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Time-dependent activation of MAPK/Erk1/2 and Akt/GSK3 cascades: modulation by agomelatine.

ABSTRACT: BACKGROUND: The novel antidepressant agomelatine, a melatonergic MT1/MT2 agonist combined with 5-HT2c serotonin antagonist properties, showed antidepressant action in preclinical and clinical studies. There is a general agreement that the therapeutic action of antidepressants needs the activation of slow-onset adaptations in downstream signalling pathways finally regulating neuroplasticity. In the last several years, particular attention was given to cAMP-responsive element binding protein (CREB)-related pathways, since it was shown that chronic antidepressants increase CREB phosphorylation and transcriptional activity, through the activation of calcium/calmodulin-dependent (CaM) and mitogen activated protein kinase cascades (MAPK/Erk1/2). Aim of this work was to analyse possible effects of chronic agomelatine on time-dependent changes of different intracellular signalling pathways in hippocampus and prefrontal/frontal cortex of male rats. To this end, measurements were performed 1 h or 16 h after the last agomelatine or vehicle injection. RESULTS: We have found that in naïve rats chronic agomelatine, contrary to traditional antidepressants, did not increase CREB phosphorylation, but modulates the time-dependent regulation of MAPK/Erk1/2 and Akt/glycogen synthase kinase-3 (GSK-3) pathways. CONCLUSION: Our results suggest that the intracellular molecular mechanisms modulated by chronic agomelatine may be partly different from those of traditional antidepressants and involve the time-dependent regulation of MAPK/Erk1/2 and Akt/GSK-3 signalling pathways. This could exert a role in the antidepressant efficacy of the drug.

SUBMITTER: Musazzi L

PROVIDER: S-EPMC4207903 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Time-dependent activation of MAPK/Erk1/2 and Akt/GSK3 cascades: modulation by agomelatine.

Musazzi Laura L Seguini Mara M Mallei Alessandra A Treccani Giulia G Pelizzari Mariagrazia M Tornese Paolo P Racagni Giorgio G Tardito Daniela D

BMC neuroscience 20141021

<h4>Background</h4>The novel antidepressant agomelatine, a melatonergic MT1/MT2 agonist combined with 5-HT2c serotonin antagonist properties, showed antidepressant action in preclinical and clinical studies. There is a general agreement that the therapeutic action of antidepressants needs the activation of slow-onset adaptations in downstream signalling pathways finally regulating neuroplasticity. In the last several years, particular attention was given to cAMP-responsive element binding protei ...[more]

PMID: 25332063

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Project description:Perturbations in the adipocytokine profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether leptin is involved in epithelial-mesenchymal transition (EMT). Here, we provide molecular evidence that leptin induces breast cancer cells to undergo a transition from epithelial to spindle-like mesenchymal morphology. Investigating the downstream mediator(s) that may direct leptin-induced EMT, we found functional interactions between leptin, metastasis-associated protein 1 (MTA1), and Wnt1 signaling components. Leptin increases accumulation and nuclear translocation of ?-catenin leading to increased promoter recruitment. Silencing of ?-catenin or treatment with the small molecule inhibitor, ICG-001, inhibits leptin-induced EMT, invasion, and tumorsphere formation. Mechanistically, leptin stimulates phosphorylation of glycogen synthase kinase 3? (GSK3?) via Akt activation resulting in a substantial decrease in the formation of the GSK3?-LKB1-Axin complex that leads to increased accumulation of ?-catenin. Leptin treatment also increases Wnt1 expression that contributes to GSK3? phosphorylation. Inhibition of Wnt1 abrogates leptin-stimulated GSK3? phosphorylation. We also discovered that leptin increases the expression of an important modifier of Wnt1 signaling, MTA1, which is integral to leptin-mediated regulation of the Wnt/?-catenin pathway as silencing of MTA1 inhibits leptin-induced Wnt1 expression, GSK3? phosphorylation, and ?-catenin activation. Furthermore, analysis of leptin-treated breast tumors shows increased expression of Wnt1, pGSK3?, and vimentin along with higher nuclear accumulation of ?-catenin and reduced E-cadherin expression providing in vivo evidence for a previously unrecognized cross-talk between leptin and MTA1/Wnt signaling in epithelial-mesenchymal transition of breast cancer cells.

Dataset Information

Time-dependent activation of MAPK/Erk1/2 and Akt/GSK3 cascades: modulation by agomelatine.

Publications

Time-dependent activation of MAPK/Erk1/2 and Akt/GSK3 cascades: modulation by agomelatine.

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