Hisaoka K, Nishida A, Koda T, Miyata M, Zensho H, Morinobu S, Ohta M, Yamawaki S
Department of Psychiatry and Neuroscience, Institute of Clinical Research, National Kure Medical Center, Kure, Japan.
J Neurochem. 2001 Oct;79(1):25-34. doi: 10.1046/j.1471-4159.2001.00531.x.
Modulation of neurotrophic factors to protect neurons from damage is proposed as a novel mechanism for the action of antidepressants. However, the effect of antidepressants on modulation of glial cell line-derived neurotrophic factor (GDNF), which has potent and widespread effects, remains unknown. Here, we demonstrated that long-term use of antidepressant treatment significantly increased GDNF mRNA expression and GDNF release in time- and concentration-dependent manners in rat C6 glioblastoma cells. Amitriptyline treatment also increased GDNF mRNA expression in rat astrocytes. GDNF release continued for 24 h following withdrawal of amitriptyline. Furthermore, following treatment with antidepressants belonging to several different classes (amitriptyline, clomipramine, mianserin, fluoxetine and paroxetine) significantly increased GDNF release, but which did not occur after treatment with non-antidepressant psychotropic drugs (haloperidol, diazepam and diphenhydramine). Amitriptyline-induced GDNF release was inhibited by U0126 (10 microM), a mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89 (1 microM), a protein kinase A inhibitor, calphostin C (100 nM), a protein kinase C inhibitor and PD 169316 (10 microM), a p38 mitogen-activated protein kinase inhibitor. These results suggested that amitriptyline-induced GDNF synthesis and release occurred at the transcriptional level, and may be regulated by MEK/MAPK signalling. The enhanced and prolonged induction of GDNF by antidepressants could promote neuronal survival, and protect neurons from the damaging effects of stress. This may contribute to explain therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.
调节神经营养因子以保护神经元免受损伤被认为是抗抑郁药作用的一种新机制。然而，抗抑郁药对具有强大而广泛作用的胶质细胞源性神经营养因子（GDNF）调节的影响仍不清楚。在此，我们证明长期使用抗抑郁药治疗能以时间和浓度依赖性方式显著增加大鼠C6胶质母细胞瘤细胞中GDNF mRNA表达和GDNF释放。阿米替林治疗也增加了大鼠星形胶质细胞中GDNF mRNA表达。停用阿米替林后GDNF释放持续24小时。此外，用几种不同类别的抗抑郁药（阿米替林、氯米帕明、米安色林、氟西汀和帕罗西汀）治疗后显著增加了GDNF释放，但用非抗抑郁精神药物（氟哌啶醇、地西泮和苯海拉明）治疗后未出现这种情况。U0126（10微摩尔），一种丝裂原活化蛋白激酶（MAPK）-细胞外信号相关激酶（ERK）激酶（MEK）抑制剂，抑制了阿米替林诱导的GDNF释放，但蛋白激酶A抑制剂H-89（1微摩尔）、蛋白激酶C抑制剂钙泊三醇C（100纳摩尔）和p38丝裂原活化蛋白激酶抑制剂PD 169316（10微摩尔）未抑制。这些结果表明，阿米替林诱导的GDNF合成和释放在转录水平发生，可能受MEK/MAPK信号通路调节。抗抑郁药对GDNF的增强和延长诱导可促进神经元存活，并保护神经元免受应激的损伤作用。这可能有助于解释抗抑郁药的治疗作用，并提示新的药理干预策略。
