京尼平抗抑郁作用的1HNMR代谢组学机制研究

1H NMR based metabonomics study on the antidepressant effect of genipin in rat hippocampus

寻找抑郁症模型大鼠海马组织中潜在的标志性代谢产物,探究京尼平抗抑郁作用机制。通过慢性温和不可预知应激(CUMS)程序对大鼠进行抑郁造模,2周后灌胃京尼平低、中、高3个剂量(25、50和100 mg·kg-1)及文拉法辛药物(空白组和模型组除外),每天1次,连续2周。采集大鼠海马组织并进行1H NMR测试,采用代谢组学技术分析海马组织中内源性代谢产物的变化。结果表明,京尼平中剂量可以显著升高抑郁模型大鼠海马组织中甘氨酸和N-乙酰天门冬氨酸,降低谷氨酸、肌醇、乳酸和丙氨酸水平,表现出较好的抗抑郁效果。海马组织中显著性变化的代谢物对神经系统功能的正常发挥有重要影响,京尼平可能是通过调节上述代谢产物来增强海马组织中神经元的活性,修复和改善神经元的功能而发挥抗抑郁效果。代谢组学方法是研究京尼平抗抑郁效果及药理作用机制的有效手段。

The purpose of this study is to explore depression metabolic markers in rat hippocampus and to investigate the anti-depressant effect of genipin and its mechanisms using nuclear magnetic resonance （NMR） metabonomics. Chronic unpredictable mild stress （CUMS） procedure was conducted to establish the depressive rat model. At the beginning of the third week, genipin low dose （25 mg ＂kg-l）, middle dose （50 mg.kg-l）, high dose （100 mg.kg-l）, and venlafaxine （50 mg＇kg-j） were given to the CUMS rats separately once daily for two weeks except control and model groups. Rat hippocampus was analyzed by tH NMR based metabonomics after drug administration for 2 weeks. Significant differences in the metabolic profile of rat hippocampus of the CUMS treated group and the control group were observed with metabolic effects of CUMS including decreasing in glycine and N-acetylaspartate, increasing in inositol, glutamate, lactate, glutamine, taurine and alanine. Genipin showed ideal antidepressive effects at a dose of 50 mg＇kg-1 in rats, decrease of inositol, glutamate, lactate, alanine were observed, while glycine and N-acetylaspartate were increased. Important influence has been found on normal nervous system function of these significant changed metabolites, which suggests that the antidepressant effect of genipin may be played by enhancing the activity of neurons in hippocampus, repairing and improving the function of the neuron. The metabonomics approach is an effective tool for the investigation of the anti-depressant effect and pharmacologic mechanisms of genipin.