Antidepressant-like effects of tetrahydroxystilbene glucoside in mice: Involvement of BDNF signaling cascade in the hippocampus

Abstract

Background and aims: Current antidepressants in clinic need weeks of administration and always have significant limitations. Tetrahydroxystilbene glucoside (TSG) is one of the major bioactive ingredients of Polygonum multiflorum with neuroprotective effects. This study aimed to evaluate the antidepressant effects of TSG in mice.

Methods: The antidepressant-like effects of TSG in mice were examined in the forced swim test (FST), tail suspension test (TST), and chronic social defeat stress (CSDS) model of depression. The effects of CSDS and TSG on the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway and neurogenesis were further investigated. Moreover, the pharmacological inhibitors and lentiviral-shRNA were used to explore the antidepressant mechanisms of TSG.

Results: TSG produced antidepressant-like effects in the FST and TST and also reversed the CSDS-induced depressive-like symptoms. Moreover, TSG treatment significantly restored the decreased hippocampal BDNF signaling pathway and neurogenesis in CSDS mice. Importantly, blockade of the hippocampal BDNF system fully abolished the antidepressant-like effects of TSG in mice.

Conclusion: In conclusion, TSG produces antidepressant-like effects in mice via enhancement of the hippocampal BDNF system.

Keywords: brain-derived neurotrophic factor; chronic social defeat stress; depression; tetrahydroxystilbene glucoside.

Figure 1

TSG exerts antidepressant‐like effects in the FST and TST. The vehicle refers to normal saline. (A) The TSG‐treated mice had significantly less immobility than the vehicle‐treated mice in the FST. (B) The TSG‐treated mice also showed significantly less immobility than the vehicle‐treated mice in the TST. (C) All the groups of mice displayed similar locomotor activity in the open‐field test. The data are expressed as means±SEM (n=10); **P<.01. The comparisons were made by one‐way ANOVA followed by post hoc LSD test

Figure 2

TSG produces antidepressant‐like effects in the CSDS model of depression. (A) The CSDS+TSG mice spent significantly more time engaged in social interaction than the CSDS+vehicle mice, indicating the antidepressant‐like effects of TSG in the social interaction test. (B) The CSDS+TSG mice displayed significantly higher sucrose preference than the CSDS+vehicle mice, suggesting the antidepressant‐like effects of TSG in the sucrose preference test. The data are expressed as means±SEM (n=10); **P<.01 vs vehicle; #P<.05, ##P<.01 vs CSDS+vehicle. The comparisons were made by two‐way ANOVA followed by post hoc Bonferroni's test

Figure 3

Chronic TSG treatment restores the CSDS‐induced decrease in the hippocampal BDNF signaling pathway. (A) Representative images of the Western blotting results. (B) Quantitative analysis showed that chronic TSG administration fully restored the CSDS‐induced decrease of BDNF signaling cascade in the hippocampus. The CSDS+TSG mice displayed significantly more expression of BDNF, pTrkB, pERK1/2, pAKT, and pCREB in the hippocampus than the CSDS+ vehicle mice. The data are expressed as means±SEM (n=5); **P<.01 vs vehicle; ##P<.01 vs CSDS+vehicle. The comparisons were made by two‐way ANOVA followed by post hoc Bonferroni's test

Figure 4

The usage of K252a attenuates the antidepressant effects of TSG. The vehicle referred to 1% DMSO in normal saline. (A) K252a pretreatment before TSG injection prevented the TSG‐induced decrease in the immobility of mice in the FST. (B) K252a pretreatment also prevented the TSG‐induced decrease in the immobility of mice in the TST. (C) The CSDS‐stressed mice were co‐injected with TSG and K252a for 14 d. The CSDS+TSG+K252a mice displayed significantly lower sucrose preference than the CSDS+TSG mice. (D) The CSDS+TSG+K252a mice also displayed significantly lower social interaction than the CSDS+TSG mice. The results are expressed as means±SEM (n=10); **P<.01 vs vehicle; ##P<.01 vs CSDS+vehicle. The comparisons were made by two‐way ANOVA followed by post hoc Bonferroni's test

Figure 5

The usage of TrkB‐shRNA abolishes the antidepressant effects of TSG. (A) Fluorescence of a fixed brain slice which expressed TrkB‐shRNA and EGFP in the hippocampus on the 14th day after the stereotactic injection of LV‐TrkB‐shRNA‐EGFP. The scale bar is 200 μm. Western blotting analysis showed the silencing effects of TrkB‐shRNA. (B) Schematic timeline of the experimental procedures. (C) TrkB‐shRNA pretreatment before TSG administration dramatically prevented the TSG‐induced decrease of immobility in the FST. (D) TrkB‐shRNA pretreatment before TSG injection also abolished the TSG‐induced decrease of immobility in the TST. (E) The CSDS+TrkB‐shRNA+TSG mice displayed significantly less sucrose preference than the CSDS+TSG mice. (F) The CSDS+TrkB‐shRNA+TSG mice showed significantly less social interaction than the CSDS+TSG mice. The results are expressed as means±SEM (n=10); **P<.01 vs vehicle; ##P<.01 vs CSDS+vehicle. The comparisons were made by two‐way ANOVA followed by post hoc Bonferroni's test

Figure 6

TrkB‐shRNA pretreatment abolishes the restoring effects of TSG on the hippocampal BDNF signaling cascade in stressed mice. (A) Representative images of the Western blotting results. (B) Quantitative analysis indicated that TrkB‐shRNA infusion prevented the TSG‐induced promotion of hippocampal BDNF, pTrkB, pERK1/2, pAKT, and pCREB expression in stressed mice. The CSDS+TSG+TrkB‐shRNA mice displayed significantly lower BDNF, pTrkB, pERK1/2, pAKT, and pCREB levels in the hippocampus than the CSDS+TSG mice. The data are expressed as means±SEM (n=5); **P<.01 vs vehicle; ##P<.01 vs CSDS+vehicle. The comparisons were made by two‐way ANOVA followed by post hoc Bonferroni's test