[Mechanisms of antidepressants and serotonin (5-HT)-induced glial cell line-derived neurotrophic factor (GDNF) releases in rat C6 gliobrastoma cells].
Recent studies show that neuronal and glial plasticity are important for the therapeutic action of antidepressants. Here, we demonstrated that amitriptyline, a tricyclic antidepressant, significantly increased GDNF mRNA and GDNF release in C6 cells. Furthermore, different classes of antidepressants increased GDNF release, but non-antidepressant psychotropic drugs did not. The amitriptyline-induced GDNF release was completely inhibited by U0126, a mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89, a protein kinase A inhibitor or calphostin C, a protein kinase C inhibitor. These results suggest that the amitriptyline-induced GDNF release may be regulated through a MEK/MAPK pathway. Next, we examined the effects of monoamines on GDNF release, because antidepressants are known to increase monoamines. 5-HT increased GDNF mRNA and GDNF release, but noradrenaline and dopamine did not. The 5-HT-induced GDNF release was partially, but significantly, blocked by ketanserin, a 5-HT2A receptor antagonist. The 5-HT-induced GDNF release was completely inhibited by U0126, but was not inhibited by H-89 or calphostin C. These results suggest that the 5-HT-induced GDNF release was mediated through a MEK/MAPK pathway and, at least, 5-HT2A receptors. GDNF, as well as other neurotrophic factors, may contribute to explain the therapeutic action of antidepressants and suggest a novel strategy of pharmacological intervention.
Hisaoka
Kazue
K
Institute of Clinical Research, National Hospital Organization Kure Medical Center, 3-1 Aoyama, Kure, 737-0023, Japan. hisaokak@kure-nh.go.jp
Takebayashi
Minoru
M
Nishida
Akira
A
Tsuchioka
Mami
M
Yamawaki
Shigeto
S
Nakata
Yoshihiro
Y
D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007546:Isoquinolines / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D012701:Serotonin / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
D000928:Antidepressive Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007546:Isoquinolines; D009414:Nerve Growth Factors; D009570:Nitriles; D012333:RNA, Messenger; D013449:Sulfonamides; C113580:U 0126; D000639:Amitriptyline; D012701:Serotonin; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide