Kumatakenin alleviates depressive-like behaviors by suppressing excessive autophagy in hippocampus via ATG5

The prevalence of depression has been escalating annually, imposing a substantial burden on both individuals and society. Radix Astragali, a multifaceted herb utilized in traditional Chinese medicine, has been employed in clinical settings for the treatment of depression. Kumatakenin, a principal active constituent of Radix Astragali, has yet to be thoroughly investigated for its potential antidepressant effects. In this study, we elucidated a novel effect of Kumatakenin, which ameliorated depression-like behaviors by modulating excessive autophagy in the hippocampus of mice exhibiting depressive symptoms. Utilizing transmission electron microscopy, we identified a significant increase in autophagosomes within the hippocampal region of depressed mice, which was notably reduced following Kumatakenin administration. Further, molecular docking analyses revealed an interaction between Kumatakenin and autophagy-related gene 5 (ATG5). At the protein level, Kumatakenin administration resulted in a marked decrease in microtubule-associated protein 1 light chain 3 (LC3) and ATG5 levels within hippocampal tissues. At the cellular level, in a corticosterone (CORT)-induced cell model, Kumatakenin significantly diminished the levels of LC3 and ATG5. Upon overexpression of ATG5 through lentiviral transfection, the ability of Kumatakenin to reduce LC3 and ATG5 levels was nullified. These observations suggested that Kumatakenin exerted its antidepressant effects by decreasing LC3 and ATG5 concentrations in hippocampal tissues.