Antidepressant Effects of Rhodomyrtone in Mice with Chronic Unpredictable Mild Stress-Induced Depression

Background: Rhodomyrtone is one of the main active compounds derived from Rhodomyrtus tomentosa, which belongs to the Myrtaceae family. In the current study, we investigated the properties of rhodomyrtone as a potential drug candidate for the treatment of stress-caused depression. Methods: We assessed the function of rhodomyrtone in chronic unpredictable mild stress, a well-validated depression model in mice. Depression-like behavior tests, including a sucrose performance test, social interaction test, and forced swimming test, were used to validate the antidepressant effects of rhodomyrtone. The Morris water maze was used to evaluate the mice's learning and memory ability. Spine density, glycogen synthase kinase-3 beta, brain-derived neurotrophic factor, postsynaptic density protein 95, and apoptosis-associated protein were detected to reveal the underlying mechanism. Results: Rhodomyrtone was found to prevent source consumption decrease, decreased social behaviors, and increase immobility in the forced swimming test, suggesting a protective effect of rhodomyrtone against depression-like behaviors. Additionally, rhodomyrtone prevented the impairment of spatial memory in mice exposed to chronic unpredictable mild stress. Rhodomyrtone administration also reversed dendritic spine density defects in chronic unpredictable mild stress. Furthermore, rhodomyrtone inhibited the increase of glycogen synthase kinase-3 beta activity and reversed the decrease of brain-derived neurotrophic factor and postsynaptic density protein 95 in chronic unpredictable mild stress mice. Elevated expression of apoptosis-associated protein Bax and cleaved-caspase 3 was also reversed by rhodomyrtone treatment. Conclusions: These results suggested that the antidepressant effect of rhodomyrtone involves the regulation of neurogenesis, neuronal survival, and synaptic plasticity in the hippocampus.