N-desalkylquetiapine activates ERK1/2 to induce GDNF release in C6 glioma cells: A putative cellular mechanism for quetiapine as antidepressant

被引:36
作者
Di Benedetto, Barbara [1 ]
Kuehn, Ralf [3 ,4 ]
Nothdurfter, Caroline [1 ,2 ]
Rein, Theo [1 ]
Wurst, Wolfgang [3 ,4 ,5 ]
Rupprecht, Rainer [1 ,2 ]
机构
[1] Max Planck Inst Psychiat, D-80804 Munich, Germany
[2] Univ Regensburg, Dept Psychiat & Psychotherapy, D-8400 Regensburg, Germany
[3] Helmholtz Ctr Munich, Inst Dev Genet, Munich, Germany
[4] Tech Univ Munich, Munich, Germany
[5] Deutsch Zentrum Neurodegenerat Erkrankungen eV, Munich, Germany
关键词
Quetiapine; Norquetiapine; Antidepressant; ERK/MAP kinase; GDNF; C6; cells; MAJOR DEPRESSIVE DISORDER; SIGNAL-REGULATED KINASE; NEUROTROPHIC FACTOR; ATYPICAL ANTIPSYCHOTICS; FUMARATE MONOTHERAPY; HEALTHY-SUBJECTS; DOUBLE-BLIND; STRESS; RECEPTORS; SECRETION;
D O I
10.1016/j.neuropharm.2011.07.001
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Quetiapine is an atypical antipsychotic which has been suggested to possess also antidepressant efficacy in the treatment of bipolar and unipolar depression. Recently, a link between the activation of the ERK/MAPK signalling pathway and the release of GDNF has been proposed as a specific feature of antidepressants. To obtain a first insight into the putative molecular mechanism of action of quetiapine, we examined its impact and that of its major metabolite norquetiapine on the activation of the ERK/MAPK signalling pathway in C6 glioma cells. Additionally, we investigated the induction of GDNF release as a possible physiological consequence of this activation. We found that norquetiapine, similarly to the antidepressant reboxetine, activated both ERK1 and ERK2 (pERK) with consequent enhanced release of GDNF; this release was dependent on pERK, as demonstrated by its reversibility after pre-treatment with a pharmacological pERK inhibitor. In contrast, quetiapine induced activation of ERK2 only. It also caused release of GDNF, but this release was independent of ERK activation. To test whether the simultaneous activation of ERK1 with ERK2 was critical for the observed pERK-dependent GDNF release, we specifically inactivated ERK1 mRNA via RNA interference. Our data show that indeed ERK1 plays an essential role, as GDNF release was hampered after Erk1 downregulation comparably to a pharmacological pERK inhibitor. Thus, activation of only ERK2 appears not to be sufficient for promoting GDNF release. Our results reveal the release of GDNF as a consequence of ERK/MAPK signalling activation by norquetiapine, which may contribute to the putative antidepressant properties of quetiapine. This article is part of a Special Issue entitled 'Anxiety and Depression'. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:209 / 216
页数:8
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