Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression

doi:10.1016/j.brainresbull.2017.08.009

Brain Research Bulletin

Volume 134, September 2017, Pages 211-219

https://doi.org/10.1016/j.brainresbull.2017.08.009 Get rights and content

Highlights

•
Ginsenoside Rg2 possesses antidepressant effects in the FST and TST.
•
Ginsenoside Rg2 has antidepressant effects in the CMS model of depression.
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Ginsenoside Rg2 has promoting effects on BDNF system in the hippocampus.

Abstract

Major depression is a common neuropsychiatric disease with high lifetime prevalence and high incidence of suicide. This study aimed to evaluate the antidepressant effects of ginsenoside Rg2 in mice, and the possible mechanism was also determined. A single injection of both Rg2 (10 and 20 mg/kg) and fluoxetine (positive control, 20 mg/kg) induced notable antidepressant-like effects in the forced swim test and tail suspension test without affecting the locomotor activity of mice, and the tests were done 30 min after the injection. Also, repeated daily treatment of Rg2 and fluoxetine for the last 2 weeks fully reversed the chronic mild stress (6 weeks)-induced depressive-like symptoms in mice. Moreover, western blot analysis showed that Rg2 administration significantly increased the BDNF signaling pathway in hippocampus. Importantly, the usage of TrkB shRNA fully blocked the antidepressant effects of Rg2 in mice. Collectively, these results suggest that Rg2 produces an antidepressant-like effect in mice which is mediated, at least in part, through promoting the hippocampal BDNF signaling pathway.

Introduction

Depression is a serious neuropsychiatric disease which afflicts one in six people at some point in life (Kessler et al., 1994, Olesen et al., 2012). It is also one of the main causes of human suffering. However, the exact neurobiologyof depression remains unclear. Currentdrugs used clinically, including the selective serotonin reuptake inhibitor (SSRI), noradrenergic reuptake inhibitor (NARI) and serotonin-noradrenaline reuptake inhibitor (SNRI), exhibited a low curative ratio and various side effects (Berton and Nestler, 2006, McGrath et al., 2006). Therefore, there is strong need for research new antidepressants with better efficacy and less adverse effects.

For the pathophysiology of depression, numerous researchers committed to the study of neurotrophic system, especially brain-derived neurotrophic factor (BDNF). BDNF is a type of nerve growth factor which is predominantly expressed in the brain and related to the survival and maintenance of neurons (Hofer et al., 1990, Conner et al., 1997). Clear evidences has demonstrated that serum BDNF level is significantly decreased in major depressive patients, while antidepressant treatment has been shown to up-regulate the BDNF expression in the hippocampus (Blendy, 2006, Castren and Rantamaki, 2010, Razzoli et al., 2011). BDNF heterogeneous knockout mice showed depressive-like behavior in the forced swim test (FST) and tail suspension test (TST), while administration of BDNF into the hippocampus produced antidepressant-like effects in animals (Shirayama et al., 2002, Hoshaw et al., 2005, Advani et al., 2009). Thus, elevating BDNF expression plays a crucial role in the treatment of depression. It is known that BDNF binds to tropomyosin-related kinase B (TrkB), and activates several downstream signaling pathways, and finally induce the phosphorylation and activation of cAMP response element-binding protein (CREB) in the nucleus (Shaywitz and Greenberg, 1999, Lim et al., 2008).

Nature product has been widely used around the world and is acknowledged as the important source of medicine. Ginsenoside Rg2, one of the most abundantand active ingredients of Panax ginseng, has been reported to have more and more pharmacological effects on the central nervous system, including protective effects against hippocampal neurotoxcity, protective effects in a rat model of vascular dementia, and so on (Li et al., 2007, Zhang et al., 2008, Shuangyan et al., 2012). We previously reported that gingsenoside Rg1, another important component of ginsenosides which has similar chemical structure to Rg2, produced antidepressant-like effects in mice via activating the hippocampal BDNF signaling pathway (Jiang et al., 2012). Here, we assumed that Rg2 may also has antidepressant-like effects. To explore this speculation, various methods including the chronic mild stress (CMS) model of depression, FST, TST, sucrose preference test, western blotting, and gene interference were used in this study.

Section snippets

Animals

Adult male C57BL/6J mice (8 weeks old) were obtained from the Experimental Animal Center of Medical College, Nantong University. Before used, mice were housed 5 per cage under standard laboratory conditions of constant temperature (23 ± 1 °C), relative humidity (50 ± 10%), 12 h light/dark cycle (light from 7:00 a.m. to 7:00 p.m.), and free access to food and water for 1 week. Each experimental group consisted of 10 mice. Behavioral experiments were carried out during the light phase. The experiment

Antidepressant-like effects of Rg2 in the FST and TST

The antidepressant effects of Rg2 were first investigated in the FST, with fluoxetine used as a positive control. As shown in Fig. 1A, compared to vehicle group, single injection of 10 mg/kg Rg2 induced a 21.2 ± 4.25% decrease of immobility, whereas single injection of 20 mg/kg Rg2 induced a 36.5 ± 4.02% decrease of immobility (n = 10, P < 0.01 vs. Vehicle). One-way ANOVA revealed a significant effect of drug treatment [F(3, 36) = 37.258, P < 0.01]. The positive control fluoxetine also decreased the

Discussion

In the present study, we have demonstrated for the first time that Rg2 has antidepressant effects in mice, which was similar to fluoxetine.The enhancing effects on hippocampal BDNF-TrkB system contributes, at least partially to the antidepressant effects of Rg2.

By now, more and more herbal medicine has been reported to possess antidepressant-like effects, like curcumin, baicalin, and so on (Xu et al., 2005, Peng et al., 2007, Su et al., 2014, Liang et al., 2016, Yu et al., 2016). Ginsenoside is

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China to Dr. Bo Jiang (No. 81401116), a grant from the Provincial Natural Science Foundation of Jiangsu Province (China) to Dr. Bo Jiang (No. BK20161284), and also an Undergraduate Innovation Project of Nantong University 2017 to Dr. Bo Jiang (No. 2017181).

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¹: These authors contributed to this paper equally.

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Research reportAntidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression

Highlights

Abstract

Introduction

Section snippets

Animals

Antidepressant-like effects of Rg2 in the FST and TST

Discussion

Conflict of interest

Acknowledgments

Neuropharmacology

Biol. Psychiatry

Encephale

Physiol. Behav.

Brain Res.

J. Pharmacol. Sci.

J. Ethnopharmacol.

J. Ethnopharmacol.

Eur. J. Pharmacol.

Life Sci.

Mol. Cell Neurosci.

Psychiatr. Clin. N. Am.

Neuroscience

J. Ethnopharmacol.

Eur. J Pharmacol.

Eur. J. Pharmacol.

Chem. Biol. Interact.

J. Ethnopharmacol.

Gender differences in the enhanced vulnerability of BDNF+/− mice to mild stress

Int. J. Neuropsychopharmacol.

New approaches to antidepressant drug discovery: beyond monoamines

Nat. Rev. Neurosci.

The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity

Dev. Neurobiol.

Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport

J. Neurosci.

The ascent of mouse: advances in modelling human depression and anxiety

Nat. Rev. Drug Discov.

Animal models of mood disorders: recent developments

Curr. Opin. Psychiatry

Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain

EMBO J.

Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus

Br. J. Pharmacol.

Research report
Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression