Metabolomics and Proteomics Analyses Reveal the Protective Effect of Crocetin Against Depressive-Like Behaviors Mice

Depression is a common neuropsychiatric disorder, and our previous study revealed that crocetin has antidepressant effects, while the antidepressant mechanism of crocetin is still unknown. This study aimed to probe the antidepressant mechanism of crocetin in chronic unpredictable mild stress (CUMS) induced depressive-like behaviors mice. The hippocampus was collected for metabolomic analyses using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The ileum was collected for proteomics analyses.The results revealed that crocetin treatment could significantly improve CUMS-induced depression. Metabolic showed that crocetin-treated suggestively altered the metabolite levels in the hippocampus of depressive-like mice. In total, 92 nominal differential abundant metabolites including 37 nominally upregulated and 55 nominally downregulated metabolites, were observed between CUMS and crocetin-treated groups. These differential metabolites were suggestively enriched in the pathway of glycerophospholipid metabolism and oxidative phosphorylation. Crocetin also significantly altered protein synthesized in the ileum of depressive-like behaviors mice. In total, 419 proteins were differentially regulated, including 231 nominally upregulated and 188 nominally downregulated proteins. These differential proteins were significantly enriched in the pathway of retinol metabolism and steroid hormone biosynthesis, and suggestively enriched in the pathway of inflammation-mediated transient receptor potential (TRP) channel, arachidonic acid metabolism, linoleic acid metabolism, and serotonergic synapse. Based on omics analysis, we have formulated a hypothesis for further verification: crocetin significantly affect the lipid metabolism due to its anti-inflammatory and antioxidant activities, especially glycerophospholipid metabolism in the body, thereby exerting an antidepressant effect. These effects may be closely related to the regulatory role of crocetin in the inflammatory state of the ileum. This study demonstrates that multi-omics analysis can provide new insights into the mechanism of drug antidepressant effects.