Resveratrol, a plant-derived polyphenol, exhibits significant antidepressant effects and notably enhances neuroplasticity in neurological diseases. However, whether the antidepressant function of resveratrol is related to neuroplasticity remains uncertain, and the underlying mechanisms is poorly understood. This study aims to investigate the role and mechanism of resveratrol in neuroplasticity in depression. Here, we adopted the chronic unpredictable mild stress (CUMS) model and resveratrol intervention by oral gavage. Thereafter, behavioral tests confirmed resveratrol’s antidepressant effect, and Nissl staining, Golgi staining, and Western blotting (WB) were employed to assess the neuronal plasticity. Moreover, proteomic analysis and WB were used to screen and identify the key proteins. To investigate the downstream target of ELAV-like RNA-binding protein 4 (ELAVL4) (one of candidate genes), the RNA Interactome Database and the National Center for Biotechnology Information databases were utilized to predict the targets of ELAVL4. Finally, Quantitative PCR, WB, and Immunofluorescence were used to verify the prediction. Our results indicate that resveratrol alleviates CUMS-induced depressive-like behaviors accompanied by the restoration of impaired hippocampal neuroplasticity. Then, proteomic analysis shows that 351 differentially expressed proteins (DEPs) decrease after CUMS, while 24 DEPs increase remarkably with the resveratrol treatment. Among which, ELAVL4 is downregulated by CUMS, simultaneously increasing after resveratrol intervention, which acts as a protective protein in this process. Finally, brain-derived neurotrophic factor (Bdnf) mRNA is predicted to be the potential target of ELAVL4 and validated by molecular technologies. In conclusion, our findings demonstrate that resveratrol’s antidepressant efficacy is closely associated with ELAVL4, an RNA-binding protein, a mediated neuroplasticity pathway, potentially intersecting with the Bdnf mRNA. Overall, this research sheds light on the role of the ELAVL4-Bdnf mRNA pathway through neuroplasticity in resveratrol’s antidepressant action, which provides an mRNA regulation perspective for the development of novel antidepressants and understanding depression pathology.

Resveratrol, a natural bitter polyphenol, exhibits significant antidepressant property. Numerous studies have linked its antidepressant effect to neuroplasticity enhancement or mitochondrial regulation. However, the interplay between these two mechanisms remains unclear. This study aims to elucidate the relationship among resveratrol's antidepressant effect, its regulatory impact on neuroplasticity and mitochondrial function, and to investigate the potential role of the type 2 bitter taste receptors (Tas2rs) in these processes. A chronic unpredictable mild stress (CUMS) model was used to induce depressive-like behaviors, while resveratrol was administered as an intervention. Following CUMS and resveratrol treatment, proteomic analysis combined with bioinformatics predicted significantly altered biological pathways in the hippocampus. The aforementioned predictions were validated using Western blotting (WB), Golgi staining, Nissl staining, and electron microscopy. Additionally, Tas2rs expression and calcium (Ca^2 +) levels in the hippocampus were quantified using quantitative PCR, WB, and calcium assay kit. Finally, immunofluorescence (IF) colocalization was used to examine the association of Tas2r123 with mitochondrial outer membrane in hippocampus. Resveratrol significantly alleviated depressive-like behaviors induced by CUMS. Proteomic analysis revealed that resveratrol's therapeutic effects are associated with neuroplasticity-related and metabolic pathways, particularly with differentially expressed proteins (DEPs) predominantly localized in the mitochondria. Gene Ontology analysis of mitochondrial DEPs further revealed substantial changes in mitochondrial organization. Furthermore, molecular biology experiments validated these proteomics findings. Additionally, resveratrol also reversed the CUMS-induced downregulation of Tas2r123 mRNA and protein expression. Moreover, IF colocalization demonstrated a strong association between Tas2r123 and mitochondria. Our findings suggest that resveratrol may exert antidepressant property by modulating neuroplasticity through the Tas2r123-mitochondrial organization pathway. This study introduces a novel perspective linking Tas2rs to resveratrol's antidepressant mechanisms, potentially pave the way for future antidepressant therapies.

Background/Objectives: Apigenin, a naturally occurring flavonoid, has shown promising antidepressant-like effects in previous studies. However, its precise mechanisms remain unclear. This study aims to investigate the underlying neurobiological mechanisms mediating the antidepressant effects of apigenin in chronic unpredictable mild stress (CUMS)-induced mice. Methods: The male mice were subjected to 4-week CUMS, with or without treatment, followed by behavioral testing. Network pharmacology analysis was employed to predict relevant signaling pathways. The mRNA and protein expression levels of the PI3K/AKT/NRF2 pathway were measured. Oxidative stress was assessed through the measurement of malondialdehyde, glutathione, and superoxide dismutase levels. Results: Apigenin significantly ameliorated CUMS-induced depression-like behaviors. The PI3K/AKT pathway may mediate the antidepressant properties of apigenin with both PI3K and AKT emerging as core target molecules. Apigenin restored the activity of the PI3K/AKT/NRF2 pathway and oxidative stress in the hippocampus downregulated by CUMS. Conclusions: The present study demonstrates that apigenin ameliorates depression-like behaviors in mice exposed to CUMS and mitigates oxidative stress in the hippocampus, which is associated with the PI3K/AKT/NRF2 signaling pathway.