A urinary metabolomics study of the metabolic dysfunction and the regulation effect of citalopram in rats exposed to chronic unpredictable mild stress†
Depression is a widespread mental disorder, however the molecular mechanism underlying depression and the antidepressive effects of diverse drugs remain largely unknown. An untargeted metabolic profiling based on Ultra High Performance Liquid Chromatography coupled with Orbitrap mass spectrometry (UPLC-Orbitrap-MS) has been performed to investigate the metabolic changes between chronic unpredictable mild stress (CUMS) in rats and healthy control rats, and screen for drug efficacy on these changed metabolites after administration of citalopram, then provide a new perspective into the understanding of the antidepressant effects of citalopram. Behavioral tests were applied as a measurement of status of depression and the antidepressive effect. Multivariate statistics including principal component analysis (PCA), and partial least squares-discriminate analysis (PLS-DA) have been applied to reveal the metabolic changes between the control, model and antidepressant-treated groups. Clear separation among three groups was achieved and a total of 26 metabolites have been considered as the potential biomarkers involved in the development of depression. Among them, 24 metabolites display the trend to return to normal levels which may correlate with the regulation of drug treatment on depression, and specifically, 10 of them could be key metabolites in the pathogenesis of depression and contribute to evaluating the effect of citalopram. These results provided new insight into the pathophysiological mechanism of depression and indicated that citalopram mediated synergistically abnormalities in metabolic networks including tryptophan metabolism, energy metabolism and synthesis of neurotransmitters, which may be helpful to evaluate its effectiveness by a metabolomics approach.