Elsevier

Journal of Ethnopharmacology

Volume 199, 6 March 2017, Pages 9-19
Journal of Ethnopharmacology

Piper sarmentosum Roxb. produces antidepressant-like effects in rodents, associated with activation of the CREB-BDNF-ERK signaling pathway and reversal of HPA axis hyperactivity

https://doi.org/10.1016/j.jep.2017.01.037Get rights and content

Abstract

Ethnopharmacological relevance

There are many plants of genus Piper which have been reported to induce antidepressant-like effects, Piper sarmentosum (PS) is one of them. PS is a Chinese herbal medicine and a traditional edible vegetable.

Materials and methods

In the present study, the antidepressant-like effects of PS extracts and the ethyl acetate fraction of PS extracts (PSY) were assessed using the open field test (OFT), forced swimming test (FST), and tail suspension test (TST) in mice. Furthermore, we applied a 4 consecutive weeks of chronic unpredictable mild stress (CUMS) as a model of depression in rats, followed by a sucrose preference test. Then we examined the possible mechanisms of this action. The activity of the hypothalamic–pituitary–adrenal (HPA) axis was evaluated by detecting the serum corticosterone (CORT) concentrations, and the protein expression levels of brain-derived neurotrophic factor (BDNF), the phosphorylated form CREB and ERK1/2 were detected by qRT-PCR or Western blot.

Results

The results showed that PS extracts (100, 200 mg/kg) and PSY (12.5, 25, 50 mg/kg) treatment produced antidepressant-like effects in mice similar to fluoxetine (20 mg/kg), indicated by the reduced immobility time in the FST and TST, while both had no influence on the locomotor activity in the OFT. PSY treatment significantly increased sucrose preference and reduced serum CORT levels in CUMS rats. Moreover, PSY up-regulated BDNF protein levels, and increased CREB and ERK phosphorylation levels in the hippocampus on CUMS rats.

Conclusions

These findings suggest that the antidepressant-like effects of PS extracts and PSY are mediated, at least in part, by modulating HPA axis, BDNF, CREB and ERK phosphorylation and expression in the hippocampus.

Graphical abstract

Piper sarmentosum Roxb. produces antidepressant-like effects in rodents, associated with activation of the CREB-BDNF-ERK signalling pathway and reversal of HPA axis hyperactivity.

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Introduction

Depression is a syndrome of abnormal mood and a widespread mental disorder with a lifetime prevalence of 16.2% (Kessler et al., 2003). Despite decades of clinical experience, the definite mechanism underlying depression development is still poorly understood. Nowadays, the current antidepressants used clinically are chemical synthetic compounds with significant side effects and have low rates of remission and response (Sarko, 2000). Thus, better antidepressants with higher efficacy and safety are urgently needed. At present, numerous herbal medicines with antidepressant effects have become the focus of attention for the treatment of depression because the natural plant extracts have higher safety, such as Hypericum perforatum L. (HP, also called St John's Wort), which is a worldwide well-known herbal antidepressant (Sarris et al., 2011), and the randomized clinical studies have shown that HP extracts are significantly superior to placebo (Lecrubier et al., 2002) and have similarly effects as standard antidepressants (Szegedi et al., 2005) in the treatment of depression. Several human clinical trials have also provided preliminary positive evidence of antidepressant effects of some herbs, such as Echiumamoenum, Crocus sativus, Rhodiolarosea and Piper methysticum (Sarris et al., 2011). Therefore, herbal medicines have become a compelling part of pharmacotherapy in the treatment of depression (Thachil et al., 2007).

The genus Piper is an important member of the family–Piperaceae in medicine, consisting of about 2000 species and approximately 60 species are distributed in the tropical areas of China. However, several recent researches have indicated that some plants of genus Piper, for instance, Piper methysticum (Sarris et al., 2011) (commonly known as Kava–Kava), Piper laetispicum C.DC. (Xie et al., 2011) and Piper sarmentosum (PS) (Wu, 2002) have antidepressant effects. Kava-Kava used to be a popular antidepressant used all around the world, but is now banned because of hepatotoxicity (Teschke et al., 2009). PS, one of the genus Piper plants distributed in the India, Vietnam, Indonesia, Philippines, Malaysia and southern part of China, such as Yunnan, Guangxi, Fujian, and Hainan Province. It is reported that PS has biological activities, including: antioxidant (Ugusman et al., 2010), anti–tuberculosis (Hussain et al., 2008), anti–atherosclerosis (Amran et al., 2011), fracture healing (Estai et al., 2011), osteoporotic (Ramli et al., 2013). In China, it has been used for treating toothache, beriberi, and abdominal distension by the local population (SATCM, 1999). PS also plays an important role in dealing with insomnia, anxiety and depression by indigene in the minority national areas of Yunnan, China (Huang et al., 2005). The local people grind the steam and leaf of PS into a powder, then they soak the powder into Chinese liquor for a month. It is reported that indigene treat insomnia, anxiety and depression by drinking such liquor. Moreover, it is worth mentioning that, PS plays an important role as a traditional edible vegetable in the southern part of China (Zheng et al., 2013) suggesting low toxicity.

Several researches have indicated a critical role of monoaminergic hypothesis in the response to depression and modulation of stress (Hou et al., 2006). However, clinical experience over the years indicates that not all patients respond to existing monoamine–based antidepressants (Cassano and Fava, 2004, Trivedi et al., 2006). This suggests that the reduction in monoamine levels might not be the only pathogenic mechanism of depression. So, in recent years, investigations have focused on non–monoamine–based antidepressants (Berton and Nestler, 2006). A leading hypothesis of depression which has received a lot of attention is that the hyperactivity of hypothalamic–pituitary–adrenal (HPA) axis plays an important role in response to stress (Hofman and Swaab, 2010). It is well known that the corticosterone (CORT) level in blood rise during persistently stressful situation or depression (Sapolsky, 2000). Besides the hypothesis of HPA, numbers of studies suggest that neurotrophic factors and adult neurogenesis also play an important role in mediating the responses to antidepressants (Krishnan and Nestler, 2008). The brain- derived neurotrophic factor (BDNF) has been demonstrated to have significant involvement in the modification of the hippocampus due to stress-causing stimuli (Nestler et al., 2002), and its overexpression elicits cellular and behavioral effects of antidepressant treatments (Shirayama et al., 2002). It has also been known that cAMP response element-binding protein (CREB) is a transcription factor that mediates gene expressions activated by cAMP cascade, CREB mediates neurogenesis, survival of neurons, and response to antidepressant-like effects (Duman et al., 2000). Antidepressant drugs counteract the cascade of cAMP–CREB in the pathophysiology of depression (Gass and Riva, 2007), and CREB has been suggested to be a potential molecular mechanism of antidepressants that maintains a balance to stressful disturbance by phosphorylation of CREB (pCREB) (Kwon et al., 2008). In addition, it has been demonstrated that CREB acts as an upstream transcription factor of BDNF and permits a transcriptional alternation in BDNF expression following antidepressant treatment (Conti et al., 2002). ERK (extracellular signal-regulated kinase) is one of the most-researched member of the MAPK (mitogen-activated protein kinase) family, and in previous studies it has been suggested that the ERK may take part in the molecular mechanism of depression (Qi et al., 2006). Moreover, ERK pathway is a down stream signal transduction protein activated by BDNF (Mebratu and Tesfaigzi, 2009) and the antidepressant treatment can induce the phosphorylation of ERK (phospho-ERK1/2, p-ERK1/2) (Mattson et al., 2004). Taken together, these results indicate that BDNF, CREB and ERK could be potential molecular targets in the treatment of depression.

In this study, we explored the antidepressant-like effect of PS, and its behavioral effects in mice were evaluated in the open field test (OFT), forced swim test (FST) and tail suspension test (TST). This was followed by a CUMS (chronic unpredictable mild stress) model to establish a depression situation followed by sucrose preference test. Furthermore, serum corticosterone, BDNF protein levels, and the phosphorylated levels of CREB and ERK were also assessed in the hippocampus of rats to investigate the potential mechanisms of action.

Section snippets

Animals and overall experimental plan

Male ICR (Institute of Cancer Research) mice weighing between 18 and 22 g and male SD (Sprague Dawley) rats weighing between 230 and 260 g were obtained from Second Military Medical University (SMMU) Animal Center. The animals were housed under standard conditions (12 h light/dark cycle; 24–26 ℃ ambient temperature; 55±10% relative humidity) for one week with free access to food and water. All experimental procedures were approved by the Animal Care and Use Committee at SMMU and complied with the

Antidepressant-like effects of PS extracts in the FST and TST in mice

In the FST, the results showed that PS extracts produced a strong antidepressant-like effect as well as fluoxetine (Fig. 2A). The data were analyzed by a one-way ANOVA with drug treatment as the factor and revealed a significant effect of drug treatment (F[4,45]=26.325, P<0.001). Subsequent LSD as post hoc analysis indicated that doses of PS extracts from 50 to 200 mg/kg decreased the immobility time in the FST in a dose-dependent manner, as immobility time was significantly reduced at the dose

Discussion

In our present study, we have demonstrated that PS and PSY produced powerful antidepressant-like effects in animal depression models, with comparable profiles to that observed for the established antidepressants, fluoxetine and HP. The results showed that administration of PS and PSY reduced immobility time in FST and TST, without the effect on spontaneous locomotor which was proved in OFT. PSY administration alleviated the depression-like behavior caused by CUMS, as indicated by an increased

Contributors

Prof. Lu-Ping Qin and Prof. Ting Han designed the study, and wrote the protocol and the first draft of the manuscript. Yue Gao managed the literature searches. Qing Li performed animal model experiments and managed the statistical analyses. Fa-Lin Qu performed the gene expression experiments. Yi-Ping Jiang, Khalid Rahman and Kuo-Hsiung Lee wrote parts of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

This work was supported by the Science & Technology Pillar Program in TCM (traditional Chinese medicine) of Science & Technology Commission of Shanghai (14401902900) and The Youth Breeding Project in Medical Science of the Whole Army (13QNP098). These institutions had no role in the study design, the collection, analysis, or interpretation of the data, the writing of the report, or the decision to submit the paper for publication. The authors gratefully acknowledge Dr. Xiong-Yu Meng and Dr.

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