Research report
Long-term treatment with peony glycosides reverses chronic unpredictable mild stress-induced depressive-like behavior via increasing expression of neurotrophins in rat brain

https://doi.org/10.1016/j.bbr.2010.02.026Get rights and content

Abstract

The root part of Paeonia lactiflora Pall., commonly known as peony, is a commonly used Chinese herb for the treatment of depression-like disorders. Previous studies in our laboratory have showed that total glycosides of peony (TGP) produced antidepressant-like action in various mouse models of behavioral despair. The present study aimed to investigate the mechanism(s) underlying the antidepressant-like action of TGP by measuring neurotrophins including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in non-stressed and chronic unpredictable mild stress (CUMS)-treated rats. TGP (80 or 160 mg/kg/day) was administered by oral gavage to the animals for 5 weeks. The results showed that CUMS caused depression-like behavior in rats, as indicated by the significant decreases in sucrose consumption and locomotor activity (assessed by open-field test). In addition, it was found that BDNF contents in the hippocampus and frontal cortex were significantly decreased in CUMS-treated rats. CUMS treatment also significantly decreased the level of NGF in the frontal cortex of the animals. Daily intragastric administration of TGP (80 or 160 mg/kg/day) during the five weeks of CUMS significantly suppressed behavioral and biochemical changes induced by CUMS. Treating non-stressed animals with TGP (160 mg/kg) for 5 weeks also significantly increased BDNF contents in the hippocampus and frontal cortex, and NGF contents in the frontal cortex. The results suggest that the antidepressant-like action of TGP is mediated, at least in part, by increasing the expression of BDNF and NGF in selective brain tissues.

Introduction

Depression is a commonly occurring, debilitating, and life-threatening psychiatric disorder. According to World Health Organization, depression is now the fourth most prevalent cause of loss in human disability adjusted life years worldwide, and it will become the second by the year 2020 [33]. Current antidepressants, which target monoaminergic systems, are widely available in the pharmaceutical market [8], [40]. However, these antidepressants only produce remission in 30% of patients because multiple pathogenic factors are involved in depression [31], and even exert adverse side effects [36]. Therefore, it is desirable to seek new antidepressants. The root part of Paeonia lactiflora Pall. (Ranunculaceae), commonly known as peony, is a commonly used medicinal herbs in China, Korea and Japan. It is a component herb of many traditional formulae, such as Jiawei-Sini-San and Xiaoyao-San, prescribed for the treatment of depression-like disorders [51], [54]. A recent study in our laboratory has demonstrated the antidepressant effect of peony in the mouse model of behavioral despair [28]. Glycosides, including paeoniflorin and albiflorin, are known to be the biologically active ingredients of peony, and the total glycosides fraction of peony has been shown to possess anti-inflammatory, antioxidant, anti-hepatic fibrosis, anti-diabetic and renoprotective properties [47], [50], [52], [55], [58]. Studies from our laboratory also showed that the intragastric administration of total glycosides of peony (TGP) caused a significant reduction of immobility time in both forced swim and tail suspension tests in mice [29]. The antidepressive effect of TGP was also observed in mice exposed to chronic unpredictable stress [30]. However, the mechanism(s) underlying the antidepressant-like action of TGP remains unclear.

It has been suggested that neuronal atrophy or destruction in the hippocampus and cortex is involved in the pathogenesis of depression [14], [27]. Thus neurotrophins, which modulate neuronal plasticity, inhibit cell death cascades and increase cell survival proteins that are responsible for proliferation and maintenance of central nervous system neurons [6], [17], may be the important factor involved in the development and treatment of depression. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are the most abundant neurotrophins in the central nervous system. Interestingly, in recent years, both neurotrophins in the hippocampus and cortex have repeatedly been postulated to be involved in the pathophysiology of stress-related behavior and depression [2], [11], [12], [21], [22], [34], [46]. Furthermore, several studies have demonstrated that antidepressant treatments might exert their beneficial action by regulating synthesis and/or release of BDNF or NGF in the hippocampus and cortex [2], [15], [24], [43], [53], [57]. As such, BDNF and NGF in the hippocampus and cortex can serve as hormonal or biochemical parameters for monitoring the development and therapeutic intervention of depression.

Chronic unpredictable mild stress (CUMS)-induced depression is generally thought to be the most promising and valuable depressive model in animals and has been widely used for investigating the pathophysiology of depression and the associated therapeutic interventions [20], [48], [49]. Therefore, in the present study, we examined whether long-term treatment with TGP (80 and 160 mg/kg, intragastrically) can reverse CUMS-induced depressive-like behavior in rats. In order to investigate the mechanism(s) underlying the antidepressant-like action of TGP, we also measured protein and mRNA levels of BDNF and NGF in brain tissues of non-stressed and CUMS-treated rats.

Section snippets

Drugs

TGP (light yellow brown powder) was supplied by Ningbo Liwah Pharmaceutical Co., Ltd. (Zhejiang, China). TGP has been characterized by high-performance liquid chromatography in our previous studies [29], [30] which mainly contains paeoniflorin and albiflorin. A voucher sample (TGP071024) was deposited in the School of Chinese Medicine for future reference. Fluoxetine, a selective serotonin reuptake inhibitor, was purchased from Sigma–Aldrich (St. Louis, MO) and used as positive control for

Effect of TGP on the percentage of sucrose consumption

Fig. 1 shows the effect of TGP treatment on the percentage of sucrose consumption in non-stressed and CUMS-treated rats. A 5-week CUMS exposure significantly reduced the percentage of sucrose consumption in the animals (43%), as compared to the non-stressed control. While long-term treatment with TGP at daily doses of 80 or 160 mg/kg significantly increased the percentage of sucrose consumption in CUMS-treated rats (25% and 34%, respectively), as compared to the CUMS-treated control. Treatment

Discussion

It is generally believed that chronic stress is a key factor in the development and acceleration of affective disorders like depression [7], [23], [39]. In this regard, an animal model of CUMS-induced depression has been developed to simulate the pathogenesis of depression in humans. Several studies suggest that CUMS can induce behavioral and physiological changes resembling symptoms of clinical depression [20], [25], [48], [49] and that CUMS-induced depression model can be used for evaluating

Acknowledgments

This study was supported by a Direct Grant for Research from the Chinese University of Hong Kong.

References (58)

  • R.J. Katz et al.

    Acute and chronic stress effects on open field activity in the rat: implications for a model of depression

    Neurosci Biobehav Rev

    (1981)
  • S. Li et al.

    Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms

    Life Sci

    (2007)
  • D.D. Luo et al.

    Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress

    Brain Res Bull

    (2008)
  • Y. Ibarguen-Vargas et al.

    Deficit in BDNF does not increase vulnerability to stress but dampens antidepressant-like effects in the unpredictable chronic mild stress

    Behav Brain Res

    (2009)
  • Q.Q. Mao et al.

    Antidepressant-like effects of peony glycosides in mice

    J Ethnopharmacol

    (2008)
  • Q.Q. Mao et al.

    Effects of peony glycosides on mice exposed to chronic unpredictable stress: further evidence for antidepressant-like activity

    J Ethnopharmacol

    (2009)
  • L.M. Monteggia et al.

    Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors

    Biol Psychiatry

    (2007)
  • E.J. Nestler et al.

    Neurobiology of depression

    Neuron

    (2002)
  • O. Schulte-Herbrüggen et al.

    Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness

    Exp Neurol

    (2006)
  • Y.I. Sheline

    3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity

    Biol Psychiatry

    (2000)
  • E. Shimizu et al.

    Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants

    Biol Psychiatry

    (2003)
  • J.A. Siuciak et al.

    Antidepressant-like effect of brain-derived neurotrophic factor (BDNF)

    Pharmacol Biochem Behav

    (1997)
  • B. Topic et al.

    Extinction-induced “despair” in aged and adult rats: links to neurotrophins in frontal cortex and hippocampus

    Neurobiol Learn Mem

    (2008)
  • S. von Richthofen et al.

    Effects of different kinds of acute stress on nerve growth factor content in rat brain

    Brain Res

    (2003)
  • Y. Wu et al.

    Renoprotective effect of total glucosides of paeony (TGP) and its mechanism in experimental diabetes

    J Pharmacol Sci

    (2009)
  • H.M. Xu et al.

    Effects and mechanisms of total glucosides of peony on adjuvant arthritis in rats

    J Ethnopharmacol

    (2007)
  • Y. Xu et al.

    Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB

    Brain Res

    (2006)
  • Z. Zhao et al.

    Antidepressant-like effect of liquiritin from Glycyrrhiza uralensis in chronic variable stress induced depression model rats

    Behav Brain Res

    (2008)
  • H. Zheng et al.

    Beneficial effects of exercise and its molecular mechanisms on depression in rats

    Behav Brain Res

    (2006)
  • Cited by (93)

    View all citing articles on Scopus
    View full text