title: Fibroblast growth factor 2 mRNA expression evoked by amitriptyline involves extracellular signal-regulated kinase-dependent early growth response 1 production in rat primary cultured astrocytes.
abstract: Recently, we demonstrated that several antidepressants including amitriptyline increased fibroblast growth factor 2 (FGF2) mRNA expression slowly over 24 h through de novo protein synthesis in rat primary cultured astrocytes. This study defined the signaling cascade that mediates amitriptyline-induced FGF2 production in rat primary cultured astrocytes. Amitriptyline treatment significantly increased early growth response 1 (EGR1), a transcription factor known to regulate FGF2 expression. Knockdown of EGR1 using siRNA blocked amitriptyline-evoked FGF2 mRNA expression. Treatment with several different classes of antidepressants leads to expression of EGR1 mRNA as well as FGF2 mRNA. These results confirm that EGR1 production is likely to be indispensable for the amitriptyline-evoked FGF2 mRNA expression. Signal transduction inhibitors were used to elaborate the cellular signaling cascade that leads to EGR1-mediated FGF2 expression following amitriptyline treatment. Amitriptyline-evoked EGR1-mediated FGF2 mRNA expression was blocked by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1/2 inhibitor. Furthermore, extracellular signal-regulated kinase/EGR1-mediated FGF2 mRNA expression evoked by amitriptyline was blocked by inhibitors of the FGF receptor, epidermal growth factor receptor (EGFR), and matrix metalloproteinase. Taken together, these results demonstrate that amitriptyline increases FGF2 mRNA expression through a matrix metalloproteinase/receptor tyrosine kinases (RTK) (FGF receptor and EGFR)/extracellular signal-regulated kinase/EGR1 signaling pathway in rat primary cultured astrocytes. Recent studies suggest that fibroblast growth factor 2 (FGF2) is involved in the antidepressant effect in the model of depression. The production of ERK-dependent early growth response 1 (EGR1) is a crucial part of the amitriptyline-induced FGF2 expression signaling cascade in rat primary cultured astrocytes. The findings elaborate an astrocytic mechanism that could be used to develop antidepressants.
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.|Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kajitani
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Hisaoka-Nakashima
authors.affiliation: Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Okada-Tsuchioka
authors.affiliation: Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Hosoi
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Yokoe
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.affiliation: Department of Pharmacology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
authors.affiliation: Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Japan.|Department of Psychiatry, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takebayashi
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis* / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism
chemical_list: D000929:Antidepressive Agents, Tricyclic; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D000639:Amitriptyline; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: amitriptyline; antidepressants; astrocytes; early growth response 1; fibroblast growth factor 2; matrix metalloproteinase