Research reportLong-term treatment with peony glycosides reverses chronic unpredictable mild stress-induced depressive-like behavior via increasing expression of neurotrophins in rat brain
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)
- et al.
Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women
Prog Neuropsychopharmacol Biol Psychiatry
(2006) - et al.
Serum brain-derived neurotrophic factor level in dysthymia: a comparative study with major depressive disorder
Prog Neuropsychopharmacol Biol Psychiatry
(2007) - et al.
Effects of fluoxetine and venlafaxine on serum brain derived neurotrophic factor levels in depressed patients
Prog Neuropsychopharmacol Biol Psychiatry
(2009) - et al.
Role of neurotrophic factors in depression
Curr Opin Pharmacol
(2007) - et al.
Exploratory behaviour and grooming after repeated restraint and chronic mild stress: effect of desipramine
Eur J Pharmacol
(2000) - et al.
A neurotrophic model for stressrelated mood disorders
Biol Psychiatry
(2006) - et al.
Suicide brain is associated with decreased expression of neurotrophins
Biol Psychiatry
(2005) - et al.
Alterations of neuroplasticity in depression: the hippocampus and beyond
Eur Neuropsychopharmacol
(2004) - et al.
Decreased serum brain-derived neurotrophic factor levels in major depressed patients
Psychiatry Res
(2002) - et al.
Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity
Biol Psychiatry
(2005)
Acute and chronic stress effects on open field activity in the rat: implications for a model of depression
Neurosci Biobehav Rev
Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms
Life Sci
Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress
Brain Res Bull
Deficit in BDNF does not increase vulnerability to stress but dampens antidepressant-like effects in the unpredictable chronic mild stress
Behav Brain Res
Antidepressant-like effects of peony glycosides in mice
J Ethnopharmacol
Effects of peony glycosides on mice exposed to chronic unpredictable stress: further evidence for antidepressant-like activity
J Ethnopharmacol
Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors
Biol Psychiatry
Neurobiology of depression
Neuron
Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness
Exp Neurol
3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity
Biol Psychiatry
Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants
Biol Psychiatry
Antidepressant-like effect of brain-derived neurotrophic factor (BDNF)
Pharmacol Biochem Behav
Extinction-induced “despair” in aged and adult rats: links to neurotrophins in frontal cortex and hippocampus
Neurobiol Learn Mem
Effects of different kinds of acute stress on nerve growth factor content in rat brain
Brain Res
Renoprotective effect of total glucosides of paeony (TGP) and its mechanism in experimental diabetes
J Pharmacol Sci
Effects and mechanisms of total glucosides of peony on adjuvant arthritis in rats
J Ethnopharmacol
Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB
Brain Res
Antidepressant-like effect of liquiritin from Glycyrrhiza uralensis in chronic variable stress induced depression model rats
Behav Brain Res
Beneficial effects of exercise and its molecular mechanisms on depression in rats
Behav Brain Res
Cited by (93)
Synergistic effects of citicoline and silymarin nanomicelles in restraint stress-exposed mice
2024, Behavioural Brain ResearchProtocatechuic acid attenuates chronic unpredictable mild stress induced-behavioral and biochemical alterations in mice
2021, European Journal of Pharmacology