Elsevier

Fitoterapia

Volume 98, October 2014, Pages 1-10
Fitoterapia

Emodin opposes chronic unpredictable mild stress induced depressive-like behavior in mice by upregulating the levels of hippocampal glucocorticoid receptor and brain-derived neurotrophic factor

https://doi.org/10.1016/j.fitote.2014.06.007Get rights and content

Abstract

Emodin, the major active component of Rhubarb, has shown neuroprotective activity. This study is attempted to investigate whether emodin possesses beneficial effects on chronic unpredictable mild stress (CUMS)-induced behavioral deficits (depression-like behaviors) and explore the possible mechanisms. ICR mice were subjected to chronic unpredictable mild stress for 42 consecutive days. Then, emodin and fluoxetine (positive control drug) were administered for 21 consecutive days at the last three weeks of CUMS procedure. The classical behavioral tests: open field test (OFT), sucrose preference test (SPT), tail suspension test (TST) and forced swimming test (FST) were applied to evaluate the antidepressant effects of emodin. Then plasma corticosterone concentration, hippocampal glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) levels were tested to probe the mechanisms. Our results indicated that 6 weeks of CUMS exposure induced significant depression-like behavior, with high, plasma corticosterone concentration and low hippocampal GR and BDNF expression levels. Whereas, chronic emodin (20, 40 and 80 mg/kg) treatments reversed the behavioral deficiency induced by CUMS exposure. Treatment with emodin normalized the change of plasma corticosterone level, which demonstrated that emodin could partially restore CUMS-induced HPA axis impairments. Besides, hippocampal GR (mRNA and protein) and BDNF (mRNA) expressions were also up-regulated after emodin treatments. In conclusion, emodin remarkably improved depression-like behavior in CUMS mice and its antidepressant activity is mediated, at least in part, by the up-regulating GR and BDNF levels in hippocampus.

Introduction

Depression, a well-known chronic, recurring, and life-threatening emotional disorder, is triggered by many environmental and genetic factors [1]. Although there are many hypotheses involved in the etiopathogenesis of depression (including monoamine deficiency hypothesis, hyperactivity of the HPA axis hypothesis, neurodegeneration and so on), the mechanism is still not very clear [2]. Especially, a majority of current clinical antidepressants only have low curative ratio and even cause side effects [3]. Therefore, looking for more effective and reliable antidepressants is necessary.

Plenty of clinical reports suggest that prolonged exposure to life stressful episodes, as a common risk factor, could provoke the development of major depression [4], [5], [6]. Currently, scientists adopt chronic unpredictable mild stress (CUMS) procedure which is performed such that animals are consecutively exposed to a series of unpredictable mild stressors to simulate a series of life stress events [7]. Indeed, a large number of ethological symptoms and neurobiological abnormalities found in CUMS-induced animals are similar to those exhibited in human depressed patients [8]. Thus, CUMS-induced depressive animal model has good validity and reliable predictability to screen new antidepressants through a series of behavioral tests [5].

The hypothalamic–pituitary–adrenal (HPA) axis is a key response element against stressors and its abnormal activation by chronic stressful conditions is regarded as an important risk factor for depression [6], [9], [10]. Previous research shows that chronic and elevated glucocorticoid levels as a result of HPA axis dysfunction existed in human depression (cortisol) and animal model (corticosterone) [11]. Because the function of glucocorticoid is mediated by glucocorticoid receptor (GR), current ideas support that the GR participates in the mechanism of HPA axis dysfunction and depression. Clinical evidence has shown that the hippocampus of depressed patients exhibits down-regulation of the GR expression (mRNA and protein) level which in turn leads to an increase in glucocorticoid [6], [12], [13]. Consistently, much strong evidence indicated that antidepressants can attenuate the decreases of hippocampal GR mRNA and protein expression [14], [15], [16].

Besides GR, brain-derived neurotrophic factor (BDNF), one of the most extensive neurotrophins, has been suggested to be involved in the pathomechanism of depression [17]. BDNF levels are reduced in the postmortem brains of depressed patients as well as in the animal models of depression [18], [19]. In addition, a growing number of clinical and experimental evidence reports that the alterations in BDNF levels are associated with the beneficial therapeutic activities of antidepressant drugs [18], [20]. Hence, BDNF has been considered as a possible target for antidepressants.

Emodin, 1,3,8-trihydroxy-6-methylanthraquinone (Fig. 1), the major active compound of Rhubarb, has been shown to have anti-cancer, liver protection, anti-inflammation, antioxidant and anti-virus effects [21]. Recently, it has been reported that emodin and its derivative has neuroprotective effects in severe cerebral injury [22], [23]. Some previous research suggests that emodin could protect the brain from glutamate excitotoxicity via decreasing the release of glutamate [24]. And, there is evidence that emodin inhibits lipid peroxidation in rat brain homogenates [25].

Based on the above premises, the target of our research was to investigate whether oral emodin treatments at doses of 20 mg/kg, 40 mg/kg and 80 mg/kg possess potential antidepressant-like effects on chronic stress depression mouse model. Behavioral tests were performed to evaluate whether emodin could oppose CUMS-induced depression in mice. Meanwhile, we analyzed plasma corticosterone concentration and detected hippocampal GR and BDNF levels to elucidate the possible molecular basis of its antidepressant effects.

Section snippets

Animals

Male ICR mice weighing 18–22 g (same batch) were purchased from Experimental Animal Center in Jiangsu Province (Nanjing, China). Prior to any experimentation, the mice were allowed to have one week to acclimatize to the laboratories. And, during the whole study, the mice were housed in group in a constant laboratory conditions at a temperature of 22 °C and 60% relative humidity under a 12 h light/12 h dark cycle. In our study, all the experimental procedures and laboratory animal care were

Effects of emodin on the percentages of sucrose consumption

As shown in Fig. 2, the value of sucrose consumption was measured three times during the experiment. At the beginning of the experiment (0-week), there were no significant differences among the 6 groups. However, after 3 weeks of CUMS periods, the sucrose consumption of stressed mice was lower than the control group. At the end of CUMS regimen (6-week), sucrose consumption in CUMS group was significantly reduced compared with that in control group [F(5,59) = 6.380, P < 0.01]. However, the sucrose

Discussion and conclusion

Currently, we primary tested the antidepressant-like effects of oral emodin treatments in mice subjected to CUMS. In this work, the CUMS mice model satisfactorily mimicked the depressive status which was described as the reduction of the sucrose solution consumption and open-field activity, and the increase of the immobility durations in TST and FST respectively. However, emodin (20, 40 and 80 mg/kg) administration could oppose the anomalous behavioral changes caused by CUMS process. This study

Conflict of interest

There is no conflict of interest.

Acknowledgments

This work was supported by grants of a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Natural Science Foundation of Jiangsu Province of China (Grant No. BK2011630).

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    These authors contributed to the work equally and should be regarded as co-first authors.

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