Ethanol normalizes glutamate‐induced elevation of intracellular sodium in olfactory neuroepithelial progenitors from subjects with bipolar illness but not nonbipolar controls: Biologic evidence for the self‐medication hypothesis

Gao, Yonglin; Lohano, Kavita; Delamere, Nicholas A.; Lei, Zhenmin; El‐Mallakh, Rif S.

doi:10.1111/bdi.12737

Cited by 7 publications

(4 citation statements)

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“…Utilize neuronal cells obtained from patients and controls (e.g., induced pluripotent cells [104] or olfactory neuroepithelial cells [105]) in order to determine the differential effect (if any) in the response of neural tissue derived from patients with BD and non-psychiatric controls. Early exploratory evidence from immortalized lymphoblasts [106], induced pluripotent cells, and olfactory neuroepithelial progenitors [107][108][109][110][111], suggests that such differences exist.…”

mentioning

confidence: 99%

Endogenous Cardiac Steroids in Bipolar Disorder: State of the Art

El‐Mallakh

Sampath²,

Horesh³

et al. 2022

IJMS

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Bipolar disorder (BD) is a severe psychiatric illness with a poor prognosis and problematic, suboptimal, treatments. Treatments, borne of an understanding of the pathoetiologic mechanisms, need to be developed in order to improve outcomes. Dysregulation of cationic homeostasis is the most reproducible aspect of BD pathophysiology. Correction of ionic balance is the universal mechanism of action of all mood stabilizing medications. Endogenous sodium pump modulators (collectively known as endogenous cardiac steroids, ECS) are steroids which are synthesized in and released from the adrenal gland and brain. These compounds, by activating or inhibiting Na+, K+-ATPase activity and activating intracellular signaling cascades, have numerous effects on cell survival, vascular tone homeostasis, inflammation, and neuronal activity. For the past twenty years we have addressed the hypothesis that the Na+, K+-ATPase-ECS system may be involved in the etiology of BD. This is a focused review that presents a comprehensive model pertaining to the role of ECS in the etiology of BD. We propose that alterations in ECS metabolism in the brain cause numerous biochemical changes that underlie brain dysfunction and mood symptoms. This is based on both animal models and translational human results. There are data that demonstrate that excess ECS induce abnormal mood and activity in animals, while a specific removal of ECS with antibodies normalizes mood. There are also data indicating that circulating levels of ECS are lower in manic individuals, and that patients with BD are unable to upregulate synthesis of ECS under conditions that increase their elaboration in non-psychiatric controls. There is strong evidence for the involvement of ion dysregulation and ECS function in bipolar illness. Additional research is required to fully characterize these abnormalities and define future clinical directions.

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confidence: 99%

Endogenous Cardiac Steroids in Bipolar Disorder: State of the Art

El‐Mallakh

Sampath²,

Horesh³

et al. 2022

IJMS

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“…We have previously demonstrated at 0.1 M glutamate treated for 6 h increased intracellular sodium ([Na] i ) concentration twice that of untreated ONPs 9 . Similarly, ONPs derived from BD were more susceptible to glutamate-induced apoptosis 17 .…”

Section: Discussionmentioning

confidence: 99%

“…Several ion regulatory systems have been shown to be uniquely disrupted in bipolar patients versus controls 7 – 10 . Furthermore, bipolar patients have been found to have excessive levels of the precursor glutamine in certain parts of their brain, as well as higher numbers of glutamate receptors 9 – 13 . These findings imply an abnormality of glutamate signaling in bipolar.…”

Section: Introductionmentioning

confidence: 99%

NMDA receptor inhibition prevents intracellular sodium elevations in human olfactory neuroepithelial precursors derived from bipolar patients

Gao

Mack

Litteral

et al. 2022

Sci Rep

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Dysregulation of ion flux across membranes and glutamate-induced excitotoxicity appear to be important pathophysiologic abnormalities in bipolar illness. Understanding ion control and responses to ionic stress is important to decipher the pathogenesis of this disorder. Monensin alone significantly increased [Na]i in ONPs from bipolar individuals (5.08 ± 0.71 vs baseline 3.13 ± 0.93, P = 0.03) and AP5 had no effect (2.0 ± 1.2 vs baseline 3.13 ± 0.93, P = 0.27). However, the combination of AP5 and monensin resulted in normalization of [Na]i (3.25 ± 1.28 vs baseline 3.13 ± 0.93, P = 0.89). This effect was not observed in cells from non-bipolar individuals (monensin alone, 1.72 ± 1.10 vs baseline 2.42 ± 1.80, P = 0.25; AP5 alone, 1.37 ± 0.74 vs baseline 2.42 ± 1.80; AP5 combined with monensin, 1.53 ± 0.98 vs baseline 2.42 ± 1.80, P = 0.31). Sodium regulation is central to neuronal function and may be disturbed in patients with bipolar disorder. Monensin is an ionophore, meaning that it incorporates itself into the membrane and allows sodium to enter independent of cellular membrane proteins. While the mechanism remains obscure, the observation that the NMDA receptor antagonist, AP5, normalizes [Na]i only in olfactory neuroepithelial precursors obtained from bipolar illness may provide novel insights into ion regulation in tissues from subjects with bipolar illness.

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“…33 One of the most reproducible biomarkers associated with manic and bipolar depressed mood states is increased intracellular sodium 38,39 and reduced ability to correct a sodium challenge. [40][41][42] By normalizing intracellular sodium levels, lithium and the mood-stabilizing anticonvulsants uniquely and specifically counter known physiologic abnormalities in patients with BD. 37,43 The role of ion dysregulation…”

Section: Changes In Pharmacotherapy For Bipolar Disordermentioning

confidence: 99%

Bipolar disorder: The foundational role of mood stabilizers

Shah¹

2023

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Ethanol normalizes glutamate‐induced elevation of intracellular sodium in olfactory neuroepithelial progenitors from subjects with bipolar illness but not nonbipolar controls: Biologic evidence for the self‐medication hypothesis

Cited by 7 publications

References 5 publications

Endogenous Cardiac Steroids in Bipolar Disorder: State of the Art

Endogenous Cardiac Steroids in Bipolar Disorder: State of the Art

NMDA receptor inhibition prevents intracellular sodium elevations in human olfactory neuroepithelial precursors derived from bipolar patients

Bipolar disorder: The foundational role of mood stabilizers

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