Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
PLoS One. 2012;7(11):e50138. doi: 10.1371/journal.pone.0050138. Epub 2012 Nov 27.
Desipramine is known principally as a tricyclic antidepressant drug used to promote recovery of depressed patients. It has also been used in a number of other psychiatric and medical conditions. The present study is the first to investigate the neuroprotective effect of desipramine.
METHODOLOGY/PRINCIPAL FINDINGS: Mes23.5 dopaminergic cells were used to examine neuroprotective effect of desipramine. Western blot, reverse transcription-PCR, MTT assay, siRNA transfection and electrophoretic mobility shift assay (EMSA) were carried out to assess the effects of desipramine. Desipramine induces endogenous anti-oxidative enzyme, heme oxygenase-1 (HO-1) protein and mRNA expression in concentration- and time-dependent manners. A different type of antidepressant SSRI (selective serotonin reuptake inhibitor), fluoxetine also shows similar effects of desipramine on HO-1 expression. Moreover, desipramine induces HO-1 expression through activation of ERK and JNK signaling pathways. Desipramine also increases NF-E2-related factor-2 (Nrf2) accumulation in the nucleus and enhances Nrf2-DNA binding activity. Moreover, desipramine-mediated increase of HO-1 expression is reduced by transfection with siRNA against Nrf2. On the other hand, pretreatment of desipramine protects neuronal cells against rotenone- and 6-hydroxydopamine (6-OHDA)-induced neuronal death. Furthermore, inhibition of HO-1 activity by a HO-1 pharmacological inhibitor, ZnPP IX, attenuates the neuroprotective effect of desipramine. Otherwise, activation of HO-1 activity by HO-1 activator and inducer protect 6-OHDA-induced neuronal death.
CONCLUSIONS/SIGNIFICANCE: These findings suggest that desipramine-increased HO-1 expression is mediated by Nrf2 activation through the ERK and JNK signaling pathways. Our results also suggest that desipramine provides a novel effect of neuroprotection, and neurodegenerative process might play an important role in depression disorder.
去甲丙咪嗪主要作为一种三环类抗抑郁药被用于促进抑郁患者的康复。它也被用于许多其他精神和医疗条件。本研究首次调查了去甲丙咪嗪的神经保护作用。
方法/主要发现：使用 Mes23.5 多巴胺能细胞来研究去甲丙咪嗪的神经保护作用。进行 Western blot、逆转录-PCR、MTT 测定、siRNA 转染和电泳迁移率变动分析（EMSA）以评估去甲丙咪嗪的作用。去甲丙咪嗪以浓度和时间依赖的方式诱导内源性抗氧化酶血红素加氧酶-1（HO-1）蛋白和 mRNA 的表达。另一种类型的抗抑郁药 SSRI（选择性 5-羟色胺再摄取抑制剂）氟西汀也显示出与去甲丙咪嗪相似的 HO-1 表达作用。此外，去甲丙咪嗪通过激活 ERK 和 JNK 信号通路诱导 HO-1 表达。去甲丙咪嗪还增加核内 Nrf2 相关因子-2（Nrf2）的积累并增强 Nrf2-DNA 结合活性。此外，用 Nrf2 的 siRNA 转染可降低去甲丙咪嗪介导的 HO-1 表达增加。另一方面，去甲丙咪嗪预处理可防止神经元细胞免受鱼藤酮和 6-羟多巴胺（6-OHDA）诱导的神经元死亡。此外，HO-1 药理学抑制剂 ZnPP IX 抑制 HO-1 活性可减弱去甲丙咪嗪的神经保护作用。相反，通过 HO-1 激活剂和诱导剂激活 HO-1 活性可保护 6-OHDA 诱导的神经元死亡。
结论/意义：这些发现表明，去甲丙咪嗪增加的 HO-1 表达是通过 Nrf2 通过 ERK 和 JNK 信号通路的激活介导的。我们的结果还表明，去甲丙咪嗪提供了一种新的神经保护作用，神经退行性过程可能在抑郁症中起重要作用。
