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
Graphical abstract
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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2022, Biomedicine and PharmacotherapyCitation Excerpt :Mechanistic analysis indicated that the protective effects were mediated by the inhibition of the AMPK/Nrf2/HO-1 signaling pathway since the inhibition of this pathway suppressed the beneficial effects of emodin. In an in vivo study, the antidepressant-like activity of emodin against chronic unpredictable mild stress (CUMS)-induced behavioral deficiency was evaluated in mice for 6 weeks using fluoxetine as a positive control [61]. After the experimental procedure, the consumption of sucrose was remarkably reduced, the immobility duration was elongated and locomotor activities such as crossing, and rearing were weakened in the CUMS-exposed group concerning the control group.
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These authors contributed to the work equally and should be regarded as co-first authors.