Metabolic Brain Disease

, Volume 31, Issue 4, pp 837–848 | Cite as

Piperine potentiates the effects of trans-resveratrol on stress-induced depressive-like behavior: involvement of monoaminergic system and cAMP-dependent pathway

  • Ying Xu
  • Chong Zhang
  • Feiyan Wu
  • Xiaoxiao Xu
  • Gang Wang
  • Mengmeng Lin
  • Yingcong Yu
  • Yiran An
  • Jianchun Pan
Original Article


Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans-resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive-like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60 % inhibition at the highest dose tested, 40 mg/kg. However, when a subthreshold dose of piperine, 2.5 mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans-resveratrol in reducing the immobility time was reduced to 20 mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress.


Trans-resveratrol Piperine Forced swimming Depression Monoamine cAMP signaling 



This project was supported by Medicine and Health Science and Technology Plan Projects in Zhejiang Province (No. 2012KYA151) and Natural Science Foundation of Zhejiang Province (No. LY15H090003) for Dr. G. Wang, the Natural Science Foundation of Zhejiang Province for Dr. J.C. Pan (No. ZD2O1413), and the National Natural Science Foundation for the Youth (NSFY 81400600) for Dr. Y.C. Yu.


  1. Ali SH, Madhana RM, K V A et al (2015) Resveratrol ameliorates depressive-like behavior in repeated corticosterone-induced depression in mice. Steroids 101:37–42PubMedCrossRefGoogle Scholar
  2. Altar CA, Whitehead RE, Chen R et al (2003) Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 54(7):703–709PubMedCrossRefGoogle Scholar
  3. Atal CK, Dubey RK, Singh J (1985) Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. J Pharmacol Exp Ther 232(1):258–262PubMedGoogle Scholar
  4. Bai Y, Mao QQ, Qin J et al (2010) Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo. Cancer Sci 101(2):488–493PubMedCrossRefGoogle Scholar
  5. Bhutani MK, Bishnoi M, Kulkarni SK (2009) Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes. Pharmacol Biochem Behav 92(1):39–43PubMedCrossRefGoogle Scholar
  6. Bidzinska EJ (1984) Stress factors in affective diseases. Br J Psychiatry 144:161–166PubMedCrossRefGoogle Scholar
  7. Blendy JA (2006) The role of CREB in depression and antidepressant treatment. Biol Psychiatry 59(12):1144–1150PubMedCrossRefGoogle Scholar
  8. Blier P, Ward NM (2003) Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 53(3):193–203PubMedCrossRefGoogle Scholar
  9. Bourin M, David DJ, Jolliet P et al (2002) Mechanism of action of antidepressants and therapeutic perspectives. Therapie 57(4):385–396PubMedGoogle Scholar
  10. Bourin M, Mocaer E, Porsolt R (2004) Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors. J Psychiatry Neurosci 29(2):126–133PubMedPubMedCentralGoogle Scholar
  11. Chakrabarti SK, Loua KM, Bai C et al (1998) Modulation of monoamine oxidase activity in different brain regions and platelets following exposure of rats to methylmercury. Neurotoxicol Teratol 20(2):161–168PubMedCrossRefGoogle Scholar
  12. Conti AC, Cryan JF, Dalvi A et al (2002) cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs. J Neurosci 22(8):3262–3268PubMedGoogle Scholar
  13. Daszuta A, Ban M Sr et al (2005) Depression and neuroplasticity: implication of serotoninergic systems. Therapie 60(5):461–468PubMedCrossRefGoogle Scholar
  14. De Foubert G, Carney SL, Robinson CS et al (2004) Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. Neuroscience 128(3):597–604PubMedCrossRefGoogle Scholar
  15. Dhingra D, Sharma A (2006) Antidepressant-like activi.ty of n-hexane extract of nutmeg (Myristica fragrans) seeds in mice. J Med Food 9(1):84–89PubMedCrossRefGoogle Scholar
  16. Dias BG, Banerjee SB, Duman RS et al (2003) Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology 45(4):553–563PubMedCrossRefGoogle Scholar
  17. Duman RS (2004) Depression: a case of neuronal life and death? Biol Psychiatry 56(3):140–145PubMedCrossRefGoogle Scholar
  18. Duman RS, Malberg J, Nakagawa S et al (2000) Neuronal plasticity and survival in mood disorders. Biol Psychiatry 48(8):732–739PubMedCrossRefGoogle Scholar
  19. Grippo AJ, Moffitt JA, Johnson AK (2008) Evaluation of baroreceptor reflex function in the chronic mild stress rodent model of depression. Psychosom Med 70(4):435–443PubMedPubMedCentralCrossRefGoogle Scholar
  20. Hines LM, Tabakoff B (2005) Platelet adenylyl cyclase activity: a biological marker for major depression and recent drug use. Biol Psychiatry 58(12):955–962PubMedCrossRefGoogle Scholar
  21. Hu Y, Liao HB, Liu P et al (2009) Antidepressant effects of piperine and its neuroprotective mechanism in rats. Zhong Xi Yi Jie He Xue Bao 7(7):667–670PubMedCrossRefGoogle Scholar
  22. Huang W, Chen Z, Wang Q et al (2013) Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system. Metab Brain Dis 28(4):585–595PubMedCrossRefGoogle Scholar
  23. Hurley LL, Akinfiresoye L, Kalejaiye O et al (2014) Antidepressant effects of resveratrol in an animal model of depression. Behav Brain Res 268:1–7PubMedCrossRefGoogle Scholar
  24. Ivy AS, Rodriguez FG, Garcia C et al (2003) Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Behav 75(1):81–88PubMedCrossRefGoogle Scholar
  25. Johnson JJ, Nihal M, Siddiqui IA, Scarlett CO, Bailey HH, Mukhtar H, Ahmad N (2011) Enhancing the bioavailability of resveratrol by combining it with piperine. Nutr Food Res 55:169–176Google Scholar
  26. Katoh-Semba R, Asano T, Ueda H et al (2002) Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. Faseb J 16(10):1328–1330PubMedGoogle Scholar
  27. Kioukia-Fougia N, Antoniou K, Bekris S et al (2002) The effects of stress exposure on the hypothalamic-pituitary-adrenal axis, thymus, thyroid hormones and glucose levels. Prog Neuropsychopharmacol Biol Psychiatry 26(5):823–830PubMedCrossRefGoogle Scholar
  28. Kuipers SD, Bramham CR (2006) Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy. Curr Opin Drug Discov Devel 9(5):580–586PubMedGoogle Scholar
  29. Kumar A, Naidu PS, Seghal N et al (2007) Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats. Pharmacology 79(1):17–26PubMedCrossRefGoogle Scholar
  30. Kwon KJ, Kim HJ, Shin CY et al (2010) Melatonin potentiates the neuroprotective properties of resveratrol against beta-amyloid-induced neurodegeneration by modulating AMP-Activated protein kinase pathways. J Clin Neurol 6(3):127–137PubMedPubMedCentralCrossRefGoogle Scholar
  31. Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82(6):1367–1375PubMedCrossRefGoogle Scholar
  32. Lee SA, Hong SS, Han XH et al (2005) Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity. Chem Pharm Bull (Tokyo) 53(7):832–835CrossRefGoogle Scholar
  33. Li S, Wang C, Wang M et al (2007) Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms. Life Sci 80(15):1373–1381PubMedCrossRefGoogle Scholar
  34. Li G, Ruan L, Chen R et al (2015) Synergistic antidepressant-like effect of ferulic acid in combination with piperine: involvement of monoaminergic system. Metab Brain Dis 30(6):1505–1514PubMedCrossRefGoogle Scholar
  35. Lin YH, Liu AH, Xu Y et al (2005) Effect of chronic unpredictable mild stress on brain-pancreas relative protein in rat brain and pancreas. Behav Brain Res 165(1):63–71PubMedCrossRefGoogle Scholar
  36. Mamounas LA, Blue ME, Siuciak JA et al (1995) Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci 15(12):7929–7939PubMedGoogle Scholar
  37. Mao QQ, Huang Z, Zhong XM et al (2014a) Piperine reverses chronic unpredictable mild stress-induced behavioral and biochemical alterations in rats. Cell Mol Neurobiol 34(3):403–408PubMedCrossRefGoogle Scholar
  38. Mao QQ, Huang Z, Zhong XM et al (2014b) Brain-derived neurotrophic factor signalling mediates the antidepressant-like effect of piperine in chronically stressed mice. Behav Brain Res 261:140–145PubMedCrossRefGoogle Scholar
  39. Mattson MP, Maudsley S, Martin B (2004) BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27(10):589–594PubMedCrossRefGoogle Scholar
  40. Mazzio EA, Harris N, Soliman KF (1998) Food constituents attenuate monoamine oxidase activity and peroxide levels in C6 astrocyte cells. Planta Med 64(7):603–606PubMedCrossRefGoogle Scholar
  41. McEwen BS (2005) Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54(5 Suppl 1):20–23PubMedCrossRefGoogle Scholar
  42. Mitani H, Shirayama Y, Yamada T et al (2006) Plasma levels of homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 30(3):531–534PubMedCrossRefGoogle Scholar
  43. Molina VA, Volosin M, Cancela L et al (1990) Effect of chronic variable stress on monoamine receptors: influence of imipramine administration. Pharmacol Biochem Behav 35(2):335–340PubMedCrossRefGoogle Scholar
  44. Molteni R, Calabrese F, Bedogni F et al (2006) Chronic treatment with fluoxetine up-regulates cellular BDNF mRNA expression in rat dopaminergic regions. Int J Neuropsychopharmacol 9(3):307–317PubMedCrossRefGoogle Scholar
  45. Mostert JP, Koch MW, Heerings M et al (2008) Therapeutic potential of fluoxetine in neurological disorders. CNS Neurosci Ther 14(2):153–164PubMedCrossRefGoogle Scholar
  46. Murua VS, Gomez RA, Andrea ME et al (1991) Shuttle-box deficits induced by chronic variable stress: reversal by imipramine administration. Pharmacol Biochem Behav 38(1):125–130PubMedCrossRefGoogle Scholar
  47. Nemeroff CB (2007) The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J Psychiatr Res 41:189–206PubMedCrossRefGoogle Scholar
  48. Pencea V, Bingaman KD, Wiegand SJ et al (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21(17):6706–6717PubMedGoogle Scholar
  49. Ranney A, Petro MS (2009) Resveratrol protects spatial learning in middle-aged C57BL/6 mice from effects of ethanol. Behav Pharmacol 20(4):330–336PubMedCrossRefGoogle Scholar
  50. Reagan LP, Hendry RM, Reznikov LR et al (2007) Tianeptine increases brain-derived neurotrophic factor expression in the rat amygdala. Eur J Pharmacol 565(1–3):68–75PubMedCrossRefGoogle Scholar
  51. Shirayama Y, Chen AC, Nakagawa S et al (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22(8):3251–3261PubMedGoogle Scholar
  52. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS (1995) Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 64(4):353–356 Google Scholar
  53. Southwick SM, Vythilingam M, Charney DS (2005) The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol 1:255–291PubMedCrossRefGoogle Scholar
  54. Spreux-Varoquaux O, Alvarez JC, Berlin I et al (2001) Differential abnormalities in plasma 5-HIAA and platelet serotonin concentrations in violent suicide attempters: relationships with impulsivity and depression. Life Sci 69(6):647–657PubMedCrossRefGoogle Scholar
  55. Thachil AF, Mohan R, Bhugra D (2007) The evidence base of complementary and alternative therapies in depression. J Affect Disord 97(1–3):23–35PubMedCrossRefGoogle Scholar
  56. Thiyagarajan M, Sharma SS (2004) Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci 74(8):969–985PubMedCrossRefGoogle Scholar
  57. Thome J, Sakai N, Shin K et al (2000) cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20(11):4030–4036PubMedGoogle Scholar
  58. Trivedi MH, Pigotti TA, Perera P et al (2004) Effectiveness of low doses of paroxetine controlled release in the treatment of major depressive disorder. J Clin Psychiatry 65(10):1356–1364PubMedCrossRefGoogle Scholar
  59. Vanamala J, Reddivari L, Radhakrishnan S et al (2010) Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer 10:238PubMedPubMedCentralCrossRefGoogle Scholar
  60. Vollmayr B, Faust H, Lewicka S et al (2001) Brain-derived-neurotrophic-factor (BDNF) stress response in rats bred for learned helplessness. Mol Psychiatry 6(4):471–474, 358 PubMedCrossRefGoogle Scholar
  61. Wang R, Li YB, Li YH et al (2008) Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic factor level and activating TrkB. Brain Res 1210:84–91PubMedCrossRefGoogle Scholar
  62. Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacol (Berl) 134(4):319–329CrossRefGoogle Scholar
  63. Xu Y, Ku BS, Yao HY et al (2005) Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Pharmacol Biochem Behav 82(1):200–206PubMedCrossRefGoogle Scholar
  64. Xu Y, Ku B, Tie L et al (2006) Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res 1122(1):56–64PubMedCrossRefGoogle Scholar
  65. Xu Y, Li S, Chen R et al (2010a) Antidepressant-like effect of low molecular proanthocyanidin in mice: involvement of monoaminergic system. Pharmacol Biochem Behav 94(3):447–453PubMedCrossRefGoogle Scholar
  66. Xu Y, Wang Z, You W et al (2010b) Antidepressant-like effect of trans-resveratrol: Involvement of serotonin and noradrenaline system. Eur Neuropsychopharmacol 20(6):405–413PubMedCrossRefGoogle Scholar
  67. Yu ZF, Kong LD, Chen Y (2002) Antidepressant activity of aqueous extracts of Curcuma longa in mice. J Ethnopharmacol 83:161–165PubMedCrossRefGoogle Scholar
  68. Zhang ZJ (2004) Therapeutic effects of herbal extracts and constituents in animal models of psychiatric disorders. Life Sci 75(14):1659–1699PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ying Xu
    • 1
    • 2
  • Chong Zhang
    • 2
  • Feiyan Wu
    • 1
  • Xiaoxiao Xu
    • 1
  • Gang Wang
    • 3
  • Mengmeng Lin
    • 1
  • Yingcong Yu
    • 1
    • 4
  • Yiran An
    • 5
  • Jianchun Pan
    • 1
  1. 1.Brain Institute, School of PharmacyWenzhou Medical UniversityWenzhouChina
  2. 2.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesState University of New York at BuffaloBuffaloUSA
  3. 3.Department of Clinical PharmacyHangzhou First People’s HospitalHangzhouChina
  4. 4.Wenzhou Third Clinical Institute affiliated to Wenzhou Medical UniversityWenzhou People’s HospitalWenzhouChina
  5. 5.University of PittsburghPittsburghUSA

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