A novel insight for high-rate and low-efficiency glucose metabolism in depression through stable isotope-resolved metabolomics in CUMS-induced rats.

BACKGROUND: Existing research has suggested that depression results in disorders of glucose metabolism in the organism which causing insufficient energy supply. However, the overall changes in glucose metabolism that arise from depression have not been clarified. METHODS: In this study, the depression-like behavior in chronically unpredictable mild stressed rats was investigated, and the fate of glucose was tracked through isotope tracing and mass spectrometry, with a focus on metabolite changes in cecal contents. RESULTS: As indicated by the results, the isotopic results of cecal contents can indicate the metabolic end of the organism. Moreover, the TCA cycle activity was notably reduced, and the gluconeogenesis pathway was abnormally up-regulated in the CUMS-induced rats. The organism expedited other glucose metabolism pathways to make up for the insufficiency of energy. As a result, the activity of the inefficient glycolysis pathway was increased. LIMITATIONS: Existing research has only investigated the metabolism of 13C-glucose, and lipids and proteins have been rarely explored. CONCLUSIONS: The chronic unpredictable mild stress can inhibit the entry of pyruvate into mitochondria in SD rats, such that the activity of TCA is reduced, and insufficient energy supply is caused. The organism is capable of expediting other glucose metabolism rate pathways to make up for the insufficiency of energy, whereas it still cannot compensate for the loss of energy. As a result, CUMS-induced rats exhibited high-rate and low-efficiency glucose metabolism.

A unique insight for Xiaoyao San exerts antidepressant effects by modulating hippocampal glucose catabolism using stable isotope-resolved metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM) theory, depression is an emotional disease, which is thought to be related to stagnation of liver qi and dysfunction of the spleen in transport. Xiaoyao San (XYS) is considered to have the effects of soothing liver-qi stagnation and invigorating the spleen. The spleen has the function to transport and transform nutrients. The liver has also termed the center of energy metabolism in the body. Therefore, exploring the antidepressant effects of XYS from the perspective of energy metabolism may reveal new findings. AIM OF THE STUDY: Glucose catabolism is an important part of energy metabolism. In recent years, several researchers have found that XYS can exert antidepressant effects by modulating abnormalities in glucose catabolism-related metabolites. The previous research of our research group found that the hippocampus glucose catabolism was disordered in depression. However, the antidepressant potential of XYS through modulating the disorders of hippocampal glucose catabolism and the specific metabolic pathways and targets of XYS action were still unknown. The aim of this study was to address the above scientific questions. MATERIALS AND METHODS: In this research, the CUMS (chronic unpredictable mild stress) model was used as the animal model of depression. The antidepressant effect of XYS was evaluated by behavioral indicators. The specific pathways and targets of XYS modulating the disorders of glucose catabolism in the hippocampus of CUMS rats were obtained by stable isotope-resolved metabolomics. Further, the isotope tracing results were also verified by molecular biology and electron transmission electron microscopy. RESULTS: The results demonstrated that XYS pretreatment could significantly improve the depressive symptoms induced by CUMS. More importantly, it was found that XYS could modulate the disorders of glucose catabolism in the hippocampus of CUMS rats. Stable isotope-resolved metabolomics and enzyme activity tests showed that Lactate dehydrogenase (LDH), Pyruvate carboxylase (PC), and Pyruvate dehydrogenase (PDH) were targets of XYS for modulating the disorders of glucose catabolism in the hippocampus of CUMS rats. The Succinate dehydrogenase (SDH) and mitochondrial respiratory chain complex V (MRCC-Ⅴ) were targets of XYS to improve abnormal mitochondrial oxidative phosphorylation in the hippocampus of CUMS rats. XYS was also found to have the ability to improve the structural damage of mitochondria and nuclei in the hippocampal caused by CUMS. CONCLUSIONS: This study was to explore the antidepressant effect of XYS from the perspective of glucose catabolism based on a strategy combining stable isotope tracing, molecular biology techniques, and transmission electron microscopy. We not only obtained the specific pathways and targets of XYS to improve the disorders of glucose catabolism in the hippocampus of CUMS rats, but also revealed the specific targets of the pathways of XYS compared with VLF.