Objective

This study investigated the antidepression mechanisms of Xiaoyaosan (XYS), a classic Chinese prescription, from the perspective of energy metabolism in the brain and intestinal tissues.

Methods

Chronic unpredictable mild stress model—a classic depression rat model—was established. Effects of XYS on behaviors and gastrointestinal motility of depressed rats were investigated. Effects of XYS on energetic charge (EC), adenosine triphosphate-related enzymes, and key enzymes of energy metabolism in both hippocampus and jejunum tissues of depressed rats were investigated using high-performance liquid chromatography, biochemical analysis, and real-time quantitative polymerase chain reaction, respectively. Spearman correlation analysis was conducted to construct a correlation network of “behavior-brain energy metabolism-intestinal energy metabolism” of depression.

Results

XYS significantly reduced the abnormal behaviors observed in depressed rats and increased the EC and the activity of Na⁺-K⁺-ATPase and Ca²⁺-Mg²⁺-ATPase in hippocampus and jejunum tissues of depressed rats. XYS restored the key energetic pathways that had been interrupted by depression, including glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. Furthermore, XYS exhibited antidepressive effects in terms of regulating energy metabolism in tissues of the brain and intestine.

Conclusion

XYS significantly corrected the disturbances in EC and energy metabolism-related enzymes of both brain and intestinal tissues, alleviating both core and concomitant symptoms of depression. The current findings underscore the role of energy metabolism in the antidepressive activity of XYS, providing a fresh perspective on depression, and novel research strategies for revealing the mechanism of actions of traditional Chinese medicines on multi-site and multi-symptom diseases.

Key words: Xiaoyaosan, Depression, Concomitant symptoms, Traditional Chinese medicine, Brain energy metabolism, Intestinal energy metabolism