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Background and Purpose: Kaempferol‐3‐O‐sophoroside (PCS‐1) is the main component in Crocus sativus (Saffron), a herb with mood‐enhancing properties. AMP‐activated protein kinase (AMPK) is a potential therapeutic target for depression. This study explores the antidepressive‐like properties of PCS‐1 and its AMPK activation to confirm AMPK as a target for antidepression. Experimental Approach: Corticosterone (CORT)‐induced PC12 cell injury served as an in vitro model to evaluate the neuroprotective effect of PCS‐1. Neuro‐2a cells and primary neurons were utilized to evaluate the synaptogenesis role of PCS‐1. CORT‐induced mouse depression model and chronic unpredictable mild stress (CUMS) model were used to assess the antidepressive‐like properties of PCS‐1 through behavioural tests, magnetic resonance imaging, and biochemical index measurements. Western blot and immunofluorescence assays were used to study the mechanisms of PCS‐1. Cellular thermal shift assay was used to confirm the binding target. Key Results: PCS‐1 (12.5–50 μM) ameliorated CORT‐induced PC12 cell damage, oxidative stress and inflammation. PCS‐1 alone promoted an increase in synapses in Neuro‐2a cells and primary neurons. Oral administration of PCS‐1 (10 and 20 mg·kg−1) ameliorated weight loss, dyskinesia, and hippocampal volume reduction induced by CORT and CUMS. PCS‐1 bound to AMPK to improve the expression of brain‐derived neurotrophic factor (BDNF) and induce autophagy. Conclusion and Implications: PCS‐1 binds to AMPK to promote BDNF production and autophagy enhancement, ultimately achieving antidepressant effects. This study provides support for the clinical application of saffron petals and provides further evidence for AMPK as a potential target for antidepression. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for 3 weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson's correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression-related molecular (corticosterone, dopamine, and BDNF). Moreover, AKK altered chronic stress–induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson's correlation coefficient analysis revealed that AKK predominantly upregulated β-alanyl-3-methyl-l-histidine and edaravone to relieve depression. Furthermore, β-alanyl-3-methyl-l-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress–induced depressive symptoms in mice by regulating gut microbiota and metabolites. Key points: • AKK reduces depressive-like behaviors induced by chronic stress. • AKK regulates the gut microbial structure and metabolomics of serum under the chronic stress. • Antidepressant effect of AKK correlates with the increase of β-alanyl-3-methyl-l-histidine and edaravone. [ABSTRACT FROM AUTHOR]