The expression of glial cell line-derived neurotrophic factor mRNA by antidepressants involves matrix metalloproteinase-9 activation in rat astroglial cells.
Neurotrophic/growth factors derived from glial cells, especially astrocytes, have been implicated in mood disorders and the pharmacological effects of antidepressant drugs. Previous studies demonstrated that the release of glial cell line-derived neurotrophic factor (GDNF) induced by the tricyclic antidepressant amitriptyline was significantly inhibited by a broad-spectrum matrix metalloproteinase (MMP) inhibitor in rat C6 astroglial cells (C6 cells). However, it is unknown whether amitriptyline affects MMP enzymatic activity or expression, and the MMP subtype has yet to be identified. The current study measured the effect of antidepressants on MMP activity with gelatin zymography, an in vitro assay for enzymatic activity, in C6 cells and primary cultured rat astrocytes (primary astrocytes). Treatment with amitriptyline increased zymographic MMP-9 activity without changing MMP-9 mRNA expression in C6 cells. Several different classes of antidepressants significantly increased zymographic MMP-9 activity in C6 cells and primary astrocytes, whereas antipsychotic drugs without antidepressant pharmacological activity did not. The amitriptyline-induced expression of GDNF mRNA was completely blocked by selective inhibition of MMP-9 in C6 cells. Treatment of C6 cells and primary astrocytes with exogenous recombinant MMP-9 increased GDNF mRNA expression, similar to that observed with amitriptyline. Inhibiting MMP-3 blocked amitriptyline-induced zymographic MMP-9 activation in C6 cells and primary astrocytes, indicating that MMP-3 is necessary for MMP-9 activity. The current study suggests that MMP-9 activation is indispensable in the amitriptyline-induced expression of GDNF mRNA in astrocytes and further supports a role of astrocytic neurotrophic/growth factors in the pharmacological effect of antidepressants.
Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan; Department of Pharmacology, Hiroshima University, Graduate School of Biomedical & Health Sciences, Hiroshima, Hiroshima, Japan.
Hiromi
H
Abe
Department of Pharmacology, Hiroshima University, Graduate School of Biomedical & Health Sciences, Hiroshima, Hiroshima, Japan.
Kazue
K
Hisaoka-Nakashima
Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan.
Naoto
N
Kajitani
Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan.
Mami
M
Okada-Tsuchioka
Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan.
Ryoya
R
Yano
Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan; Department of Psychiatry, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan.
Kei
K
Itagaki
Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan.
Chiyo
C
Shibasaki
Department of Pharmacology, Hiroshima University, Graduate School of Biomedical & Health Sciences, Hiroshima, Hiroshima, Japan.
Norimitsu
N
Morioka
Department of Pharmacology, Hiroshima University, Graduate School of Biomedical & Health Sciences, Hiroshima, Hiroshima, Japan.
Yoshihiro
Y
Nakata
Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan; Department of Psychiatry, National Hospital Organization (NHO) Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan. Electronic address: mtakebayashi@kure-nh.go.jp.
Minoru
M
Takebayashi
D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D000928:Antidepressive Agents; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D000639:Amitriptyline; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
Antidepressant; Astrocyte; Depression; Gelatin zymography; Glial cell line-derived neurotrophic factor; Matrix metalloproteinase-9