Myricetin Attenuates Depressant-Like Behavior in Mice Subjected to Repeated Restraint Stress

Abstract

Increasing evidence has shown that oxidative stress may be implicated in chronic stress-induced depression. Several flavonoids with anti-oxidative effects have been proved to be anti-depressive. Myricetin is a well-defined flavonoid with the anti-oxidative, anti-inflammatory, anti-apoptotic, and neuroprotective properties. The aim of the present study is to investigate the possible effects of chronic administration of myricetin on depressant-like behaviors in mice subjected to repeated restraint (4 h/day) for 21 days. Our results showed that myricetin administration specifically reduced the immobility time in mice exposed to chronic stress, as tested in both forced swimming test and tail suspension test. Myricetin treatment improved activities of glutathione peroxidase (GSH-PX) in the hippocampus of stressed mice. In addition, myricetin treatment decreased plasma corticosterone levels of those mice subjected to repeated restraint stress. The effects of myricetin on the brain-derived neurotrophic factor (BDNF) levels in hippocampus were also investigated. The results revealed that myricetin normalized the decreased BDNF levels in mice subjected to repeated restraint stress. These findings provided more evidence that chronic administration of myricetin improves helpless behaviors. The protective effects of myricetin might be partially mediated by an influence on BDNF levels and might be attributed to myricetin-mediated anti-oxidative stress in the hippocampus.

Keywords: anti-oxidation; brain-derived neurotrophic factor; chronic stress; depression; myricetin.

Figure 1

Effects of myricetin on repeated restraint stress-induced depressant-like behavior in mice. (A) Immobility time during the forced swimming test showing that myricetin treatment reversed the increase in the immobility time of the mice subjected to repeated restraint stress. Regular two-way Analysis of Variance (ANOVA), drug(myricetin) × treatment(stress) interaction F_(1,23) = 19.44, p < 0.001; significant drug variation F_(1,23) = 12.68, p < 0.01, Boferroni post-test, *** p < 0.001 significant difference between groups; (B) immobility time during the tail suspension test showing that myricetin treatment reversed the increase in the immobility time of the mice subjected to repeated restraint stress. Regular two-way ANOVA, drug(myricetin) × treatment(stress) interaction F_(1,23) = 6.85, p < 0.05; significant treatment variation F_(1,23) = 15.28, p < 0.001; significant drug variation F_(1,23) = 5.41, p < 0.05, Boferroni post-test, ** p < 0.001 significant difference between groups; and (C) the open field analysis showing that mice received different treatment spent similar time in the central (50%) area and the peripheral (50%) area of tested arena.

Figure 2

Effects of myricetin on the plasma corticosterone levels of mice subjected to repeated restraint stress for 21 consecutive days. Myricetin treatment reversed the increase in the plasma corticosterone of the mice subjected to repeated restraint stress. Regular two-way ANOVA, drug(myricetin) × treatment(stress) interaction F_(1,24) = 8.68, p < 0.01; significant treatment variation F_(1,24) = 353.07, p < 0.001; significant drug variation F_(1,24) = 28.17, p < 0.001, Boferroni post-test, *** p < 0.001 significant difference between groups.

Figure 3

Effects of myricetin on the activities of glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) in the hippocampus of mice subjected to repeated restraint stress for 21 consecutive days. (A) Myricetin treatment reversed the decrease in the GSH-PX activity of the mice subjected to repeated restraint. Regular two-way ANOVA, significant treatment variation F_(1,23) = 12.21, p < 0.01, Boferroni post-test, * p < 0.05 significant difference between groups; and (B) the SOD activity in hippocampus of mice subjected to stress exhibited a tendency of decrease, as compared to the control group, however, was not significant.

Figure 4

Effects of myricetin on brain-derived neurotrophic factor (BDNF) levels in the hippocampus of mice subjected to repeated restraint stress for 21 consecutive days. (A) The expressions of BDNF significantly decreased in the hippocampus of mice subjected to repeated restraint stress for 21 consecutive days. These effects were partially restored by myricetin administration. (M + S: Myricetin + repeated restraint stress; M: Myricetin; C: Control; S: repeated restraint stress); and (B) statistical analysis. Data were presented as the ratio of BDNF to β-actin. Each bar represented the mean ± SEM of three independent experiments. * p < 0.05, ** p < 0.01 respectively.