Park Sung Woo, Lee Jung Goo, Ha Eun Kyung, Choi Sang Mi, Cho Hye Yeon, Seo Mi Kyoung, Kim Young Hoon
Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea.
Eur Neuropsychopharmacol. 2009 May;19(5):356-62. doi: 10.1016/j.euroneuro.2008.12.012. Epub 2009 Feb 3.
Recent studies have suggested that first and second generation antipsychotics (FGAs and SGAs) have different neuroprotective effects. However, the molecular mechanisms of SGAs are not fully understood, and investigations into changes in intracellular signaling related to their neuroprotective effects remain scarce. In the present study, we compared the SGA aripiprazole with the FGA haloperidol in SH-SY5Y human neuroblastoma cells via brain-derived neurotrophic factor (BDNF)-mediated signaling, notably BDNF, glycogen synthase kinase-3beta (GSK-3beta), and B cell lymphoma protein-2 (Bcl-2). We examined the effects of aripiprazole (five and 10 microM) and haloperidol (one and 10 microM) on BDNF gene promoter activity in SH-SY5Y cells transfected with a rat BDNF promoter fragment (-108 to +340) linked to the luciferase reporter gene. The changes in BDNF, p-GSK-3beta, and Bcl-2 levels were measured by Western blot analysis. The haloperidol was not associated with a significant difference in BDNF promoter activity. In contrast, aripiprazole was associated with increased BDNF promoter activity only with a dose of 10 microM (93%, p<0.01). Treatment with aripiprazole at 10 microM increased the levels of BDNF by 85%, compared with control levels (p<0.01), whereas haloperidol had no effect. Moreover, cells treated with aripirazole effectively increased the levels of GSK-3beta phosphorylation and Bcl-2 at doses of five and 10 microM (30% and 58% and 31% and 80%, respectively, p<0.05 or p<0.01). However, haloperidol had no effects on p-GSK-3 beta and Bcl-2 expression. This study showed that aripiprazole, but not haloperidol, appeared to offer neuroprotective effects on human neuronal cells. The actions of signaling systems associated with BDNF may represent key targets for both aripiprazole and haloperidol, but the latter may be associated with distinct effects. These differences might be related to the different therapeutic effects of FGAs and SGAs in patients with schizophrenia.
近期研究表明，第一代和第二代抗精神病药物（FGA和SGA）具有不同的神经保护作用。然而，SGA的分子机制尚未完全明确，关于其神经保护作用相关的细胞内信号变化的研究仍然较少。在本研究中，我们通过脑源性神经营养因子（BDNF）介导的信号通路，特别是BDNF、糖原合酶激酶-3β（GSK-3β）和B细胞淋巴瘤蛋白-2（Bcl-2），在SH-SY5Y人神经母细胞瘤细胞中比较了SGA阿立哌唑和FGA氟哌啶醇。我们检测了阿立哌唑（5和10微摩尔）和氟哌啶醇（1和10微摩尔）对转染了与荧光素酶报告基因相连的大鼠BDNF启动子片段（-108至+340）的SH-SY5Y细胞中BDNF基因启动子活性的影响。通过蛋白质免疫印迹分析检测BDNF、磷酸化GSK-3β（p-GSK-3β）和Bcl-2水平的变化。氟哌啶醇与BDNF启动子活性的显著差异无关。相比之下，仅在剂量为10微摩尔时阿立哌唑与BDNF启动子活性增加有关（增加93%，p<0.01）。与对照水平相比，10微摩尔阿立哌唑处理使BDNF水平增加了85%（p<0.01），而氟哌啶醇没有影响。此外，在5和10微摩尔剂量下，用阿立哌唑处理的细胞有效增加了GSK-3β磷酸化水平和Bcl-水平（分别为30%和58%以及31%和80%，p<0.05或p<0.01）。然而，氟哌啶醇对p-GSK-3β和Bcl-2表达没有影响。本研究表明，阿立哌唑而非氟哌啶醇似乎对人神经元细胞具有神经保护作用。与BDNF相关的信号系统作用可能是阿立哌唑和氟哌啶醇的关键靶点，但后者可能具有不同的作用。这些差异可能与FGA和SGA对精神分裂症患者的不同治疗效果有关。
