LAUSR

Depression is a leading cause of disability worldwide. Here, we explored the role of the HMGB1-RAGE pathway in lipopolysaccharide (LPS)-induced depression-like behavior and microglial autophagy flux, neuroinflammation, and polarization in a mouse model. Male C57BL/6 mice were infused with LPS in the abdominal cavity to induce a depression model. They then underwent testing to assess behavior and cognition. Real-time fluorescent quantitative polymerase chain reaction was used to detect the expression of the M1/M2 microglia polarization markers, HMGB1, and RAGE. Microglial activation and phenotypic transformation in the hippocampus were identified. mRFP-GFP-LC3 and Western blotting were used to detect autophagy flux in each treatment group. Finally, an LPS-induced BV2 cell model was developed to verify the involvement of the HMGB1-RAGE pathway, autophagy flux, and polarization. Ketamine improved LPS-induced depression-like behavior, inhibited the LPS-induced upregulation of HMGB1 and RAGE and the nuclear translocation of HMGB1. Moreover, ketamine reversed the blocked autophagy flux of microglia caused by LPS and regulated microglial autophagy flux through the HMGB1-RAGE pathway and microglial polarization. These results suggest that ketamine may reduce HMGB1 and RAGE accumulation in patients with depression, thereby providing a new therapeutic target for preventing and treating this disease.