文拉法辛和氟西汀抗抑郁作用机制和药效特点的代谢组学研究

Antidepressant Mechanism and Pharmacodynamic Characteristics of Venlafaxine and Fluxetine Based on Metabolomics

目的采用代谢组学技术比较并评价文拉法辛和氟西汀两种药物的抗抑郁药效及作用机制。方法采用两种药物对慢性不可预知应激(CUMS)动物模型进行干预,观察大鼠的行为学变化;同时采集尿液,进行GC-MS代谢组学分析,并寻找生物标志物。结果行为学数据显示,与模型组相比,文拉法辛和氟西汀组在行为学指标上均有显著性差异(P<0.05),显示出抗抑郁作用。代谢组学分析结果显示,散点图中文拉法辛距离正常对照组较近,其抗抑郁效果较优,通过正常对照与模型组的载荷图寻找出了CUMS抑郁模型的15个潜在生物标志物,文拉法辛所能回调的标志物较氟西汀多。结论两种药物都有明显的抗抑郁效果,且文拉法辛效果较优;运用代谢组学技术分析了两种药物对抑郁症有关标志物的回归调节作用并对其机制进行了初步比较研究,为药物药效的评价提供了新思路和新方法。

OBJECTIVE To evaluate and compare the antidepressant effects and mechanisms of venlafaxine and fluoxetine by metabolomic approach. METHODS Two positive drugs were employed to intervene the chronic unpredictable mild stress （CUMS） induced rat depression model. The behavioral changes of rats were observed ; meanwhile, urine samples were collected and subjected to GC-MS analysis to find potential biomarkers of depression. RESULTS The behavioral data of the drug treatment groups were signifi- cantly different （ P 〈 0. 05 ） with the model group, showing obvious antidepressant effect. Metabolomic analysis showed that venlafaxine group located closer to the healthy controls, showing better antidepressant efficacy than f[uoxetine. Fifteen potential biomarkers were i- dentified from the loading plot between control and model group, and more perturbed metabolites were reversed by venlafaxine. CON- CLUSION Both drugs have significant antidepressant efficacy, and venlafaxine shows better effect. Metabolomie approach was ap- plied in this study to analyze the regulation of biomarkers and compare the mechanisms of the two drugs. These results provide new methods for the evaluation of drug efficacy.