Electroacupuncture Ameliorates Depressive-Like Behaviors by Enhancing Autophagy to Attenuate Hippocampal...

The high prevalence of depression and limitations of current antidepressants necessitate alternative therapies. Electroacupuncture (EA) shows promise, but its mechanisms remain unclear. Hippocampal impairment in depression involves neuroinflammation linked to defective autophagy. This study investigated whether EA alleviates depressive-like behaviors by enhancing autophagy via the VEGF/AKT1/ERK pathway to attenuate hippocampal neuroinflammation. Bioinformatic analysis of the GEO dataset GSE53987 was performed to identify autophagy- and neuroinflammation-related differentially expressed genes in depression. A chronic unpredictable mild stress (CUMS) rat model was used for validation. Rats were divided into control, CUMS, EA, EA + VEGFR2 inhibitor (SU5416) (EA+SU5416), EA + 3-methyladenine (3-MA), and FXL (fluoxetine) groups. Comprehensive assessments included behavioral tests, Nissl staining for histomorphology, transmission electron microscopy (TEM) for neuronal ultrastructure, immunofluorescence(IF), immunohistochemistry (IHC), Western blot (WB), enzyme-linked immunosorbent assay (ELISA), and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to evaluate therapeutic effects and hippocampal alterations, focusing on VEGF/AKT1/ERK pathway expression and phosphorylation. AKT1 was identified as a key gene linking autophagy and inflammation. CUMS rats exhibited upregulation of hippocampal AKT1 transcription but decreased phosphorylation, along with enrichment of the VEGF pathway. EA at LI4/LR3 significantly ameliorated depressive-like behaviors and hippocampal damage in CUMS rats. Mechanistically, EA upregulated hippocampal VEGF expression and promoted synergistic phosphorylation of AKT1 and ERK. This was accompanied by enhanced autophagic activity (increased LC3-II/I ratio, decreased p62) and attenuated neuroinflammation (reduced IL-1β, TNF-α). Co-administration of the VEGFR2 inhibitor SU5416 largely abolished these therapeutic effects, including behavioral improvement, AKT1/ERK phosphorylation, autophagy enhancement, and anti-neuroinflammation. Furthermore, the autophagy inhibitor 3-MA also blocked EA's benefits, indicating autophagy as the essential downstream executor. EA ameliorated depressive-like behaviors in CUMS rats, suggesting that the mechanism may involve the activation of the VEGF/AKT1/ERK pathway, leading to enhanced autophagy and attenuated hippocampal neuroinflammation.