title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases (CEND), Università degli Studi di Milano, Via Balzaretti 9, Milano, 20133, Italy. laura.musazzi@unimi.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Musazzi
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases (CEND), Università degli Studi di Milano, Via Balzaretti 9, Milano, 20133, Italy. mara.seguini@guest.unimi.it.
authors.forename: Mara
authors.initials: M
authors.lastname: Seguini
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases (CEND), Università degli Studi di Milano, Via Balzaretti 9, Milano, 20133, Italy. alessandra.mallei@unimi.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mallei
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases (CEND), Università degli Studi di Milano, Via Balzaretti 9, Milano, 20133, Italy. giulia.treccani@guest.unimi.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: Treccani
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases (CEND), Università degli Studi di Milano, Via Balzaretti 9, Milano, 20133, Italy. mariagrazia.pelizzari@gmail.com.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pelizzari
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases (CEND), Università degli Studi di Milano, Via Balzaretti 9, Milano, 20133, Italy. paolo.tornese@unimi.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tornese
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases (CEND), Università degli Studi di Milano, Via Balzaretti 9, Milano, 20133, Italy. giorgio.racagni@unimi.it.|Istituto di Ricovero e Cura a Carattere Scientifico Centro S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. giorgio.racagni@unimi.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases (CEND), Università degli Studi di Milano, Via Balzaretti 9, Milano, 20133, Italy. daniela.tardito@unimi.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Tardito
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects* / Q000201:enzymology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D017362:Cyclic AMP Response Element-Binding Protein; D038362:Glycogen Synthase Kinase 3; D051057:Proto-Oncogene Proteins c-akt; C084711:agomelatine; D009281:Naphthalenes