Wang Xing, Zou Zhilu, Shen Qinqin, Huang Zhiheng, Chen Jie, Tang Juanjuan, Xue Wenda, Tao Weiwei, Wu Haoxin, Wang Dawei, Chen Gang
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Center for Translational Systems Biology and Neuroscience and Key Laboratory of Integrative Biomedicine for Brain Diseases, College of Basic Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Front Pharmacol. 2019 Jan 9;9:1537. doi: 10.3389/fphar.2018.01537. eCollection 2018.
Fast-onset antidepressants are urgently needed. Chaihu-jia-Longgu-Muli-tang (CLM), a classic Chinese herbal medicine, has been used for antidepressant treatment with long history. Olfactory bulbectomization (OB) model is validated for identification of rapid antidepressant efficacy. Here we used OB model for investigating the rapid onset activity of CLM in mice, and also tested the involvement of prefrontal Akt-mTOR and associated AMPA/NMDA receptors as well as hippocampal BDNF in the rapid antidepressant-like effect of CLM. The OB model was first characterized with depression-like behaviors and the time course changes of the behaviors. The fast onset of antidepressant effect of CLM was evaluated using sucrose preference test, tail suspension test and forced swim test in OB mice after a single administration. The expression of synaptic proteins of AMPA and NMDA subunits as well as Akt/mTOR signaling in the prefrontal cortex, and hippocampal BDNF was evaluated with the immunoblotting method. A single dose of CLM significantly improved the deficiency in the sucrose preference and decreased the immobility time in the tail suspension test in OB mice. In the prefrontal cortex (PFC) in OB mice, there was lower expression level of the AMPA receptor subunit GluR1, rescued by a single dose of CLM. Additionally, the expression of NMDA subunit NR1 was up-regulated in OB mice, whereas mTOR and its upstream Akt signalings were both down-regulated. These deficiencies were reversed by a single dose of CLM. The CLM treatment also attenuated the expressions of NMDA receptor subunits NR2A and NR2B, which did not change in OB mice. In the hippocampus, expressions of GluR1 and brain derived neurotrophic factor (BDNF) were both up-regulated in OB mice, although CLM increased GluR1, but not BDNF. CLM elicited rapid antidepressant-like effects in the OB model mice, and CLM reversal of the abnormality in PFC expression of AMPA and NMDA receptors and associated Akt-mTOR signaling may underlie the effects.
急需起效迅速的抗抑郁药。柴胡加龙骨牡蛎汤（CLM）是一种经典的中药，用于抗抑郁治疗已有悠久历史。嗅球切除（OB）模型已被验证可用于鉴定快速抗抑郁疗效。在此，我们使用OB模型研究CLM在小鼠中的快速起效活性，并测试前额叶Akt-mTOR及相关的AMPA/NMDA受体以及海马脑源性神经营养因子（BDNF）在CLM快速抗抑郁样效应中的作用。首先对OB模型进行抑郁样行为及行为的时间进程变化特征分析。在单次给药后，使用蔗糖偏好试验、悬尾试验和强迫游泳试验评估CLM在OB小鼠中的快速抗抑郁作用起效情况。用免疫印迹法评估前额叶皮质中AMPA和NMDA亚基的突触蛋白表达以及Akt/mTOR信号传导，以及海马BDNF。单剂量CLM显著改善了OB小鼠蔗糖偏好的缺陷，并减少了悬尾试验中的不动时间。在OB小鼠的前额叶皮质（PFC）中，AMPA受体亚基GluR1的表达水平较低，单剂量CLM可使其恢复。此外，OB小鼠中NMDA亚基NR1的表达上调，而mTOR及其上游Akt信号传导均下调。单剂量CLM可逆转这些缺陷。CLM治疗还减弱了NMDA受体亚基NR2A和NR2B的表达，而这在OB小鼠中未发生变化。在海马中，OB小鼠中GluR1和脑源性神经营养因子（BDNF）的表达均上调，尽管CLM增加了GluR1，但未增加BDNF。CLM在OB模型小鼠中引发了快速抗抑郁样效应，CLM逆转PFC中AMPA和NMDA受体表达及相关Akt-mTOR信号传导异常可能是其作用的基础。
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