7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress
7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress
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7-氯炔脲酸 (7-CTKA) 产生快速抗抑郁样作用：通过调节暴露于慢性不可预测的轻度应激的小鼠中涉及 TrkB-ERK/Akt 信号通路的海马 microRNA 表达
DOI：
10.1007/s00213-014-3690-3
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发表时间：
2015-02-01
影响因子：
3.4
通讯作者：
Yi, Li-Tao
中科院分区：
文献类型：
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作者：
Liu, Bin-Bin;Luo, Liu;Yi, Li-Tao
7-氯犬尿喹啉酸（7-CTKA）是一种NMDA受体拮抗剂，是一种潜在的快速抗抑郁药，但其作用机制尚不清楚。microRNAs（miRNAs）是中枢神经系统可塑性的重要调节因子，在抑郁症的发生发展中起着重要作用。本研究的目的是探讨7-CTKA在慢性不可预测的轻度应激（CHNS）动物模型中抗抑郁作用的分子机制。（原肌球蛋白相关激酶受体B（Trk B）拮抗剂），U 0126（细胞外信号调节激酶（ERK）磷酸化抑制剂），LY 294002（丝氨酸-苏氨酸激酶（Akt）磷酸化抑制剂）或媒介物在7-CTKA或媒介物腹膜内注射之前30分钟脑室内给予各组中的小鼠。采用蔗糖偏好实验观察小鼠行为学变化，并采用miRNA芯片检测小鼠海马miRNA水平。结果7-CTKA不仅能逆转海马神经元对蔗糖的偏好性降低，而且能通过TrkB-ERK/Akt通路介导15种常见的miRNAs表达。其中4种miRNAs（miR-34 a-5 p、miR-200 a-3 p、miR-144- 3 p、miR-1894- 5 p）的表达水平通过实时定量PCR（qRT-PCR）进行验证。结论TrkB-ERK/Akt通路共有的15个miRNA靶点可能参与抗抑郁药7-CTKA的快速作用分子机制。
Rationale7-Chlorokynurenic acid (7-CTKA), a NMDA receptor antagonist, has been reported as a potential rapid antidepressant with poor understanding about the molecular mechanism of its therapeutic action. MicroRNAs (miRNAs) are emerging as critical regulators of central nervous system plasticity and may play an important role in depression.ObjectiveThe objective of this study was to investigate the molecular mechanism of antidepressant action of 7-CTKA in chronic unpredictable mild stress (CUMS) animal model.MethodsK252a (tropomyosin-related kinase receptor B (TrkB) antagonist), U0126 (extracellular signal-regulated kinase (ERK) phosphorylation inhibitor), LY294002 (serine-threonine kinase (Akt) phosphorylation inhibitor), or vehicle was given intracerebroventricularly to mice in each group 30 min before 7-CTKA or vehicle intraperitoneal injection. Behavioral changes were observed by sucrose preference test and miRNA microarray was performed to examine hippocampal miRNAs levels in mice. Quantitative RT-PCR was conducted to further confirm results in microarray study.Results7-CTKA not only reversed the decrease in sucrose preference and multiple hippocampal miRNAs changes induced by CUMS but also mediated 15 common miRNAs via TrkB-ERK/Akt pathways. Among them, the expression levels of four miRNAs (miR-34a-5p, miR-200a-3p, miR-144-3p, miR-1894-5p) were validated by quantitative real-time PCR (qRT-PCR). The findings from qRT-PCR study support results from microarray analysis except for the non-significance of miR-1894-5p expression.ConclusionsThis demonstrated that the 15 miRNA targets shared by TrkB-ERK/Akt pathways might participate in rapid-acting molecular mechanism of antidepressant 7-CTKA.