial physiology remains unknown. In this study, the effects of combined GWI toxicant exposure on mitochondrial function were determined in a commonly used and readily available immortalized cell line (N2a), whose higher rate of oxygen consumption resembles that of highly metabolic neurons in vivo. We report that combined exposure containing pesticide CPF 71 μM, insect repellants DEET 78 μM, and antitoxins PB 19 μM, causes profound mitochondrial dysfunction after a 4-h incubation resulting in decreased mitochondrial respiratory states in the absence of proapoptotic signaling, proton leak, or significant increase in reactive oxygen species production.

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“…Recent papers have reviewed mechanisms underlying brain dysfunction and therapeutic strategies in animal models of GWI and GWI veterans. 58 , 59 The focus of this paper was to discuss findings related to alterations in neuronal Ca 2+ levels and subsequently review how restoration of protracted Ca 2+ levels using FDA approved therapeutics alleviates neurological signs of GWI in our rat DFP model which, then led us to propose the Ca 2+ hypothesis of GWI. Whether the protracted Ca 2+ elevations reported in our repeated, low-dose DFP model are also observed in other GWI models would help validate and expand this Ca 2+ hypothesis as a major mechanism for GWI neurological dysfunctions.…”

Section: Future Directionsmentioning

confidence: 99%

Calcium Hypothesis of Gulf War Illness: Role of Calcium Ions in Neurological Morbidities in a DFP-Based Rat Model for Gulf War Illness

Phillips

Deshpande

2020

J Exp Neurosci

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Gulf War Illness (GWI) refers to a multi-system disorder that afflicts approximately 30% of First Gulf War (GW) veterans. Amongst the symptoms exhibited, mood and memory impairment are commonly reported by GW veterans. Exposure to organophosphate (OP) compounds which target the cholinergic system is considered a leading cause for GWI symptoms. It is hypothesized that chronic OP-based war-time stimulation of cholinergic signaling led to recruitment of excitatory glutamatergic signaling and other downstream signaling cascades leading to neuronal injury, neuroinflammation, generation of reactive oxygen species, oxidative stress, and mitochondrial damage within the central nervous system. These findings have been observed in both experimental models and GWI veterans. In this context the role of calcium (Ca2+) signaling in GWI has come to the forefront. Here we present our Ca2+ hypothesis of GWI that suggests sustained neuronal Ca2+ elevations serve as a molecular trigger for pathological synaptic plasticity that has allowed for the persistence of GWI symptoms. Subsequently we discuss that therapeutic targeting of Ca2+ homeostatic mechanisms provides novel targets for effective treatment of GWI-related neurological signs in our rodent model.

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Gulf War Illness: Mechanisms Underlying Brain Dysfunction and Promising Therapeutic Strategies

Cited by 39 publications

References 241 publications

Adaptive Immune Responses Associated with the Central Nervous System Pathology of Gulf War Illness

Adaptive Immune Responses Associated with the Central Nervous System Pathology of Gulf War Illness

Pyridostigmine bromide, chlorpyrifos, and DEET combined Gulf War exposure insult depresses mitochondrial function in neuroblastoma cells

Calcium Hypothesis of Gulf War Illness: Role of Calcium Ions in Neurological Morbidities in a DFP-Based Rat Model for Gulf War Illness

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