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Metabolic Brain Disease

, Volume 30, Issue 1, pp 47–55 | Cite as

The effect of curcumin on the brain-gut axis in rat model of irritable bowel syndrome: involvement of 5-HT-dependent signaling

  • Yingcong Yu
  • Shujuan Wu
  • Jianxin Li
  • Renye Wang
  • Xupei Xie
  • Xuefeng Yu
  • Jianchun Pan
  • Ying Xu
  • Liang Zheng
Research Article

Abstract

Irritable bowel syndrome (IBS) is induced by dysfunction of central nervous and peripheral intestinal systems, which affects an estimated 10–15 % population worldwide annually. Stress-related psychiatric disorders including depression and anxiety are often comorbid with gastrointestinal function disorder, such as IBS. However, the mechanism of IBS still remains unknown. Curcumin is a biologically active phytochemical presents in turmeric and has pharmacological actions that benefit patients with depression and anxiety. Our study found that IBS rats showed depression- and anxiety-like behaviors associated with decreased 5-HT (serotonin), BDNF (Brain-derived neurotrophic factor) and pCREB (phosphorylation of cAMP response element-binding protein) expression in the hippocampus after chronic acute combining stress (CAS). However, these decreased parameters were obviously increased in the colonic after CAS. Curcumin (40 mg/kg) reduced the immobility time of forced swimming and the number of buried marbles in behavioral tests of CAS rats. Curcumin also decreased the number of fecal output and abdominal withdrawal reflex (AWR) scores in response to graded distention. Moreover, curcumin increased serotonin, BDNF and pCREB levels in the hippocampus, but they were decreased in the colonic of CAS rats. 5-HT1A receptor antagonist NAN-190 reversed the effects of curcumin on behaviors and the changes of intestine, pCREB and BDNF expression, which are related to IBS. These results suggested that curcumin exerts the effects on IBS through regulating neurotransmitters, BDNF and CREB signaling both in the brain and peripheral intestinal system.

Keywords

Irritable bowel syndrome Brain-gut axis Depression 5-HT BDNF CREB 

Notes

Acknowledgments

The authors do not have financial or personal conflicts of interest associated with this work.

The project was sponsored by the foundation of Science Technology Department of Zhejiang Province (No. 2012C33118) and Natural Science and Technology Foundation of Zhejiang Province (No. Y2110896).

References

  1. Abdul-Baki H, El Ihab I, Hajj LEZ, Azar C, Aoun E, Skoury A, Chaar H, Sharara AI (2009) A randomized controlled trial of imipramine in patients with irritable bowel syndrome. World J Gastroenterol 15:3636–3642PubMedCentralPubMedCrossRefGoogle Scholar
  2. Al-Chaer ED, Kawasaki M, Pasricha PJ (2000) A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology 119:1276–1285PubMedCrossRefGoogle Scholar
  3. Bambico FR, Nguyen NT, Gobbi G (2009) Decline in serotonergic firing activity and desensitization of 5-HT1A autoreceptors after chronic unpredictable stress. Eur Neuropsychopharmacol 19:215–228PubMedCrossRefGoogle Scholar
  4. Barone FC, Deegan JF, Price WJ, Fowler PJ, Fondacaro JD, Ormsbee HS 3rd (1990) Cold-restraint stress increases rat fecal pellet output and colonic transit. Am J Physiol 258:G329–G337PubMedGoogle Scholar
  5. Bian ZX, Zhang M, Han QB, Xu HX, Sung JJ (2010) Analgesic effects of JCM-16021 on neonatal maternal separation-induced visceral pain in rats. World J Gastroenterol 16:837–845PubMedCentralPubMedGoogle Scholar
  6. Bueno L, Fioramonti J (2002) Visceral perception: inflammatory and non-inflammatory mediators. Gut 51(Suppl 1):i19–i23PubMedCentralPubMedCrossRefGoogle Scholar
  7. Clouse RE (2003) Antidepressants for irritable bowel syndrome. Gut 52:598–599PubMedCentralPubMedCrossRefGoogle Scholar
  8. Drossman DA, Camilleri M, Mayer EA, Whitehead WE (2002) AGA technical review on irritable bowel syndrome. Gastroenterology 123:2108–2131PubMedCrossRefGoogle Scholar
  9. Dunlop SP, Coleman NS, Blackshaw E, Perkins AC, Singh G, Marsden CA, Spiller RC (2005) Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol 3:349–357PubMedCrossRefGoogle Scholar
  10. Franklin KPG (1997) The rat brain in tereotaxic coordinatesGoogle Scholar
  11. Friedrich M, Grady SE, Wall GC (2010) Effects of antidepressants in patients with irritable bowel syndrome and comorbid depression. Clin Ther 32:1221–1233PubMedCrossRefGoogle Scholar
  12. Garnett WR (1999) Management of irritable bowel syndrome. J Am Soc Consult Pharmac 14(suppl 8)Google Scholar
  13. Gershon MD, Tack J (2007) The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132:397–414PubMedCrossRefGoogle Scholar
  14. Holt PR, Katz S, Kirshoff R (2005) Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci 50:2191–2193PubMedCrossRefGoogle Scholar
  15. Jailwala J, Imperiale TF, Kroenke K (2000) Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med 133:136–147PubMedCrossRefGoogle Scholar
  16. Johansson M, Norrgard O, Forsgren S (2007) Study of expression patterns and levels of neurotrophins and neurotrophin receptors in ulcerative colitis. Inflamm Bowel Dis 13:398–409PubMedCrossRefGoogle Scholar
  17. Kirkup AJ, Brunsden AM, Grundy D (2001) Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents. Am J Physiol Gastrointest Liver Physiol 280:G787–G794PubMedGoogle Scholar
  18. Li Y, Deuring J, Peppelenbosch MP (2012) STAT1, STAT6 and Adenosine 3′,5 ′-Cyclic Monophosphate (cAMP) Signaling Drive SOCS3 Expression in Inactive Ulcerative Colitis. Mol Med 18:1412–1419PubMedCentralPubMedGoogle Scholar
  19. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC (2006) Functional bowel disorders. Gastroenterology 130:1480–1491PubMedCrossRefGoogle Scholar
  20. Lydiard RB (2001) Irritable bowel syndrome, anxiety, and depression: What are the links? J Clin Psychiatry 62(suppl 8):38–45PubMedGoogle Scholar
  21. Mattson MP, Maudsley S, Martin B (2004) BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27:589–594PubMedCrossRefGoogle Scholar
  22. Ness TJGG (1988) Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat. Brain Res 450:153–169PubMedCrossRefGoogle Scholar
  23. Nitta A, Furukawa Y, Hayashi K, Hiramatsu M, Kameyama T, Hasegawa T, Nabeshima T (1992) Denervation of dopaminergic neurons with 6-hydroxydopamine increases nerve growth factor content in rat brain. Neurosci Lett 144:152–156PubMedCrossRefGoogle Scholar
  24. Njung’e K, Handley SL (1991) Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Br J Pharmacol 104:105–112PubMedCentralPubMedCrossRefGoogle Scholar
  25. Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336PubMedGoogle Scholar
  26. Porsolt RD, Bertin A, Jalfre M (1978) “Behavioural despair” in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol 51:291–294PubMedCrossRefGoogle Scholar
  27. Qiao LY, Gulick MA, Bowers J, Kuemmerle JF, Grider JR (2008) Differential changes in brain-derived neurotrophic factor and extracellular signal-regulated kinase in rat primary afferent pathways with colitis. Neurogastroenterol Motil 20:928–938PubMedCrossRefGoogle Scholar
  28. Rahimi R, Nikfar S, Rezaie A, Abdollahi M (2009) Efficacy of tricyclic antidepressants in irritable bowel syndrome: A meta-analysis. World J Gastroenterol 15:1548–1553PubMedCentralPubMedCrossRefGoogle Scholar
  29. Ren TH, Wu J, Yew D, Ziea E, Lao L, Leung WK, Berman B, Hu PJ, Sung JJ (2007) Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 292:G849–G856PubMedCrossRefGoogle Scholar
  30. Schneider T, Popik P (2007) Attenuation of estrous cycle-dependent marble burying in female rats by acute treatment with progesterone and antidepressants. Psychoneuroendocrinology 32:651–659PubMedCrossRefGoogle Scholar
  31. Siuciak JA, Altar CA, Wiegand SJ, Lindsay RM (1994) Antinociceptive effect of brain-derived neurotrophic factor and neurotrophin-3. Brain Res 633:326–330PubMedCrossRefGoogle Scholar
  32. Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM (1996) BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res 710:11–20PubMedCrossRefGoogle Scholar
  33. Talley NJ, Owen BK, Boyce P, Paterson K (1996) Psychological treatments for irritable bowel syndrome: a critique of controlled treatment trials. Am J Gastroenterol 91:277–283PubMedGoogle Scholar
  34. Wheatcroft J, Wakelin D, Smith A, Mahoney CR, Mawe G, Spiller R (2005) Enterochromaffin cell hyperplasia and decreased serotonin transporter in a mouse model of postinfectious bowel dysfunction. Neurogastroenterol Motil 17:863–870PubMedCrossRefGoogle Scholar
  35. Wu JC, Ziea ET, Lao L, Lam EF, Chan CS, Liang AY, Chu SL, Yew DT, Berman BM, Sung JJ (2010) Effect of electroacupuncture on visceral hyperalgesia, serotonin and fos expression in an animal model of irritable bowel syndrome. J Neurogastroenterol Motil 16:306–314PubMedCentralPubMedCrossRefGoogle Scholar
  36. Xu YX, Pindolia KR, Janakiraman N, Noth CJ, Chapman RA, Gautam SC (1997) Curcumin, a compound with anti-inflammatory and anti-oxidant properties, down-regulates chemokine expression in bone marrow stromal cells. Exp Hematol 25:413–422PubMedGoogle Scholar
  37. Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, Li XJ (2005a) Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Pharmacol Biochem Behav 82:200–206PubMedCrossRefGoogle Scholar
  38. Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, Li XJ (2005b) The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol 518:40–46PubMedCrossRefGoogle Scholar
  39. Xu Y, Ku B, Tie L, Yao H, Jiang W, Ma X, Li X (2006) Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res 1122:56–64PubMedCrossRefGoogle Scholar
  40. Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC, Ogle WO (2007) Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res 1162:9–18PubMedCrossRefGoogle Scholar
  41. Yeo ABP, Lumsden S (2004) Association between a functional polymorphism in the serotonin transporter gene and diarrhea predominant irritable bowel syndrome in women. Gut 53:1452Y–1458YCrossRefGoogle Scholar
  42. Yu YB, Zuo XL, Zhao QJ, Chen FX, Yang J, Dong YY, Wang P, Li YQ (2012) Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome. Gut 61:685–694PubMedCrossRefGoogle Scholar
  43. Zou N, Lv H, Li J, Yang N, Xue H, Zhu J, Qian J (2008) Changes in brain G proteins and colonic sympathetic neural signaling in chronic-acute combined stress rat model of irritable bowel syndrome (IBS). Transl Res 152:283–289PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yingcong Yu
    • 1
  • Shujuan Wu
    • 2
  • Jianxin Li
    • 1
  • Renye Wang
    • 3
  • Xupei Xie
    • 2
  • Xuefeng Yu
    • 2
  • Jianchun Pan
    • 2
  • Ying Xu
    • 4
  • Liang Zheng
    • 1
  1. 1.Department of GastroenterologyWenzhou No.3 Clinical Institute of Wenzhou Medical University, Wenzhou people’s hospitalWenzhouChina
  2. 2.Brain Institute, School of PharmacyWenzhou Medical UniversityWenzhouChina
  3. 3.Taizhou Institute for Food and Drug ControlTaizhouChina
  4. 4.Departments of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesState University of New York at BuffaloBuffaloUSA

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