Neohesperidin Improves Depressive-Like Behavior Induced by Chronic Unpredictable Mild Stress in Mice

Depression is a common and complex neuropsychiatric disorder affecting people of all ages worldwide, associated with high rates of relapse and disability. Neohesperidin (NEO) is a dietary flavonoid with applications in therapeutics; however, its effects on depressive-like behavior remain unknown. Here, we evaluated the effects of NEO on depressive-like behavior induced by chronic and unpredictable mild stress (CUMS). NEO (25, 50, and 100 mg kg^-1) treatment for two weeks dose-dependently improved CUMS-induced depressive-like behavior measured by the sucrose preference, open field, forced swimming, and tail suspension tests. Moreover, NEO effectively blocked the decrease of superoxide dismutase, catalase, and glutathione peroxidase activity and the increase of malondialdehyde levels, which are markers of oxidative stress. In addition, NEO inhibited microglial activation and the production of proinflammatory cytokines interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNF-α) in the hippocampus and prefrontal cortex. Molecular docking and dynamic simulations showed that NEO has good affinity for NOD-like receptor protein 3 (NLRP3), suggesting that NEO may play an antidepressant role by regulating the NLRP3 signaling pathway. Western blotting results further revealed that the increased expression level of NLRP3 inflammasome components (NLRP3, caspase-1, and ASC) in CUMS mice was significantly reversed by NEO treatment. These results suggest that NEO is a candidate for treating depression and should be considered for further clinical development.