Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):1001-6. doi: 10.1016/j.pnpbp.2010.05.013. Epub 2010 May 28.
Atypical antipsychotics have neuroprotective effects, which may be one of the mechanisms for their success in the treatment of schizophrenia. Growing evidence suggest that brain-derived neurotrophic factor (BDNF) is abnormally regulated in patients with schizophrenia, and its expression can be up-regulated by atypical antipsychotics. Atypical antipsychotic drugs may positively regulate transcription of the BDNF gene, but the molecular mechanism of atypical antipsychotic drug action on BDNF gene activity has not been investigated. The aim of the present study was to explore the possible involvement of some intracellular signaling pathways in olanzapine action on BDNF promoter activity.
We examined the effects of olanzapine 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 glycogen synthase kinase-3beta (GSK-3beta) and cAMP response element (CRE) binding protein (CREB) phosphorylation were measured by Western blot analysis.
Olanzapine treatment (10-100 microM) increased basal BDNF gene promoter activity in a dose-dependent manner and increased protein levels at high dose, and inhibitors of protein kinase A (PKA), H-89 (10 microM), phosphatidylinositol 3-kinase (PI3K), wortmannin (0.01 microM), PKC (protein kinase C), GF109203 (10 microM), calcium/calmodulin kinase II (CaMKII), and KN-93 (20 microM) partially attenuated the stimulatory effect of olanzapine on BDNF promoter activity. In line with these results, a Western blot study showed that olanzapine (100 microM) increased phosphorylated levels of GSK-3beta and CREB, which are notable downstream effectors of the PKA, PI3K, PKC, and CaMKII signaling pathways.
These results demonstrate that the up-regulation of olanzapine on BDNF gene transcription is linked with enhancement of CREB-mediated transcription via PKA, PI3K, PKC, and CaMKII signaling pathways, and olanzapine may exert neuroprotective effects through these signaling pathways in neuronal cells.
非典型抗精神病药物具有神经保护作用，这可能是其在精神分裂症治疗中成功的机制之一。越来越多的证据表明，脑源性神经营养因子（BDNF）在精神分裂症患者中异常调节，其表达可以被非典型抗精神病药物上调。非典型抗精神病药物可能正向调节 BDNF 基因的转录，但非典型抗精神病药物对 BDNF 基因活性的作用的分子机制尚未得到研究。本研究旨在探讨一些细胞内信号通路在奥氮平对 BDNF 启动子活性的作用中可能的参与。
我们研究了奥氮平对转染大鼠 BDNF 启动子片段（-108 至+340）与荧光素酶报告基因相连的 SH-SY5Y 细胞中 BDNF 基因启动子活性的影响。通过 Western blot 分析测量糖原合酶激酶-3β（GSK-3β）和 cAMP 反应元件（CRE）结合蛋白（CREB）磷酸化的变化。
奥氮平处理（10-100μM）以剂量依赖性方式增加基础 BDNF 基因启动子活性，并在高剂量时增加蛋白水平，蛋白激酶 A（PKA）抑制剂 H-89（10μM）、磷脂酰肌醇 3-激酶（PI3K）抑制剂wortmannin（0.01μM）、蛋白激酶 C（PKC）抑制剂 GF109203（10μM）、钙/钙调蛋白激酶 II（CaMKII）抑制剂 KN-93（20μM）部分减弱了奥氮平对 BDNF 启动子活性的刺激作用。与这些结果一致，Western blot 研究表明，奥氮平（100μM）增加了 GSK-3β和 CREB 的磷酸化水平，这是 PKA、PI3K、PKC 和 CaMKII 信号通路的显著下游效应物。
这些结果表明，奥氮平对 BDNF 基因转录的上调与通过 PKA、PI3K、PKC 和 CaMKII 信号通路增强 CREB 介导的转录有关，奥氮平可能通过这些信号通路在神经元细胞中发挥神经保护作用。
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