Effects of rhynchophylline on the hippocampal miRNA expression profile in ketamine-addicted rats
Effects of rhynchophylline on the hippocampal miRNA expression profile in ketamine-addicted rats
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钩藤碱对氯胺酮成瘾大鼠海马 miRNA 表达谱的影响
DOI：
10.1016/j.pnpbp.2018.02.009
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发表时间：
2018-08-30
影响因子：
5.6
通讯作者：
Mo，Zhixian
中科院分区：
文献类型：
--
作者：
Li，Chan;Tu，Genghong;Mo，Zhixian
近年来，氯胺酮作为一种非竞争性的NMDA拮抗剂，作为一种新型的合成毒品在世界范围内被广泛滥用，严重影响了氯胺酮滥用者的身心健康。以往的研究表明，钩藤碱可以缓解药物滥用，逆转由滥用引起的条件性位置偏爱。microRNAs（miRNAs）是调节基因表达的重要因子，参与药物成瘾过程。海马体是大脑中与药物成瘾有关的关键区域。然而，海马miRNA表达谱和钩藤碱对氯胺酮滥用过程中miRNA表达的影响尚未报道。因此，本研究分析了氯胺酮依赖形成过程中海马miRNA的表达谱以及钩藤碱对氯胺酮诱导的miRNA差异表达的影响。芯片分析结果显示，对照组、氯胺酮组和氯胺酮+钩藤碱组miR-331- 5 p的表达水平差异有统计学意义。氯胺酮模型组中miR-331- 5 p水平显著降低，氯胺酮+钩藤碱组中miR-331- 5 p水平上调。生物信息学分析miR-331- 5 p与核受体相关蛋白1（Nurr 1）3' UTR的结合位点，发现其表达下调，而miR-331- 5 p在海马组织中的过表达表明miR-331 - 5 p是Nurr 1的负性转录调控因子。有趣的是，我们发现Nurr 1的下游蛋白，脑源性神经营养因子（BDNF），在海马中表现出与Nurr 1相同的表达趋势。然而，Nurr 1上游的蛋白质，环磷酸腺苷反应元件结合蛋白（CREB）的转录，氯胺酮组和氯胺酮+钩藤碱组之间没有显示出任何显着差异。然而，在钩藤碱干预后，氯胺酮和氯胺酮+钩藤碱组之间的p-CREB显示出显著差异。综上所述，miR-331- 5 p是Nurr 1的关键调控因子，钩藤碱可通过miR-331- 5 p/Nurr 1/BDNF通路或抑制CREB磷酸化参与氯胺酮成瘾的耐受过程。
In the past few years, ketamine, a noncompetitive NMDA antagonist, has been widely abused worldwide as a new type of synthetic drug, severely affecting the physical and mental health of ketamine abusers. Previous studies have suggested that rhynchophylline can alleviate drug abuse and reverse the conditioned place preference caused by the abuse. MicroRNAs (miRNAs) are important factors regulating gene expression and are involved in the drug addiction process. The hippocampus is a critical area in the brain involved in causing drug addiction. However, the hippocampal miRNA expression profile and the effects of rhynchophylline on miRNA expression during ketamine abuse have not been reported. Thus, this study analyzed the hippocampal miRNA expression profile during ketamine-dependence formation and the effects of rhynchophylline on the differential expression of miRNAs induced by ketamine. The results of microarray analysis suggested that the expression levels of miR-331-5p were significantly different among three groups (the control, ketamine, and ketamine + rhynchophylline groups). miR-331-5p levels were significantly decreased in the ketamine model group and were upregulated in the ketamine + rhynchophylline group. Bioinformatics analysis of miR-331-5p and the 3’ UTR of nuclear receptor related 1 protein (Nurr1) identified binding sites and showed downregulation, and the overexpression of miR-331-5p in hippocampal tissues showed that miR-331-5p is a negative transcription regulatory factor of Nurr1. Interestingly, we found that the downstream protein of Nurr1, brain-derived neurotrophic factor (BDNF), showed identical expression trends in the hippocampus as Nurr1. However, the transcription of the protein upstream of Nurr1, cyclic adenosine monophosphate response element-binding protein (CREB), did not show any significant differences between the ketamine group and the ketamine + rhynchophylline group. However, after rhynchophylline intervention, p-CREB showed significant differences between the ketamine and the ketamine + rhynchophylline groups. In summary, miR-331-5p is a key regulatory factor of Nurr1, and rhynchophylline can participate in the process of resistance to ketamine addiction through the miR-331-5p/Nurr1/BDNF pathway or inhibition of CREB phosphorylation.