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

• Published in: BMC neuroscience Vol. 15; no. 1; p. 119
• Main Authors: Musazzi, Laura, Seguini, Mara, Mallei, Alessandra, Treccani, Giulia, Pelizzari, Mariagrazia, Tornese, Paolo, Racagni, Giorgio, Tardito, Daniela
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21.10.2014; BioMed Central
• Subjects: Acetamides - pharmacology; Animals; Antidepressive Agents - pharmacology; Behavior; Blotting, Western; Central nervous system agents; Cyclic adenylic acid; Cyclic AMP Response Element-Binding Protein - metabolism; Frontal Lobe - drug effects; Frontal Lobe - enzymology; Gene expression; Glycogen Synthase Kinase 3 - metabolism; Health aspects; Hippocampus - drug effects; Hippocampus - enzymology; Kinases; Laboratories; Male; MAP Kinase Signaling System - drug effects; Medical research; Medicine, Experimental; Mitogens; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Random Allocation; Rats, Sprague-Dawley; Rodents; Software; Statistical analysis; Time Factors
• ISSN: 1471-2202; 1471-2202
• DOI: 10.1186/s12868-014-0119-1

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. 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. 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.