Abstract: Purpose: To investigate the ameliorative effect of Citrus aurantium L. var. amara Engl. flower essential oil (CEO) on depressive-like behaviors in mice and its potential antidepressant mechanism from the aspects of peripheral serum and central hippocampus. Methods: The major volatile components of CEO were analyzed using gas chromatography-mass spectrometry (GC-MS). A mouse model of depressive-like behavior was established via chronic corticosterone injection combined with chronic restraint stress. The antidepressant effect of CEO was evaluated by behavioral tests and histopathological analysis. Transcriptomics and untargeted metabolomics were used to analyze changes in hippocampal gene expression and peripheral serum metabolites in mice. Molecular docking was performed between the major components of CEO and the key pathway proteins. Results: CEO, containing 40 chemical components, effectively improved the behavioral performance of depressive-like mice and alleviated damage to their hippocampal and colonic tissues. Analysis of differentially expressed genes in the hippocampus revealed that CEO may upregulate the expression of genes encoding multiple key complexes in the oxidative phosphorylation pathway via the adenosine monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) signaling pathway. In addition, CEO increased the serum level of indole-3-acetic acid and decreased the abundance of various metabolites such as pantothenic acid and corticosterone, which are involved in pathways including tryptophan metabolism, pantothenic acid and coenzyme A biosynthesis, and steroid hormone biosynthesis. These findings suggest that CEO may alleviate depressive symptoms by regulating peripheral energy metabolism-related signals to activate the oxidative phosphorylation pathway in the hippocampus. Molecular docking indicated that β-ocimene, nerolidol, and geranyl acetate present in CEO could bind stably to the key complexes in the oxidative phosphorylation pathway. Conclusion: CEO exerts a definite antidepressant effect, which may be mediated through activating the oxidative phosphorylation pathway and further via the “peripheral-central-energy metabolism” pathway. This study establishes a preliminary basis for the development of functional foods based on C. aurantium L. var. amara Engl. flower.

Key words: Citrus aurantium L. var. amara Engl. flowers essential oil; depression; periphery; central; energy metabolism; oxidative phosphorylation