Elsevier

Biomedicine & Pharmacotherapy

Volume 106, October 2018, Pages 1153-1160
Biomedicine & Pharmacotherapy

Gypenosides reverses depressive behavior via inhibiting hippocampal neuroinflammation

https://doi.org/10.1016/j.biopha.2018.07.040Get rights and content

Highlights

Abstract

Gypenosides, a saponins extract isolated from the Gynostemma pentaphyllum plant, produces neuroprotective effects in the brain. Our previous studies have shown that hippocampal glucocorticoid receptor (GR)-brain-derived neurotrophic factor (BDNF)-TrkB signaling was involved in the antidepressant-like effects of gypenosides. It remains unknown whether gypenosides could alleviate neuroinflammation in depressive-like animals. The aim of the present study was to address this issue in chronic unpredictable mild stress (CUMS). Gypenosides was administrated for four weeks, followed by sucrose preference test and tail suspension test, which were performed to evaluate the effects of gypenosides. The results showed that gypenosides reversed both the decreased sucrose preference and increased immobility time in CUMS mice. In addition, gypenosides also attenuated the increase of pro-inflammatory cytokine levels in the hippocampus of CUMS animals. Furthermore, the activation of NF-κB, as well as its upstream mediators IKKα and IKKβ were inhibited by gypenosides. Last but not the least, CUMS promoted the activation of microglia, while gypenosides suppressed it according to the reduced number of iba1 positive cells. In conclusion, this study demonstrates that gypenosides exhibits the antidepressant-like effects in mice, which may be mediated by the inhibition of microglia and NF-κB signaling in the hippocampus.

Introduction

Depression is a common and serious medical illness that has a negative impact on both physical and mental health. The factors that contribute to the onset of depression are very complex. Due to the medical restrictions, we currently have no way of knowing the specific pathophysiology of depression. Until now, the widely accepted viewpoints hold that the typical cause of depression is associated with genetic factors, immunology, neuroendocrine, neurochemistry as well as social and environmental factors.

According to the latest research, the endothelial and dendritic cells around the neuronal membrane will be activated to generate immune substances such as cytokines or chemokines after the tissue is damaged, and then the immune substances induce the immune cells to enter the nervous system and induce neuroinflammation [1]. From the brains of patients who had suicide due to depression, the researchers found that the number of carbon monoxide synthetase in microglia was significantly increased [2]. This phenomenon was found in macrophages and astrocytes [2]. Studies have also shown that the loss of balance between pro-inflammatory cytokines and anti-inflammatory factors leads to depression. Generally, the pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are increased in the serum or plasma of patients with depression [3]. The meta analysis shows that the pro-inflammatory factors in patients with depression are positively related to the degree of depression [4]. According to current clinical evidence, both pro-inflammatory cytokines and microglia are increased in the brain [5,6], suggesting that neuroinflammation plays an important role in the pathophysiology of depression.

Gypenosides, a saponin extract isolated from Gynostemma pentaphyllum includes approximate 140 types of gypenosides [[7], [8], [9]]. These compounds have been reported to possess antitumor [10], antioxidant [11], neuroprotective [12,13] and anti-inflammatory activities [14,15]. Nowadays, gypenosides is approved for use as a traditional Chinese OTC in clinics by the Central Drug Administration of China. Previous study showed that gypenosides protected dopaminergic neurons in primary culture against MPP(+)-induced oxidative injury [16], which provided the possibility of gypenosides for treatment of mental disorders. Recently, our previous studies demonstrated that gypenosides produced an antidepressant-like effect in mice exposed to chronic unpredictable mild stress (CUMS) or long-term corticosterone injection, which was mediated via miR-124-glucocorticoid receptor (GR)-brain-derived neurotrophic factor (BDNF)-TrkB signaling [17,18]. Considering that neuroinflammation might be involved in the pathophysiology of depression, the present study investigated whether neuroinflammation inhibition was involved in the antidepressant-like effects of gypenosides in chronic unpredictable mild stress mice.

Section snippets

Animals

Male C57/BL mice (24 ± 2 g; 8 weeks old) were purchased from Shanghai Slac Animal Center, PR China. Animals were housed five per cage (320 × 180 × 160 mm) under a normal 12 h/12 h light to dark schedule with lights on at 07:00 a.m. Animals were allowed to adjust to the housing conditions before experiments began. Ambient temperature and relative humidity were maintained at 22 ± 2 °C and at 55 ± 5%, respectively. During the entire experiment, animals had access to food and water unless otherwise

The effects of gypenosides on behaviors in mice

As shown in the Fig. 1A, CUMS induced a significant decrease in the sucrose preference [P < 0.01]. Gypenosides treatment significantly increased the sucrose preference in the CUMS group [P < 0.01]. Additionally, gypenosides didn't significantly alter the sucrose preference in the Control group.

As shown in the Fig. 1B, CUMS significantly increased the immobility time [P < 0.05] in the tail suspension test. The post-hoc test revealed that 4-week treatment with gypenosides significantly decreased

Discussion

In the present study, our results not only exhibited that gypenosides possessed the antidepressant-like action in CUMS mice, but also underlined the effects of gypenosides on neuroinflammation during the treatment. Our results clearly demonstrated that gypenosides reversed the depressive-like behaviors by inhibiting neuroinflammation in the hippocampus. To be more specific, gypenosides reversed the abnormalities as follows: (1) CUMS induced a significant decrease in sucrose preference and a

Conflict of interest

The Authors declares that there is no conflict of interest.

Acknowledgements

Funding for this study was provided by the Promotion Program for Young and Middle-aged Teacher in Science and Technology Research of Huaqiao University (ZQN-PY218) and the Outstanding Youth Scientific Research Training Program in Colleges and Universities of Fujian Province (JA14015). Also, we would like to thank Dr. Shi-Bin Wang, who kindly assisted with the experimental design, and thank Instrumental Analysis Center of HQU for the help of confocal testing.

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