The Journal of Physiological Sciences

, Volume 67, Issue 6, pp 673–679 | Cite as

Prostaglandins mediate zymosan-induced sickness behavior in mice

  • Juliana B. M. Lima
  • Clarice C. Veloso
  • Fabiana C. Vilela
  • Alexandre Giusti-Paiva
Original Paper


Previous studies have demonstrated that zymosan, a cell wall component of the yeast Saccharomyces cerevisiae, induces inflammation in experimental models. However, few studies have evaluated the potential of zymosan to induce sickness behavior, a central motivational state that allows an organism to cope with infection. To determine whether zymosan administration results in sickness behavior, mice were submitted to the forced swim (FST) and open field (OFT) tests 2, 6, and 24 h after treatment with zymosan (1, 10, or 100 mg/kg). Additionally, to evaluate the possible relationship between zymosan-induced sickness behavior and prostaglandin synthesis, mice were pretreated with the cyclooxygenase inhibitors indomethacin (10 mg/kg) and nimesulide (5 mg/kg) and the glucocorticoid drug dexamethasone (1 mg/kg). Zymosan induced time-dependent decreases in locomotor activity in the OFT, and an increase in immobility in the FST, and increased plasma levels of corticosterone at 2 h. Pretreatment with indomethacin, nimesulide, or dexamethasone blocked zymosan-induced behavioral changes in both the FST and OFT at 2 h post administration. These findings confirm previous observations that zymosan induces sickness behavior. Furthermore, our results provide new evidence that prostaglandin synthesis is necessary for this effect, as anti-inflammatory drugs that inhibit prostaglandin synthesis attenuated zymosan-induced behavioral changes.


Cyclooxygenase Fungal infection Prostaglandin Saccharomyces cerevisiae Sickness behavior Zymosan 



We would like to thank Dr. Lucila L. K. Elias and Dr. José Antunes-Rodrigues from the University of São Paulo for assistance with the hormonal measurements. We also acknowledge the Brazilian National Council for Scientific and Technical Development (CNPq; #300977/2013-1) and the Research Support Foundation of Minas Gerais (FAPEMIG; #APQ-00041-15) for financial support.

Compliance with ethical standards

Ethical approval

All experiments were conducted according to the Declaration of Helsinki regulations addressing the welfare of experimental animals and were approved by the Ethics Committee of the Federal University of Alfenas (#360/2011).

Conflict of interest

All authors declare that they have no conflicts of interest.


  1. 1.
    Cremeanssmith J, Newberry B (2003) Zymosan: induction of sickness behavior and interaction with lipopolysaccharide. Physiol Behav 80:177–184CrossRefGoogle Scholar
  2. 2.
    Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hubschle T, Rafalzik S, Gerstberger R, Roth J (2007) Induction of fever and sickness behavior in telemetrically monitored rats during systemic inflammation induced by zymosan. J Anim Vet Adv 6:569–575Google Scholar
  4. 4.
    McCusker RH, Kelley KW (2013) Immune-neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol 216:84–98CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    de Paiva VN, Lima SN, Fernandes MM, Soncini R, Andrade CA, Giusti-Paiva A (2010) Prostaglandins mediate depressive-like behaviour induced by endotoxin in mice. Behav Brain Res 215:146–151CrossRefPubMedGoogle Scholar
  6. 6.
    Kelley KW, Bluthé RM, Dantzer R, Zhou JH, Shen WH, Johnson RW, Broussard SR (2003) Cytokine-induced sickness behavior. Brain Behav Immun 17:112–118CrossRefGoogle Scholar
  7. 7.
    Liu J, Buisman-Pijlman F, Hutchinson MR (2014) Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder. Front Neurosci 8:309PubMedPubMedCentralGoogle Scholar
  8. 8.
    Turnbull AV, Rivier CL (1999) Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 79:1–71CrossRefPubMedGoogle Scholar
  9. 9.
    Volman TJ, Hendriks T, Goris RJ (2005) Zymosan-induced generalized inflammation: experimental studies into mechanisms leading to multiple organ dysfunction syndrome. Shock 23:291–297CrossRefPubMedGoogle Scholar
  10. 10.
    Alvarez Y, Valera I, Municio C, Hugo E, Padrón F, Blanco L, Rodríguez M, Fernández N, Crespo MS (2010) Eicosanoids in the innate immune response: TLR and non-TLR routes. In: Parker A (ed) Mediators of inflammation, vol. 2010. p 14 Google Scholar
  11. 11.
    Bastos-Pereira AL, Fraga D, Ott D, Simm B, Murgott J, Roth J, Zampronio AR (2014) Involvement of brain cytokines in zymosan-induced febrile response. J Appl Physiol 116:1220–1229CrossRefPubMedGoogle Scholar
  12. 12.
    Engblom D, Ek M, Saha S, Ericsson-Dahlstrand A, Jakobsson PJ, Blomqvist A (2002) Prostaglandins as inflammatory messengers across the blood-brain barrier. J Mol Med 80:5–15CrossRefPubMedGoogle Scholar
  13. 13.
    Dunn AJ, Swiergiel AH (2005) Effects of interleukin-1 and endotoxin in the forced swim and tail suspension tests in mice. Pharmacol Biochem Behav 81:688–693CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Haroon E, Raison CL, Miller AH (2012) Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37:137–162CrossRefPubMedGoogle Scholar
  15. 15.
    Rorato R, Menezes AM, Giusti-Paiva A, de Castro M, Antunes-Rodrigues J, Elias LL (2009) Prostaglandin mediates endotoxaemia-induced hypophagia by activation of pro-opiomelanocortin and corticotrophin-releasing factor neurons in rats. Exp Physiol 94:371–379CrossRefPubMedGoogle Scholar
  16. 16.
    Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacody Ther 229:327–336Google Scholar
  17. 17.
    Ribeiro DE, Maiolini VM, Soncini R, Antunes-Rodrigues J, Elias LL, Vilela FC, Giusti-Paiva A (2013) Inhibition of nitric oxide synthase accentuates endotoxin-induced sickness behavior in mice. Pharmacol Biochem Behav 103:535–540CrossRefPubMedGoogle Scholar
  18. 18.
    Haba R, Shintani N, Onaka Y, Wang H, Takenaga R, Hayata A, Baba A, Hashimoto H (2012) Lipopolysaccharide affects exploratory behaviors toward novel objects by impairing cognition and/or motivation in mice: possible role of activation of the central amygdala. Behav Brain Res 228:423–431CrossRefPubMedGoogle Scholar
  19. 19.
    Ohgi Y, Futamura T, Kikuchi T, Hashimoto K (2013) Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. Pharmacol Biochem Behav 103:853–859CrossRefPubMedGoogle Scholar
  20. 20.
    Tahara Y, Aoyama S, Shibata S (2016) The mammalian circadian clock and its entrainment by stress and exercise. J Physiol Sci 1–10. doi: 10.1007/s12576-016-0450-7
  21. 21.
    Antunes-Rodrigues J, de Castro M, Elias LL, Valença MM, McCann SM (2004) Neuroendocrine control of body fluid metabolism. Physiol Rev 84:169–208CrossRefPubMedGoogle Scholar
  22. 22.
    Karatsoreos IN, McEwen BS (2011) Psychobiological allostasis: resistance, resilience and vulnerability. Trends Cogn Sci 15:576–584CrossRefPubMedGoogle Scholar
  23. 23.
    McEwen BS (2003) Mood disorders and allostatic load. Biol Psychiatry 54:200–207CrossRefPubMedGoogle Scholar
  24. 24.
    McEwen BS (1998) Stress, adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci 840:33–44CrossRefPubMedGoogle Scholar
  25. 25.
    Flower RJ, Rothwell NJ (1994) Lipocortin-1: cellular mechanisms and clinical relevance. Trends Pharmacol Sci 15:71–76CrossRefPubMedGoogle Scholar
  26. 26.
    Gerke V, Moss SE (2002) Annexins: from structure to function. Physiol Rev 82:331–371CrossRefPubMedGoogle Scholar
  27. 27.
    Abraham SM, Lawrence T, Kleiman A, Warden P, Medghalchi M, Tuckermann J, Saklatvala J, Clark AR (2006) Anti-inflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J Exp Med 203:1883–1889CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Goulding NJ, Euzger HS, Butt SK, Perretti M (1998) Novel pathways for glucocorticoid effects on neutrophils in chronic inflammation. Inflamm Res 47(Suppl 3):S158–S165CrossRefPubMedGoogle Scholar
  29. 29.
    King EM, Holden NS, Gong W, Rider CF, Newton R (2009) Inhibition of NF-kappaB-dependent transcription by MKP-1: transcriptional repression by glucocorticoids occurring via p38 MAPK. J Biol Chem 284:26803–26815CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Teeling JL, Cunningham C, Newman TA, Perry VH (2010) The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: implications for a role of COX-1. Brain Behav Immun 24:409–419CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Romero LM, Dickens MJ, Cyr NE (2009) The reactive scope model—a new model integrating homeostasis, allostasis, and stress. Horm Behav 55:375–389CrossRefPubMedGoogle Scholar
  32. 32.
    Teeling JL, Felton LM, Deacon RM, Cunningham C, Rawlins JN, Perry VH (2007) Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines. Brain Behav Immun 21:836–850CrossRefPubMedGoogle Scholar
  33. 33.
    Bondeson J, Browne KA, Brennan FM, Foxwell BM, Feldmann M (1999) Selective regulation of cytokine induction by adenoviral gene transfer of IkappaBalpha into human macrophages: lipopolysaccharide-induced, but not zymosan-induced, proinflammatory cytokines are inhibited, but IL-10 is nuclear factor-kappaB independent. J Immunol 162:2939–2945PubMedGoogle Scholar
  34. 34.
    Cao C, Matsumura K, Shirakawa N, Maeda M, Jikihara I, Kobayashi S, Watanabe Y (2001) Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase-2 in brain endothelial cells and also upregulate their receptors. Eur J Neurosci 13:1781–1790CrossRefPubMedGoogle Scholar
  35. 35.
    Sanguedolce MV, Capo C, Bongrand P, Mege JL (1992) Zymosan-stimulated tumor necrosis factor-alpha production by human monocytes. Down-modulation by phorbol ester. J Immunol 148:2229–2236PubMedGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2016

Authors and Affiliations

  1. 1.Department of PhysiologyRibeirão Preto School of Medicine, University of São PauloRibeirão PretoBrazil
  2. 2.Laboratory of Translational Physiology, Department of Physiological SciencesInstitute of Biomedical Sciences, Federal University of Alfenas-MGAlfenasBrazil

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