Dihydromyricetin attenuates depressive-like behaviors in mice by inhibiting the AGE-RAGE signaling pathway

Jun Huang, Bin Chen, Hao Wang, Sheng Hu, Xudong Yu, James Reilly, Zhiming He, Yong You, Xinhua Shu

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Depression is a complex mental disorder, affecting appropriate 280 million individuals globally. The pathobiology of depression is not fully understood and development of new treatments is urgently needed. Dihydromyricetin (DHM) is a natural flavanone, mainly distributed in Ampe-lopsis grossedentata. DHM has demonstrated a protective role against cardiovascular disease, dia-betes, liver disease, cancer, kidney injury and neurodegenerative disorders. In the present study, we examined the protective effect of DHM against depression in a chronic depression mouse model induced by corticosterone (CORT). Animals exposed to CORT displayed depressive-like be-haviors; DHM treatment reversed these behaviors. Network pharmacology analyses showed that DHM’s function against depression involved a wide range of targets and signaling pathways, of which the inflammation-linked targets and signaling pathways were critical. Western blotting showed that CORT-treated animals had significantly increased levels of the advanced glycation end product (AGE) and receptor of AGE (RAGE) in the hippocampus, implicating activation of the AGE-RAGE signaling pathway. Furthermore, enzyme-linked immunosorbent assay (ELISA) detected a marked increase in the production of proinflammatory cytokines, interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNFα) in the hippocampus of CORT-treated mice. DHM administration significantly counteracted these CORT-induced changes. These findings suggest that protection against depression by DHM is mediated by suppression of neuroin-flammation, predominantly via the AGE-RAGE signaling pathway.
Original languageEnglish
Article number3730
Number of pages13
Issue number23
Publication statusPublished - 22 Nov 2022


  • depression
  • dihydromyricetin
  • inflammation
  • network pharmacology
  • ACE-RAGE signalling pathway


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