Rhodomyrtus tomentosa fruit alleviates hippocampal neuroinflammation and apoptosis and rescues neurogenesis to ameliorate depressive-like behaviors in CUMS-challenged mice

Abstract

Rhodomyrtus tomentosa fruit is an edible berry with diverse bioactivities. However, its antidepressant effects remain unexplored. The purpose of this study was to evaluate the impact of Rhodomyrtus tomentosa fruit ethanol extract (RTEE) on depressive-like behaviors resulting from chronic unpredictable mild stress (CUMS) exposure in mice and to investigate the underlying molecular mechanisms. The results demonstrated that RTEE significantly ameliorated depressive-like behaviors in CUMS-challenged mice, as indicated by increased total distance traveled, velocity, and central zone entries (in the open field test), enhanced sucrose preference (in the sucrose preference test), and decreased immobility time (in the forced swim and tail suspension tests). Meanwhile, RTEE significantly reduced the number of Iba-1⁺ and GFAP⁺ cells and down-regulated COX-2, TNF-α, and IL-6 expression in the hippocampus by suppressing the TLR4/MyD88/NF-κB signaling axis, thus alleviating neuroinflammation. In addition, RTEE significantly reduced the number of TUNEL⁺ cells in the dentate gyrus (DG), thus attenuating hippocampal apoptosis. Moreover, RTEE significantly increased the number of DCX⁺ and BrdU⁺ cells, up-regulated PSD95 expression, and restored the AMPK/BDNF/CREB and Wnt/β-catenin signaling axes in the hippocampus, thus rescuing hippocampal neurogenesis. These findings indicated that RTEE ameliorated depressive-like behaviors in CUMS-challenged mice by alleviating hippocampal neuroinflammation and apoptosis and rescuing neurogenesis. Therefore, this study establishes a mechanistic basis for the potential of Rhodomyrtus tomentosa fruit as an innovative nutritional therapy for depression.