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
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.
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.
References (72)
- et al.
Regulation of hippocampal gene expression is conserved in two species subjected to different stressors and antidepressant treatments
Biol. Psychiatry
(2006) - et al.
Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes
Pharmacol. Biochem. Behav.
(2009) - et al.
TORCs: transducers of regulated CREB activity
Mol. Cell
(2003) - et al.
From synapse to nucleus: novel targets for treating depression
Neuropharmacology
(2010) - et al.
The neurobiology of anhedonia and other reward-related deficits
Trends Neurosci.
(2012) - et al.
Hippocampal neurogenesis: regulation by stress and antidepressants
Biol. Psychiatry
(2006) - et al.
Neuronal plasticity and survival in mood disorders
Biol. Psychiatry
(2000) - et al.
A synthetic biology project–developing a single-molecule device for screening drug–target interactions
FEBS Lett.
(2012) - et al.
Chronic mild stress and sucrose consumption: validity as a model of depression
Physiol. Behav.
(1996) - et al.
Increased limbic phosphorylated extracellular-regulated kinase 1 and 2 expression after chronic stress is reduced by cyclic 17β-estradiol administration
Neuroscience
(2006)
Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression
Biol. Psychiatry
The involvement of ERK/CREB/Bcl-2 in depression-like behavior in prenatally stressed offspring rats
Brain Res. Bull.
Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial
Lancet
CSF serotonin, 5-hydroxyindolacetic acid and neuropeptide Y levels in severe major depressive disorder
Brain Res.
The differential effects of emotional or physical stress on pain behaviors or on c-Fos immunoreactivity in paraventricular nucleus or arcuate nucleus
Brain Res.
Disrupted MEK/ERK signaling in the medial orbital cortex and dorsal endopiriform nuclei of the prefrontal cortex in a chronic restraint stress mouse model of depression
Neurosci. Lett.
Antidepressant-like effects of tea polyphenols on mouse model of chronic unpredictable mild stress
Pharmacol. Biochem. Behav.
Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method
Methods
Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress
Brain Res. Bull.
A neural signaling triumvirate that influences ageing and age-related disease: insulin/igf-1, BDNF and serotonin
Ageing Res. Rev.
From magic bullets to designed multiple ligands
Drug Discov. Today
Neurobiology of depression
Neuron
Behavioural despair in rats: a new model sensitive to antidepressant treatments
Eur. J. Pharmacol.
Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress
Neurobiol. Dis.
The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress
Behav. Brain Res.
Multicomponent phytotherapeutic approach gaining momentum: is the “one drug to fit all” model breaking down?
Phytomedicine
Antidepressants, old and new: a review of their adverse effects and toxicity in overdose
Emerg. Med. Clin. North Am.
Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence
Eur. Neuropsychopharmacol.
The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression
Eur. Neuropsychopharmacol.
The stress system in the human brain in depression and neurodegeneration
Ageing Res. Rev.
Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism
Neuron
Kava hepatotoxicity: comparison of aqueous, ethanolic, acetonic kava extracts and kava–herbs mixtures
J. Ethnopharmacol.
The evidence base of complementary and alternative therapies in depression
J. Affect. Disord.
Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy
Exp. Neurol.
Piper sarmentosum increases nitric oxide production in oxidative stress: a study on human umbilical vein endothelial cells
Clinics
Chronic mild stress-induced anhedonia: a realistic animal model of depression
Neurosci. Biobehav. Rev.
Cited by (29)
Saffron essential oil ameliorates CUMS-induced depression-like behavior in mice via the MAPK-CREB1-BDNF signaling pathway
2023, Journal of EthnopharmacologyRole of the cAMP–PKA–CREB–BDNF pathway in abnormal behaviours of serotonin transporter knockout mice
2022, Behavioural Brain ResearchCitation Excerpt :People with low 5-HT levels usually have downregulated BDNF levels; for example, BDNF levels in serum, plasma and hippocampus of depressed patients were significantly lower than those of normal population [68,69]. Studies have found that the antidepressant effects of some medicine were related to the activation of the BDNF pathway [70,71] and vice versa. In our study, the cAMP–PKA–CREB–BDNF pathway of homozygous 5-HTT knockout mice was downregulated, proving that neurotrophic factors play an important role in the occurrence and treatment of affective disorders [72].
Piper sarmentosum Roxb.: A review on its botany, traditional uses, phytochemistry, and pharmacological activities
2020, Journal of EthnopharmacologyDL0410 attenuates oxidative stress and neuroinflammation via BDNF/TrkB/ERK/CREB and Nrf2/HO-1 activation
2020, International ImmunopharmacologyCitation Excerpt :Some people develop dementia every three seconds and the annual cost of dementia is currently estimated to be $1trillion, a figure will double by 2030 [3]. Although there have been decades of clinical research experience on AD, the exact mechanism of its progression and development remains deficiently known [4]. Amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) have been undoubtedly considered to be the main causes of AD pathogenesis for years [5].
Protoilludane sesquiterpenoid aromatic esters from Armillaria mellea improve depressive-like behavior induced by chronic unpredictable mild stress in mice
2020, Journal of Functional FoodsCitation Excerpt :CREB is activated by phosphorylation, while active CREB is involved in neuronal plasticity and neurogenesis. Abnormal CREB signaling is related to the pathological condition of depression, so up-regulating the CREB pathway is beneficial for depression (Li, 2017; Tyler, 2002). This study found that PSAM could reverse the decrease of CUMS-induced BDNF levels and CREB phosphorylation levels.
- 1
These authors contributed equally to this research.