Anti-depressant-like effect of peony: a mini-review

Abstract

Context: Depression is a common psychiatric disorder, yet the clinical efficacy of antidepression therapies is unsatisfactory. Thus, the search for new anti-depressants continues, and natural products remain a promising source of new therapeutic agents. The root part of Paeonia lactiflora Pall. (Ranunculaceae), known as peony, is often used in Chinese herbal prescriptions for the treatment of depression-like disorders.

Objectives: The objective of this review is to provide scientific evidence to support further research on peony as a potential anti-depressant drug.

Methods: This review summarizes the results obtained in our laboratory, together with other literature data obtained through a comprehensive search in databases including PubMed, ScienceDirect, Scirus, and Web of Science.

Results: The peony extract is active in the mouse forced swim test and tail suspension test, and it produces anti-depressant effects in chronic unpredictable mild stress-induced depression model in mice and rats. The anti-depressant mechanisms of peony are likely mediated by the inhibition of monoamine oxidase activity, neuro-protection, modulation of the function of hypothalamic−pituitary−adrenal axis, inhibition of oxidative stress, and the up-regulation of neurotrophins.

Conclusions: Peony is used clinically to treat depression-like symptoms in Chinese medicine, and it has been shown to possess anti-depressant property in a battery of test models using laboratory animals. Its effect is likely mediated by multiple targets. Further studies are warranted to delineate the molecular mechanisms of action, determine the pharmacokinetics, establish the toxicological profile, and assess the potentials of peony in clinical applications. Identification of the clinically active ingredient(s) is also warranted.

Keywords::

• Paeonia lactiflora
• Chinese medicine
• paeonol
• paeoniflorin
• albiflorin
• forced swim test
• tail suspension test
• chronic unpredictable mild stress (CUMS)

Introduction

Depression is a chronic mental disorder clinically characterized by a pervasive low mood, loss of interest or pleasure in daily activities, low self-esteem, and a high suicidal tendency (Hankin, 2006; Perahia et al., 2009). It is a common disease that affects the quality of life of a large population worldwide and has become a major cause of suicidal death (Perahia et al., 2009). According to the statistics of the World Health Organization, depression is the fourth most prevalent cause of loss in human disability adjusted life years, and the disease is projected to become the second by 2020 (Nowak et al., 2003). At present, there are several types of anti-depressants available for clinical use; they include tricyclic anti-depressants, monoamine oxidase (MAO) inhibitors, selective serotonin reuptake inhibitors, noradrenergic reuptake inhibitors, as well as serotonin and noradrenaline reuptake inhibitors (Bouvier et al., 2003; Shen & Liang, 2007). However, due to the multiple pathogenic factors involved in depression, many anti-depressant drugs show low response rates and may cause adverse side-effects such as cardiotoxicity, hypertensive crisis, sexual dysfunction, and sleep disorder (Park et al., 2007). Thus, there is always an unmet need for safe, better tolerated, and efficacious anti-depressants.

Traditional Chinese medicine has recorded over 10,000 herbal formulae, including those possessing psychotropic potentials. In recent years, a number of herbal preparations have been evaluated using animal models of depression (Zhang 2004); and among them, the root part of Paeonia lactiflora Pall. (Ranunculaceae), commonly known as peony, is one of the most common ingredients. As a cooling herb possessing blood- and liver-tonic properties, peony has wide applications for the treatment of extravasated or stagnated blood conditions and gynecological ailments. Pharmacological studies have shown the antiallergic, anti-inflammatory, anticancer, antioxidant, immunomodulatory, and neuroprotective properties of this medicinal herb (Lee et al., 2002, 2005, 2008a,b; Xu et al., 2007). Chemical ingredients identified in this plant drug include monoterpene glycosides (such as paeoniflorin and its derivatives), tannins, and flavonoids (He et al., 2010). Among these constituents, the monoterpene glycosides are best studied, and they are usually ascribed to be the major active principles of peony (He et al., 2010).

In the practice of Chinese medicine, peony is always prescribed together with other herbs in the form of medicinal formulae (such as Sini-San and Xiaoyao-San) for the treatment of depression-like disorders, which are often diagnosed to be caused by stagnation of the liver energy (Xie & Wang, 2005; Zhang et al., 1998). As a multiherb medicinal formulation, Xiaoyao-San has been reported to show clinical effects in patients suffering from depression (Yang et al., 2007). In a proteomic study, this medicinal formula displayed protein expression patterns similar to those of St. John’s wort in the HT-22 mouse hippocampal cell line (Pennington et al., 2009). When tested in a rat model of chronic unpredictable mild stress (CUMS), the drug-treated animals displayed urinary metabolomic pattern similar to that of the normal controls (Dai et al., 2010). More recently, the petroleum ether fraction of Xiaoyao-San preparation was also reported to be active in CUMS-rats (Zhou et al., 2011).

In the past 5 years, investigations made in our laboratory not only demonstrated the anti-depressant-like effects of peony extract in stress-induced animal models of depression but also revealed some possible mechanisms mediated by multiple targets. In this paper, an overview is provided on the major findings of anti-depressant-like effects of peony and its possible mechanisms.

Anti-depressant-like effects of peony

Animal models of forced swimming and tail suspension tests have been widely used for the evaluation of antidepression activity (Porsolt et al., 1977; Steru et al., 1985). In these tests, mice are put in a stressful environment from which they cannot escape. After an initial period of struggling, they would become immobile, resembling a state of despair and mental depression. The anti-depressant effects of an ethanol extract and a glycoside-rich fraction of peony were evaluated by using these two models. It was observed that, after being treated with a peony ethanol extract at daily doses of 250 or 500 mg/kg for 7 days, the mice showed a significant shortening of the immobilization time in both forced swimming (decreased by 35.7 and 47.7%, respectively, compared with the control) and tail suspension tests (decreased by 32.1 and 45.0%, respectively) (Mao et al., 2008a). Treating the animals with the glycoside-rich fraction of peony (80 or 160 mg/kg/day) for 7 days also significantly shortened the immobilization time in both forced swimming (decreased by 29.7 and 43.2%, respectively) and tail suspension tests (decreased by 35.7 and 47.7%, respectively) as compared with the controls (Mao et al., 2008b). In a similar study, Shao et al., (2008) observed the anti-depressant effect of peony in reserpine-treated mice.

The CUMS-induced depression model is a widely used tool in antidepression research. Several studies have suggested that CUMS can induce long-term behavioral disturbances resembling the clinical symptoms observed in patients suffered from depression (Katz et al., 1981; Willner, 1997, 2005), and that the CUMS model is useful for evaluating the efficacy of anti-depressant drug candidates through behavioral tests such as the tail suspension test, sucrose preference test, and open-field test (Katz et al., 1981; Willner, 1997, 2005). In this regard, our results indicated that a 24-day CUMS exposure significantly prolonged the immobilization time of mice in the tail suspension test, while treatment with a glycoside-rich extract of peony (80 or 160 mg/kg/day) during the course of CUMS resulted in a significant reversal of the changes in immobilization time (Mao et al., 2009b). Wang et al., (2010) reported similar observations on the anti-depressant effect of peony root.

Sucrose preference test has also been employed as an indicator of anhedonia-like behavioral changes (Willner, 1997, 2005). Anhedonia, a core symptom of human major depression, can be mimicked by inducing a decrease in responsiveness to rewards reflected by a reduced consumption and/or preference of sweetened solutions. Using this model, our findings indicated that mice subjected to 6-week CUMS procedure consumed less sucrose solution when compared with nonstressed controls (Mao et al., 2009b). Long-term treatment with a glycoside-rich extract of peony (80 or 160 mg/kg/day) during the 6 weeks of CUMS exposure significantly increased sucrose consumption, as compared with the vehicle-treated CUMS-mice (Mao et al., 2009b). Similar results were obtained in another study using rats. In this study, treatment with a glycoside-rich extract of peony (80 or 160 mg/kg/day) during the 5-week period of CUMS significantly reversed the decreased CUMS-induced sucrose consumption in rats (Mao et al., 2010).

The open-field test is commonly used to assess locomotor activity. During the test, normal animals will show an increased locomotor activity in a novel open-field, driven by the instinct of exploration in a new environment (Luo et al., 2008). However, during chronic stress, animals would develop a tendency to decrease the locomotor activity in a novel open-field (Katz et al., 1981), which is indicative of a behavioral change to reflect a refractory loss of interest. In our studies, CUMS exposure for a period of 5 weeks led to a significant reduction of the number of crossings and rearing in the open-field test, which was ameliorated by the treatment with a glycoside-rich extract of peony (80 or 160 mg/kg/day) during the course of CUMS (Mao et al., 2010).

All in all, the above findings point to the suggestion that peony possesses anti-depressant-like property as indicated in stress-induced depression models both in mice and in rats.

Inhibition of MAO activity

It is well known that MAO plays an important role in the pathogenesis of depression (Wouters, 1998), and MAO inhibitors are widely used in the clinics for the treatment of the disease (Macedo et al., 2011). MAO can be classified into types A and B according to the substrate specificity (Wouters, 1998). MAO-A preferentially oxidizes noradrenaline and 5-hydroxytrytamine, whereas MAO-B preferentially oxidizes phenylethylamine. Dopamine can be metabolized by both types of MAOs. Our finding showed that treatment with the glycoside-rich extract of peony (80 or 160 mg/kg/day) for 7 days would lead to an inhibition of both MAO-A and MAO-B activities in the mouse brain tissue (Mao et al., 2009b). Further experiments are required to explore the contribution of such an activity toward anti-depressant effect of the plant drug.

Neuroprotective effects

Hippocampus is one of the brain structures of importance to emotional and cognitive functions. A recent magnetic resonance imaging study indicated that depression is closely associated with reduced hippocampal volume, and a positive correlation was established between hippocampus atrophy and the time course of depression (Li et al., 2003; Saylam et al., 2006). Postmortem analyses have also shown a reduction of neuronal cells in the hippocampus of depressive patients (Stockmeier et al., 2004). Therefore, it is generally believed that neuronal atrophy and destruction in the hippocampus play a causal role in the development and progression of depression (Fuchs et al., 2004; Manji & Duman, 2001). In addition, it has been reported that some anti-depressants possess neurotrophic and neuroprotective properties, and they were able to ameliorate impairments in cellular plasticity and resilience underlying the pathophysiology of major depressive disorders (Bachmann et al., 2005). Our unpublished results demonstrated that 5-week CUMS treatment would induce neuronal injury in the CA3 region of hippocampus of rats (shown by Nissl staining), while treatment with a glycoside-rich extract of peony (80 or 160 mg/kg/day) during the course of CUMS resulted in significant neuroprotection.

The neuroprotective effects of the glycoside-rich extract of peony was also demonstrated in vitro. In our studies, the rat adrenal pheochromocytoma (PC12) cells, which possess typical features of neurons and expresses a high level of glucocorticoid receptors, were treated with high concentrations of glucocorticoid to induce neuronal damages. The glycoside-rich extract of peony at increasing doses (1−10 mg/L) produced protective effect in corticosterone-treated PC12 cells in a dose-dependent manner (Mao et al., 2009c, 2011a).

Targeting the hypothalamic−pituitary−adrenal (HPA) axis

The HPA axis plays a key role in eliciting physiological responses to various stressful stimuli (Pan et al., 2006). It is well known that the HPA axis is activated in response to stress, with resultant increase in the circulating glucocorticoids such as corticosterone in rodents or cortisol in primates. Sustained activation of the HPA axis is associated with an abnormally high blood glucocorticoid level and an impaired glucocorticoid receptor-mediated negative feedback, which may eventually lead to pathological conditions such as depression (Johnson et al., 2006; Pan et al., 2006; Watson & Mackin, 2006). In this connection, it has been reported that the therapeutic actions of anti-depressants are produced through the intermediacy of HPA axis in depressive patients (Himmerich et al., 2007; Schüle et al., 2006). Thus, the restoration of a normal functional status of the HPA axis may be critically involved in the therapeutic intervention (Pan et al., 2006). Our findings showed that the beneficial effect of the glycoside-rich extract of peony (80 or 160 mg/kg/day) on 6-week CUMS-induced depressive behaviors was paralleled by the attenuation of HPA hyperactivity, as indicated by an inhibition of the serum corticosterone level and increasing hippocampal glucocorticoid receptor messenger RNA (mRNA) expression (Mao et al., 2009a).

Increasing neurotrophins expression

Neurotrophins are a family of proteins, which modulate neuronal plasticity, inhibit cell death cascades, and increase cell survival proteins that are responsible for the proliferation and maintenance of neurons (Huang & Reichardt, 2001). Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are the most abundant neurotrophins in the central nervous system. Interestingly, both neurotrophins have been postulated to involve in the pathophysiology of stress-related behavior and depression (Angelucci et al., 2003; Lang et al., 2004a,b; Nestler et al., 2002; von Richthofen et al., 2003). Furthermore, several studies have demonstrated that anti-depressant treatments might exert beneficial actions by regulating the synthesis and/or release of BDNF or NGF in the hippocampus and the cortex (Angelucci et al., 2003; Li et al., 2007; Song et al., 2006; Xu et al., 2006). In this respect, we were able to demonstrate that BDNF and NGF are indeed involved in the anti-depressant-like action of the glycoside-rich extract of peony (Mao et al., 2009a, 2010). Thus, the BDNF mRNA levels were decreased in the hippocampus and the cortex of mice after exposure to 6-week CUMS procedures, and treatment with a glycoside-rich extract of peony (80 or 160 mg/kg/day) significantly reversed the CUMS-induced changes (Mao et al., 2009a). Similar results were observed in the 5-week CUMS-induced depression model in rats. Treatment with the glycoside-rich extract of peony (80 or 160 mg/kg/day) not only reversed the CUMS-induced depressive-like behavior but also increased the BDNF protein and mRNA levels in the hippocampus and the cortex of rats (Mao et al., 2010). Furthermore, it was found that daily intragastric administration of the glycoside-rich extract (160 mg/kg/day) during the 5 weeks of CUMS significantly restored the decreased NGF protein and mRNA levels in rat cortex (Mao et al., 2010).

Antioxidant actions

Oxidative stress, defined as a disturbance in the balance between the production of reactive oxygen species (ROS) and antioxidant defenses, is believed to play a role in the pathogenesis of neuropsychiatric disorders (Bilici et al., 2001; Khanzode et al., 2003). Excessive ROS production can cause oxidative damages to macromolecules such as lipids, proteins, and DNA (Zhao et al., 2008), culminating in neuronal dysfunction and depression (Fuchs et al., 2004; Manji & Duman, 2001). On the other hand, biological antioxidants are natural compounds, which can prevent the excessive formation of free radicals and activated oxygen species, or inhibit their reaction with the biological structures. These compounds include antioxidative enzymes, such as superoxide dismutase (SOD) and catalase (CAT), and nonenzymatic antioxidants, such as glutathione (GSH) (Yazdanparast et al., 2008). The efficiency of such an antioxidant defense system is apparently weakened in depressive disorders resulting in an ineffective scavenging of the free radicals, which eventually leads to tissue damages (Bilici et al., 2001; Khanzode et al., 2003). Our findings showed that a 24-day CUMS would lead to an oxidative stress in mice, as indicated by the depletion of GSH and an increase in malondialdehyde (MDA) (i.e. lipid peroxidation) levels in the brain, while treatment with the glycoside-rich extract of peony (80 or 160 mg/kg/day) during the course of CUMS significantly reversed the biochemical changes (Mao et al., 2009b). In another study, a protective effect of the glycoside-rich extract on corticosterone-induced neurotoxicity in PC12 cells was found to be associated with a decrease in the intracellular ROS and MDA levels, as well as an increase in the GSH level, SOD activity, and CAT activity (Mao et al., 2011a). An extract of peony has also been reported to protect PC12 cells from H₂O₂-indcued cell death and apoptosis (Lee et al., 2008b). The glycoside-rich extract of peony was also found to display antioxidant properties in the cell-free 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid radical cation-scavenging assay, the IC50 value being 9.9 mg/L (Mao et al., 2011a). The above results suggest that the anti-depressant-like effect of the glycoside-rich extract of peony is likely to be related to its antioxidant action.

Active anti-depressant principles of peony

Among the secondary metabolites of peony, paeonol has been reported to be active in both tail suspension and forced swimming tests (Zhu et al., 2006). The compound was further demonstrated to be able to protect PC12 cells from lesions induced by corticosterone (Zhu et al., 2006), and the protective activity may be related to its antioxidation property (Zhong et al., 2009a). On the other hand, paeoniflorin has also been shown to possess neuroprotective property against N-methyl-d-aspartate-induced toxicity (Mao et al., 2011b) and MPP-induced toxicity (Cao et al., 2010) in PC12 cells, as well as Abeta-mediated neurotoxicity in rats (Zhong et al., 2009b). Recently, both paeoniflorin and albiflorin were suggested to be clinically useful for the prevention and treatment of depression (Zhu et al., 2009; Zhang 2011a,b). However, no scientific evidence has yet been established to support such claims.

Conclusions

Clearly, in vitro and in vivo evidence is available in the literature to indicate an anti-depressant-like property of peony, which is likely mediated by multiple targets, including the inhibition of MAO activity, neuro-protection, modulation of the HPA axis, inhibition of oxidative stress, and the up-regulation of neurotrophins. Although available information seems to be supportive of the potential application of peony for treating depression, further studies are warranted to reveal the molecular mechanisms of action, to evaluate the pharmacokinetics, to establish the toxicological profile, and to assess its clinical efficacy. Identification of the clinically active ingredient(s) of peony is also warranted.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.