Dihydromyricetin Mitigates Depression-Related Memory Impairments Through Regulation of Hippocampal PKA-CREB-BDNF Pathway in Mice

Background: Depression-associated memory impairment is a clinically significant comorbidity that responds poorly to conventional antidepressants. Dihydromyricetin (DHM), a natural dihydroflavonoid, exhibits neuroprotective and antidepressant-like effects, but its impact on stress-induced memory deficits and the underlying mechanisms remain unclear. Methods: A chronic restraint stress (CRS) mouse model was employed. DHM was intraperitoneally administered daily (20 mg/kg bodyweight) for 8 consecutive days. Depression-like behavior and memory functions were assessed with the tail suspension test, the object recognition memory (ORM) task, and the Y-maze test. Network pharmacology, molecular docking, and molecular dynamics (MD) simulations were integrated to predict potential targets and associated signal pathways. Expression of hippocampal PKA, p-CREB, CREB, and BDNF was measured through Western blotting. Results: CRS significantly increased immobility time in the tail suspension test and impaired both recognition memory (ORM) and spatial working memory (Y-maze), without affecting locomotor activity. DHM treatment effectively reversed behavioral despair and memory deficits. Network pharmacology identified 47 intersecting targets between DHM and depression-related memory impairment, with CREB1, ESR1 and NOS1 as core hub nodes. KEGG enrichment particularly implicated the involvement of the cAMP signaling pathway and other signaling pathways, which are associated with depression and/or memory impairment. Molecular docking predicted strong binding affinities of DHM to CREB1 (−9.225 kcal/mol), NOS1 (−9.113 kcal/mol) and ESR1 (−7.903 kcal/mol). MD simulations confirmed the thermodynamic stability of DHM-ESR1 and DHM-NOS1 complexes. Western blot analysis demonstrated that DHM treatment significantly increased the levels of hippocampal PKA, p-CREB and BDNF, without altering total CREB expression in CRS mice. Conclusions: DHM alleviated CRS-induced depression-like behaviors and memory deficits, possibly through regulation of multiple signaling pathways, including the hippocampal PKA-CREB-BDNF signaling pathway. These findings highlight DHM as a promising natural therapeutic candidate for depression-associated cognitive impairment.