Dihydromyricetin attenuates chronic stress-induced depressive-like phenotypes and modulates Akt/FoxO3a-related signaling in the hippocampus.

Major depressive disorder (MDD) is closely associated with chronic stress, hypothalamic-pituitary-adrenal axis dysfunction, neuroinflammation, and hippocampal neuronal injury. Dihydromyricetin (DMY), a major flavonoid from Ampelopsis grossedentata, has neuroprotective and anti-inflammatory activities. However, the molecular alterations associated with its effects during chronic stress remain incompletely understood. In this study, we investigated the protective effects and associated molecular alterations of DMY during chronic stress using network pharmacology, molecular docking, and a chronic unpredictable mild stress (CUMS) mouse model. Network analysis identified 238 overlapping targets between DMY and depression, which were mainly enriched in the PI3K/Akt signaling pathway, apoptosis, and inflammatory cytokine-related processes. Molecular docking predicted potential interactions between DMY and several hub targets. In vivo, DMY administration during CUMS exposure attenuated the development of depressive- and anxiety-like behavioral abnormalities. It also attenuated CUMS-induced hippocampal histopathological alterations and increased the number of Nissl-positive neurons. Moreover, DMY reduced CRH, ACTH, and corticosterone levels, indicating attenuation of CUMS-associated HPA-axis abnormalities. It also decreased IL-1β levels, suggesting partial inhibition of stress-induced inflammation. Consistent with these findings, DMY increased hippocampal Akt, NPW, and Bcl-2 expression while decreasing FoxO3a and Caspase-3 expression, with reduced FoxO3a immunoreactivity in the CA1 and CA3 regions. These findings indicate that DMY alleviates CUMS-induced depressive-like phenotypes, accompanied by reduced hippocampal neuronal damage and attenuation of HPA-axis dysregulation.