Activation of mTOR dependent signaling pathway is a necessary mechanism of antidepressant-like activity of zinc

Szewczyk, Bernadeta; Pochwat, Bartłomiej; Rafalo, Anna; Pałucha-Poniewiera, Agnieszka; Domin, Helena; Nowak, Gabriel

doi:10.1016/j.neuropharm.2015.08.026

Cited by 43 publications

(25 citation statements)

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“…Those authors demonstrated the involvement of MAPK/ERK and PI3K in the acute antidepressant-like effect of ferulic acid, which is consistent with our results showing the involvement of these signaling pathways in the antidepressant activity of Lu AA33810. The present data are also consistent with our previous findings and results of other authors demonstrating that pretreatment with LY294002 prevented the antidepressant-like effect of compounds in the FST in mice (Budni et al 2012) and in the FST in rats (Szewczyk et al 2015). …”

Section: Discussionsupporting

confidence: 94%

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence

et al. 2016

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RationaleIt has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model.ObjectiveIn the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression.ResultsWe observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 μg/2 μl) and the selective PI3K inhibitor LY294002 (10 nmol/2 μl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810.ConclusionOur results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy.

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Section: Discussionsupporting

confidence: 94%

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence

et al. 2016

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“…In contrast, antidepressants such as imipramine or fluoxetine or electroconvulsive seizures did not significantly influence mTOR signaling [158]. Recent study demonstrated that a single dose of zinc (5 mg/kg) administered 30 minutes prior to the FST produced antidepressant-like effect, which lasted up to 3 h [159]. Unlike ketamine, zinc did not produce a sustained antidepressant-like effect [159]; however, in contrast to conventional antidepressants (imipramine, fluoxetine) or electroconvulsive seizures [158], it induced a transient (observed 30 min and 3 h after the treatment) increase in the protein levels of phosphorylated mTOR and ribosomal protein S6 kinase (p70S6K).…”

Section: Link To Neural Plasticitymentioning

confidence: 99%

“…An elevated level of GluA1 and synapsin I was still observed 24 h after the zinc treatment. In addition, antidepressant-like effect of zinc in the FST was blocked by pretreatment with rapamycin, mTOR inhibitor [159], which suggest that mTOR is involved in the antidepressant-like action of zinc. Also, blockade of mTOR signaling blocked ketamine behavioral effects and induction of synaptogenesis [158].…”

Section: Link To Neural Plasticitymentioning

confidence: 99%

“…In contrast, conventional antidepressants require weeks to induce an increase in BDNF protein expression, for example, 2 weeks of treatment with fluoxetine produced region-specific increase in BDNF mRNA, whereas BDNF protein level remained unaltered until 3 weeks of the treatment and reached significance after 3 weeks in CA1 and CA3 but not in other subregions of the hippocampus [165]. There were no changes in the level of BDNF protein in the prefrontal cortex 30 min after zinc treatment [159]. Also, 1 h after zinc administration Manosso et al did not observe changes in BDNF protein levels in either the prefrontal cortex or hippocampus [162].…”

Section: Link To Neural Plasticitymentioning

confidence: 99%

“…Also, 1 h after zinc administration Manosso et al did not observe changes in BDNF protein levels in either the prefrontal cortex or hippocampus [162]. However, an increase in the level of BDNF protein in the prefrontal cortex was found 3 h after zinc treatment [159]. Ranjbar et al [72] observed in patients with major depression that zinc supplementation of the therapy with SSRIs (fluoxetine, citalopram) reduced depressive symptoms more effectively that a respective SSRI and placebo, however, these effects were not associated with alterations in serum BDNF level.…”

Section: Link To Neural Plasticitymentioning

confidence: 99%

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Zinc in the Monoaminergic Theory of Depression: Its Relationship to Neural Plasticity

et al. 2017

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Preclinical and clinical studies have demonstrated that zinc possesses antidepressant properties and that it may augment the therapy with conventional, that is, monoamine-based, antidepressants. In this review we aim to discuss the role of zinc in the pathophysiology and treatment of depression with regard to the monoamine hypothesis of the disease. Particular attention will be paid to the recently described zinc-sensing GPR39 receptor as well as aspects of zinc deficiency. Furthermore, an attempt will be made to give a possible explanation of the mechanisms by which zinc interacts with the monoamine system in the context of depression and neural plasticity.

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Involvement of mTOR‐related signaling in antidepressant effects of Sophoraflavanone G on chronically stressed mice

Wang

Tong

Xiao

et al. 2020

Phytotherapy Research

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SophoraflavanoneG (SG), an important prenylated flavonoid isolated from Sophoraalopecuroides.L, is effective for many illnesses. The present study was designed to investigate whether the compound could reverse depressive‐like symptoms and investigate its possible mechanisms. Chronic Unpredictable Mild Stress (CUMS) mice were treated with fluoxetine and SG. The immobility time in forced swimming test (FST) and tail suspension test (TST) were recorded. The levels of pro‐inflammatory cytokines and neurotransmitters in the hippocampus were evaluated. Furthermore, the protein expressions of PI3K, AKT, mTOR, p70S6K, BDNF, and Trkb in hippocampus were detected. Rapamycin, the selective mTOR inhibitor, was used to estimate the potential mechanism. As a result, after 7 days of SG treatment, the immobility time in FST and TST was declined obviously. The levels of IL‐6, IL‐1β, and TNF‐α in the hippocampus were significantly reduced, and the quantity of 5‐HT and NE was raised considerably in SG‐treated group compared with the CUMS‐exposed group. Additionally, SG could up‐regulate the expressions of PI3K, AKT, mTOR, 70S6K, BDNF, and Trkb. The blockade of mammalian target of rapamycin signaling blunted the antidepressant effect and reversed the up‐regulation of BDNF expression caused by SG. These findings suggested that SG treatment alleviated depressive‐like symptoms via mTOR‐mediated BDNF/Trkb signaling.

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Activation of mTOR dependent signaling pathway is a necessary mechanism of antidepressant-like activity of zinc

Cited by 43 publications

References 53 publications

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence

Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence

Zinc in the Monoaminergic Theory of Depression: Its Relationship to Neural Plasticity

Involvement of mTOR‐related signaling in antidepressant effects of Sophoraflavanone G on chronically stressed mice

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