Zhou Dongsheng, Zhang Zhongmin, Liu Lingjiang, Li Chenli, Li Mengmeng, Yu Hanjie, Cai Xiongxiong, Sun Xin, Shen Xinbei, Wang Jinting, Geng Jiacheng, Wang Chuang, Shi Yaosheng
Ningbo Kangning Hospital, Ningbo, Zhejiang 315201, PR China; Ningbo Key Laboratory of Behavioral Neuroscience, Medical School of Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang 315211, PR China.
Department of Neurology, Hongqi Hospital, Mudanjiang Medical College, Mudanjiang, Heilongjiang 157011, PR China.
Pharmacol Biochem Behav. 2017 Jun;157:47-57. doi: 10.1016/j.pbb.2017.02.004. Epub 2017 Feb 17.
Preclinical and clinical studies suggest that neuronal muscarinic acetylcholine receptor (M-AchR) antagonists have antidepressant-like properties. Despite the recent interest in bicaudal C homolog 1 gene (BICC1) as a target for the treatment of depression, the upstream signaling molecules that regulate BICC1 are unknown, and very few studies have addressed the involvement of BICC1 in the antidepressant-like effects of the selective M1-AchR inhibitor, biperiden. Growing evidence indicates that activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor B (TrkB) signaling may be involved in antidepressant-like activities. In this study, we investigated the role of BDNF/TrkB signaling in the regulation of BICC1 expression in the chronic unpredictable stress (CUS) mouse model of depression. Furthermore, we also examined whether BDNF/TrkB signaling contributes to the antidepressant-like effects of biperiden via down-regulation of BICC1 in the hippocampus and prefrontal cortex of mice. Our current data show that CUS exposure induced significant depression-like behaviors, down-regulation of BDNF/TrkB signaling and up-regulation of BICC1 in the hippocampus and prefrontal cortex of mice. However, biperiden significantly alleviated the CUS-induced abnormalities. Moreover, we found that the effects of biperiden were antagonized by pretreatment with the TrkB antagonist K252a. Our results indicate that BDNF/TrkB signaling may be the major upstream mediator of BICC1 involvement in the antidepressant-like effects of biperiden.
临床前和临床研究表明，神经元毒蕈碱型乙酰胆碱受体（M-AchR）拮抗剂具有类抗抑郁特性。尽管最近对双尾C同源蛋白1基因（BICC1）作为抑郁症治疗靶点颇感兴趣，但调节BICC1的上游信号分子尚不清楚，而且很少有研究探讨BICC1在选择性M1-AchR抑制剂比哌立登的类抗抑郁作用中的参与情况。越来越多的证据表明，脑源性神经营养因子（BDNF）/原肌球蛋白相关激酶受体B（TrkB）信号的激活可能参与类抗抑郁活动。在本研究中，我们在慢性不可预测应激（CUS）抑郁症小鼠模型中研究了BDNF/TrkB信号在调节BICC1表达中的作用。此外，我们还研究了BDNF/TrkB信号是否通过下调小鼠海马体和前额叶皮质中的BICC1来促进比哌立登的类抗抑郁作用。我们目前的数据表明，CUS暴露会诱导小鼠海马体和前额叶皮质出现显著的类抑郁行为、BDNF/TrkB信号下调以及BICC1上调。然而，比哌立登显著缓解了CUS诱导的异常情况。此外，我们发现用TrkB拮抗剂K252a预处理可拮抗比哌立登的作用。我们的结果表明，BDNF/TrkB信号可能是BICC1参与比哌立登类抗抑郁作用的主要上游介质。
