A diet enriched with curcumin promotes resilience to chronic social defeat stress

Abstract

Chronic exposure to stress is a well-known risk factor for the development of mood and anxiety disorders. Promoting resilience to stress may prevent the development of these disorders, but resilience-enhancing compounds are not yet clinically available. One compound that has shown promise in the clinical setting is curcumin, a polyphenol compound found in the rhizome of the turmeric plant (Curcuma longa) with known anti-inflammatory and antidepressant properties. Here, we tested the efficacy of 1.5% dietary curcumin at promoting resilience to chronic social defeat stress (CSDS) in 129/SvEv mice, a strain that we show is highly susceptible to this type of stress. We found that administration of curcumin during CSDS produced a 4.5-fold increase in stress resilience, as measured by the social interaction test. Although the overall effects of curcumin were striking, we identified two distinct responses to curcumin. While 64% of defeated mice on curcumin were resilient (responders), the remaining 36% of mice were susceptible to the effects of stress (non-responders). Interestingly, responders released less corticosterone following acute restraint stress and had lower levels of peripheral IL-6 than nonresponders, implicating a role for the NF-κB pathway in treatment response. Importantly, curcumin also prevented anxiety-like behavior in both responders and non-responders in the elevated-plus maze and open field test. Collectively, our findings provide the first preclinical evidence that curcumin promotes resilience to CSDS and suggest that curcumin may prevent the emergence of a range of anxiety-like symptoms when given to individuals during exposure to chronic social stress.

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References

  1. 1.

    Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21:169–84.

  2. 2.

    Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry. 1999;156:837–41.

  3. 3.

    Köhler CA, Evangelou E, Stubbs B, Solmi M, Veronese N, et al. Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies. J Psychiatr Res 2018;5:1–9.

  4. 4.

    Bagot RC, Cates HM, Purushothaman I, Lorsch ZS, Walker DM, et al. Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility. Neuron. 2016;90:969–83.

  5. 5.

    Krishnan V, Han MH, Graham DL, Berton O, Renthal W, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.

  6. 6.

    Bagot RC, Parise EM, Pena CJ, Zhang HX, Maze I, et al. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat Commun. 2015;6:7062.

  7. 7.

    Chuang J-C, Krishnan V, Hana GY, Mason B, Cui H, et al. A β3-adrenergic-leptin-melanocortin circuit regulates behavioral and metabolic changes induced by chronic stress. Biol Psychiatry. 2010a;67:1075–82.

  8. 8.

    Chuang JC, Cui H, Mason BL, Mahgoub M, Bookout AL, et al. Chronic social defeat stress disrupts regulation of lipid synthesis. J Lipid Res. 2010b;51:1344–53.

  9. 9.

    Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA. 2014;111:16136–41.

  10. 10.

    Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532.

  11. 11.

    Donahue RJ, Muschamp JW, Russo SJ, Nestler EJ, Carlezon WA. Effects of striatal ΔFosB overexpression and ketamine on social defeat stress–induced anhedonia in mice. Biol Psychiatry. 2014;76:550–58.

  12. 12.

    Duvoix A, Blasius R, Delhalle S, Schnekenburger M, Morceau F, et al. Chemopreventive and therapeutic effects of curcumin. Cancer Lett. 2005;223:181–90.

  13. 13.

    Xu Y, Lin D, Li S, Li G, Shyamala SG, et al. Curcumin reverses impaired cognition and neuronal plasticity induced by chronic stress. Neuropharmacology. 2009;57:463–71.

  14. 14.

    Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, et al. Curcumin blocks cytokine-mediated NF-κB activation and proinflammatory gene expression by inhibiting inhibitory factor I-κB kinase activity. J Immunol. 1999;163:3474–83.

  15. 15.

    Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R, Phisalaphong C, Jirawatnotai S. Curcumin extract for prevention of type 2 diabetes. Diabetes Care. 2012;35:2121–27.

  16. 16.

    Daily JW, Yang M, Park S. Efficacy of turmeric extracts and curcumin for alleviating the symptoms of joint arthritis: a systematic review and meta-analysis of randomized clinical trials. J Med Food. 2016;19:717–29.

  17. 17.

    Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4:1502–06.

  18. 18.

    McFadden R-MT, Larmonier CB, Shehab KW, Midura-Kiela M, Ramalingam R, et al. The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention. Inflamm Bowel Dis. 2015;21:2483–94.

  19. 19.

    Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: a randomised, double-blind, placebo-controlled study. J Affect Disord. 2017;207:188–96.

  20. 20.

    Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. J Affect Disord. 2014;167:368–75.

  21. 21.

    Hurley LL, Akinfiresoye L, Nwulia E, Kamiya A, Kulkarni AA, Tizabi Y. Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behav Brain Res. 2013;239:27–30.

  22. 22.

    Xu Y, Ku B, Tie L, Yao H, Jiang W, et al. Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res. 2006;1122:56–64.

  23. 23.

    Monsey MS, Gerhard DM, Boyle LM, Briones MA, Seligsohn M, Schafe GE. A diet enriched with curcumin impairs newly acquired and reactivated fear memories. Neuropsychopharmacology. 2015;40:1278–88.

  24. 24.

    Prasad S, Tyagi AK, Aggarwal BB. Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: the golden pigment from golden spice. Cancer Res Treat. 2014b;46:2–18.

  25. 25.

    Golden SA, Covington HE III, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.

  26. 26.

    Brachman RA, McGowan JC, Perusini JN, Lim SC, Pham TH, et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry. 2016;79:776–86.

  27. 27.

    Holmes A, Wrenn C, Harris A, Thayer K, Crawley J. Behavioral profiles of inbred strains on novel olfactory, spatial and emotional tests for reference memory in mice. Genes Brain Behav. 2002;1:55–69.

  28. 28.

    Dadomo H, Sanghez V, Di Cristo L, Lori A, Ceresini G, Malinge I, et al. Vulnerability to chronic subordination stress-induced depression-like disorders in adult 129SvEv male mice. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1461–71.

  29. 29.

    Herman JP. Neural control of chronic stress adaptation. Front Behav Neurosci. 2013;7:61.

  30. 30.

    Carola V, D’Olimpio F, Brunamonti E, Mangia F, Renzi P. Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice. Behav Brain Res. 2002;134:49–57.

  31. 31.

    Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012;26:1719–25.

  32. 32.

    Irving GR, et al. Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration—a clinical pilot study including assessment of patient acceptability. Cancer Prev Res. 2013;6:119–128.

  33. 33.

    Sanmukhani J, Satodia V, Trivedi J, Patel T, Tiwari D, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res. 2014;28:579–85.

  34. 34.

    Haider S, Naqvi F, Batool Z, Tabassum S, Sadir S, et al. Pretreatment with curcumin attenuates anxiety while strengthens memory performance after one short stress experience in male rats. Brain Res Bull. 2015;115:1–8.

  35. 35.

    Kopp EB, Ghosh S. NF-kB and Rel proteins in innate immunity. Adv Immunol. 1995;58:241–249.

  36. 36.

    Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci. 2011;31:314–21.

  37. 37.

    Christoffel DJ, Golden SA, Heshmati M, Graham A, Birnbaum S, et al. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior. Neuropsychopharmacology. 2012;37:2615

  38. 38.

    Bhatt D, Ghosh S. Regulation of the NF-κB-mediated transcription of inflammatory genes. Front Immunol. 2014;5:1–9.

  39. 39.

    Jain SK, Rains J, Croad J, Larson B, Jones K. Curcumin supplementation lowers TNF-α, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-α, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxid Redox Signal. 2009;11:241–249.

  40. 40.

    Irving GR, et al. Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration—a clinical pilot study including assessment of patient acceptability. Cancer Prev Res. 2013;6:119–128.

  41. 41.

    Irving GR, et al. Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration—a clinical pilot study including assessment of patient acceptability. Cancer Prev Res. 2013;6:119–128.

  42. 42.

    Irving GR, et al. Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration—a clinical pilot study including assessment of patient acceptability. Cancer Prev Res. 2013;6:119–128.

  43. 43.

    Lopresti AL. The problem of curcumin and its bioavailability: could its gastrointestinal influence contribute to its overall health-enhancing effects? Adv Nutr. 2018;9:41–50.

  44. 44.

    Ma TY, Iwamoto GK, Hoa NT, Akotia V, Pedram A, Boivin MA, et al. TNF-α-induced increase in intestinal epithelial tight junction permeability requires NF-κB activation. Am J Physiol Gastrointest Liver Physiol. 2004;286:G367–G376.

  45. 45.

    Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci. 2015;9:392.

  46. 46.

    Kiraly D, Horn S, Van Dam N, Costi S, Schwartz J, et al. Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Transl Psychiatry. 2017;7:e1065.

  47. 47.

    Yoshimura R, Hori H, Ikenouchi-Sugita A, Umene-Nakano W, Ueda N, Nakamura J. Higher plasma interleukin-6 (IL-6) level is associated with SSRI-or SNRI-refractory depression. Progr Neuropsychopharmacol Biol Psychiatry. 2009;33:722–26.

  48. 48.

    Bagot RC, Cates HM, Purushothaman I, Vialou V, Heller EA, et al. Ketamine and imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles. Biol Psychiatry. 2017;81:285–95.

  49. 49.

    Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161.

  50. 50.

    Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311:864–8.

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Correspondence to Nesha S. Burghardt.

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