Ouabain inhibitor rostafuroxin attenuates dextromethorphan-induced manic potential

Shin, Eun‐Joo; Nguyen, Bao-Trong; Jeong, Ji Hoon; Nguyen, Bao Trong; Tran, Ngoc Kim Cuong; Sharma, Naveen; Kim, Dae-Joong; Nah, Seung-Yeol; Lichtstein, David; Nabeshima, Toshitaka; Kim, Hyoung‐Chun

doi:10.1016/j.fct.2021.112657

Cited by 5 publications

(3 citation statements)

References 103 publications

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“…However, further study is required to determine whether low-dose ketamine induces mania-like behavior in AKT-overexpressing transgenic mice. Exposure to the specific PI3K inhibitor LY294002 is reported to inhibit locomotor activity during the OFT ( Shin et al, 2021 ; Xing et al, 2019 ). Our data also confirmed that LY294002 significantly decreased locomotor activity in mice.…”

Section: Discussionmentioning

confidence: 99%

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Ni¹,

Gao²,

Wang³

et al. 2022

Zoological Research

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Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

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Section: Discussionmentioning

confidence: 99%

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Ni¹,

Gao²,

Wang³

et al. 2022

Zoological Research

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“…Thus, the administration of anti-ouabain antibodies, which reduced amphetamine-induced hyperactivity, protected against OS in the brain [56]. Moreover, administration of the ouabain antagonist rostafuroxin ameliorated behavioral and brain biochemical changes in the dextromethorphan-induced mania model [57].…”

Section: Using Cardiotonic Steroids To Model Dopaminergic System Dysf...mentioning

confidence: 91%

Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies

Markina,

Kazanskaya,

Timoshina

et al. 2023

Biomedicines

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In recent years, enough evidence has accumulated to assert that cardiotonic steroids, Na+,K+-ATPase ligands, play an integral role in the physiological and pathophysiological processes in the body. However, little is known about the function of these compounds in the central nervous system. Endogenous cardiotonic steroids are involved in the pathogenesis of affective disorders, including depression and bipolar disorder, which are linked to dopaminergic system dysfunction. Animal models have shown that the cardiotonic steroid ouabain induces mania-like behavior through dopamine-dependent intracellular signaling pathways. In addition, mutations in the alpha subunit of Na+,K+-ATPase lead to the development of neurological pathologies. Evidence from animal models confirms the neurological consequences of mutations in the Na+,K+-ATPase alpha subunit. This review is dedicated to discussing the role of cardiotonic steroids and Na+,K+-ATPase in dopaminergic system pathologies—both the evidence supporting their involvement and potential pathways along which they may exert their effects are evaluated. Since there is an association between affective disorders accompanied by functional alterations in the dopaminergic system and neurological disorders such as Parkinson’s disease, we extend our discussion to the role of Na+,K+-ATPase and cardiotonic steroids in neurodegenerative diseases as well.

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“…Simultaneous ICV infusion of anti-ouabain antibodies, which should immunoneutralize EO in the brain, prevented the d -amphetamine-induced changes in brain antioxidant enzyme levels and the hyperactivity ( 505 ). Also, dextromethorphan, an abused cough suppressant that can cause mania in humans ( 600 – 602 ), induced hyperlocomotion in mice that was significantly attenuated by rostafuroxin ( 603 ).…”

Section: The Physiology and Pathophysiology Of Cts-nka Interactionsmentioning

confidence: 99%

Sensational site: the sodium pump ouabain-binding site and its ligands

Blaustein,

Hamlyn

2024

American Journal of Physiology-Cell Physiology

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Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950's and 60's we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, sub-nanomolar ouabain sometimes stimulates NKA whilst higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcome in HF patients. Fourth, cloning of NKA in 1985 revealed multiple NKA α and β subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent: e.g., ouabain induces hypertension in rodents while digoxin is anti-hypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous activities are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain binding site on physiology and pathophysiology.

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Ouabain inhibitor rostafuroxin attenuates dextromethorphan-induced manic potential

Cited by 5 publications

References 103 publications

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies

Sensational site: the sodium pump ouabain-binding site and its ligands

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