Molecular mechanisms for the antidepressant-like effects of a low-dose ketamine treatment in a DFP-based rat model for Gulf War Illness

Ribeiro, Ana C.R.; Zhu, Jackie; Kronfol, Mohamad M.; Jahr, Fay M.; Younis, Rabha M.; Hawkins, Elisa; McClay, Joseph L.; Deshpande, Laxmikant S.

doi:10.1016/j.neuro.2020.06.011

Cited by 26 publications

(32 citation statements)

References 47 publications

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“…Data adapted from References. [22][23][24] levels within the hippocampus of DFP rats. 24 Thus, "leaky" neuronal RyR could also underlie GWI neuropathology and could possibly prove to be effective targets for therapeutic interventions.…”

Section: Molecular Mechanism For Neuronal Ca 2+ Dysfunction In Dfp-bamentioning

confidence: 91%

“…This indicates that low-dose, sub-chronic exposure to OP agents can reproduce long-lasting neurological deficits that are associated with GWI. This OP-based DFP rat model has been helpful in identifying molecular mechanisms underlying the development of GWI 22,23 and has been used to screen drugs for effective treatment of GWI-related neurological signs. 24,25…”

Section: Rodent Model For Gwimentioning

confidence: 99%

“…Interestingly we observed that BDNF expression was significantly lower in the hippocampus of DFP-rats compared to age-matched control rats. 23 Given the pleiotropic actions of BDNF signaling on neuronal survival and synaptic plasticity pathways, BDNF dysregulation could be an important downstream mechanism for GWI neuropathology (Also see Figure 4). In the context of GWI, we recently investigated molecular mechanisms for ketamine's antidepressant action using our DFP-based rat model of GWI-like depressive signs.…”

Section: Ketamine In a Dfp-based Rat Model For Gwimentioning

confidence: 99%

“…While the inhibition of the NMDAR-Ca 2+ pathway contributed to the rapid onset antidepressant effects of ketamine while, the long-lasting antidepressant actions involved upregulation of BDNF signaling. 23 Like the LEV studies, these pre-clinical studies provide impetus for further assessment of ketamine in clinical trials with GWI veterans for treatment of GWI-related depression.…”

Section: Ketamine In a Dfp-based Rat Model For Gwimentioning

confidence: 99%

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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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Section: Molecular Mechanism For Neuronal Ca 2+ Dysfunction In Dfp-bamentioning

confidence: 91%

Section: Rodent Model For Gwimentioning

confidence: 99%

Section: Ketamine In a Dfp-based Rat Model For Gwimentioning

confidence: 99%

Section: Ketamine In a Dfp-based Rat Model For Gwimentioning

confidence: 99%

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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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“…in the original rat model of depression is accompanied by a decrease in the level of intracellular Ca 2+ in CA1 hippocampal neurons. However, after 24 h, only ketamine caused an antidepressant-like effect, which was combined with an increase in BDNF level in the hippocampus and was eliminated by the trkB antagonist [212].…”

Section: Glutamatergic Neurotransmissionmentioning

confidence: 97%

Chaperone Sigma1R and Antidepressant Effect

Voronin

Vakhitova

Seredenin

2020

IJMS

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This review analyzes the current scientific literature on the role of the Sigma1R chaperone in the pathogenesis of depressive disorders and pharmacodynamics of antidepressants. As a result of ligand activation, Sigma1R is capable of intracellular translocation from the endoplasmic reticulum (ER) into the region of nuclear and cellular membranes, where it interacts with resident proteins. This unique property of Sigma1R provides regulation of various receptors, ion channels, enzymes, and transcriptional factors. The current review demonstrates the contribution of the Sigma1R chaperone to the regulation of molecular mechanisms involved in the antidepressant effect.

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Ketamine and Esketamine in Clinical Trials: FDA‐Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations

Vekhova,

Namiot,

Jonsson

et al. 2024

Clin Pharma and Therapeutics

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Ketamine has a long and very eventful pharmacological history. Its enantiomer, esketamine ((S)‐ketamine), was approved by the US Food and Drug Administration (FDA) and EMA for patients with treatment‐resistant depression (TRD) in 2019. The number of approved indications for ketamine and esketamine continues to increase, as well as the number of clinical trials. This analysis provides a quantitative overview of the use of ketamine and its enantiomers in clinical trials during 2014–2024. A total of 363 trials were manually assessed from clinicaltrial.gov with the search term “Ketamine.” The highest number of trials were found for the FDA‐approved indications: anesthesia (~22%) and pain management (~28%) for ketamine and TRD for esketamine (~29%). Clinical trials on TRD for both ketamine and esketamine also comprised a large proportion of these trials, and interestingly, have reached phase III and phase IV status. Combinatorial treatment of psychiatric disorders and non‐psychiatric conditions with pharmacological and non‐pharmacological combinations (electroconvulsive therapy, psychotherapeutic techniques, virtual reality, and transcranial magnetic stimulation) is prevalent. Sub‐anesthetic doses of ketamine may represent novel therapeutic avenues in neuropsychiatric conditions, that is, major depression, schizophrenia, and bipolar disorder, where glutamate excitotoxicity and oxidative stress are likely to be involved. The study suggests that the number of ketamine studies will continue to grow and possible ketamine variants can be approved for treatment of additional indications.

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Molecular mechanisms for the antidepressant-like effects of a low-dose ketamine treatment in a DFP-based rat model for Gulf War Illness

Cited by 26 publications

References 47 publications

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

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

Chaperone Sigma1R and Antidepressant Effect

Ketamine and Esketamine in Clinical Trials: FDA‐Approved and Emerging Indications, Trial Trends With Putative Mechanistic Explanations

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