Molecular Mechanisms Underlying Apple Extract Ameliorates Depression-Incident Cognitive Dysfunction Based on Network Pharmacology.

The apple was found to be involved in antidepressant properties. Thus, this study aimed to explore the effects of apple extract (AE) on depression and to elucidate the underlying mechanisms. Our network pharmacology analysis indicated that AE may exert its antidepressant effects through the regulation of inflammatory responses and the cAMP signaling pathway. Behavioral tests showed that AE significantly improved spatial learning, exploratory behavior, anhedonia, and despair in CUMS mice. Biochemical analyses revealed that AE increased synaptic density in the hippocampus, enhanced brain levels of 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA), and reduced the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in both serum and brain tissue. In vitro, AE demonstrated significant neuroprotective effects against CORT-induced cytotoxicity. Furthermore, AE treatment upregulated the levels of cAMP, phosphorylated PKA (pPKA), and phosphorylated CREB (pCREB) while downregulating PTGS2 expression, suggesting that the cAMP/PKA/CREB/PTGS2 signaling pathway is a key mechanism underlying the antidepressant effects of AE. Therefore, our study indicated that AE can improve cognitive dysfunction and alleviate depressive-like behavior by targeting the cAMP/PKA/CREB/PTGS2 signaling pathway in CUMS mice. This study paved the way for the clinical application of AE as a novel treatment for depression and provided new targeted therapeutic strategies.