, Volume 40, Issue 5, pp 1735–1741 | Cite as

Antipyretic Effects of Citral and Possible Mechanisms of Action

  • Maycon T. Emílio-Silva
  • Clarissa M. D. Mota
  • Clélia A. Hiruma-Lima
  • José Antunes-Rodrigues
  • Evelin C. Cárnio
  • Luiz G. S. BrancoEmail author


Citral is a mixture of the two monoterpenoid isomers (neral and geranial) widely used as a health-promoting food additive safe for human and animal (approved by the US Food and Drug Administration). In vitro studies have reported on the capability of citral to reduce inflammation. Here, we report antipyretic effects of citral in vivo using the most well-accepted model of sickness syndrome, i.e., systemic administration of lipopolysaccharide (LPS) to rats. Citral given by gavage caused no change in control euthermic rats (treated with saline) but blunted most of the assessed parameters related to the sickness syndrome [fever (hallmark of infection), plasma cytokines (IL-1β, IL-6, and TNF-α) release, and prostaglandin E2 (PGE2) synthesis (both peripherally and hypothalamic)]. Moreover, LPS caused a sharp increase in plasma corticosterone levels that was unaltered by citral. These data are consistent with the notion that citral has a corticosterone-independent potent antipyretic effect, acting on the peripheral febrigenic signaling (plasma levels of IL-1β, IL-6, TNF-α, and PGE2), eventually down-modulating hypothalamic PGE2 production.


endotoxin fever LPS IL-1β IL-6 TNF-α corticosterone systemic inflammation sickness syndrome 


Compliance with Ethical Standards

Funding Sources

This study was funded by Grant No. 2016/17681–9 São Paulo Research Foundation (FAPESP) and National Council for Scientific and Technological Development (CNPq), Brazil.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Bachiega, T.F., and J.M. Sforcin. 2011. Lemongrass and citral effect on cytokines production by murine macrophages. Journal of Ethnopharmacology 137: 909–913.CrossRefPubMedGoogle Scholar
  2. 2.
    Blatteis, C.M. 2006. Endotoxic fever: New concepts of its regulation suggest new approaches to its management. Pharmacology & Therapeutics 111: 194–223.CrossRefGoogle Scholar
  3. 3.
    Blatteis, C.M., and E. Sehic. 1998. Cytokines and fever. Annals of the New York Academy of Sciences 840: 608–618.CrossRefPubMedGoogle Scholar
  4. 4.
    Branco, L.G., R.N. Soriano, and A.A. Steiner. 2014. Gaseous mediators in temperature regulation. Comprehensive Physiology 4: 1301–1338.CrossRefPubMedGoogle Scholar
  5. 5.
    Chaouki, W., D.Y. Leger, B. Liagre, J.L. Beneytout, and M. Hmamouchi. 2009. Citral inhibits cell proliferation and induces apoptosis and cell cycle arrest in MCF-7 cells. Fundamental & Clinical Pharmacology 23: 549–556.CrossRefGoogle Scholar
  6. 6.
    Coelho, M.M., G.E. Souza, and I.R. Pela. 1992. Endotoxin-induced fever is modulated by endogenous glucocorticoids in rats. American Journal Physiology 263: R423–R427.Google Scholar
  7. 7.
    Dinarello, C.A. 2004. Infection, fever, and exogenous and endogenous pyrogens: Some concepts have changed. Journal of Endotoxin Research 10: 201–222.PubMedGoogle Scholar
  8. 8.
    Dinarello, C.A. 2009. Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology 27: 519–550.CrossRefPubMedGoogle Scholar
  9. 9.
    Dinarello, C.A., H.A. Bernheim, J.G. Cannon, G. Lopreste, S.J.C. Warner, A.C. Webb, and P.E. Auron. 1985. Purified, 35MET, 3-LEU-labelled human monocyte interleukin-1 (IL-1) with endogenous pyrogen activity. British Journal of Rheumatology 24: 59–64.CrossRefGoogle Scholar
  10. 10.
    Dudai, N., Y. Weinstein, M. Krup, T. Rabinski, and R. Ofir. 2005. Citral is a new inducer of caspase-3 in tumor cell lines. Planta Medica 71: 484–488.CrossRefPubMedGoogle Scholar
  11. 11.
    Fantuzzi, G., H. Zheng, R. Faggioni, F. Benigni, P. Ghezzi, J.D. Sipe, A.R. Shaw, and C.A. Dinarello. 1996. Effect of endotoxin in IL-1 beta-deficient mice. The Journal of Immunology 157: 291–296.PubMedGoogle Scholar
  12. 12.
    Kapur, A., M. Felder, L. Fass, J. Kaur, A. Czarnecki, K. Rathi, S. Zeng, K.K. Osowski, C. Howell, M.P. Xiong, R.J. Whelan, and M.S. Patankar. 2016. Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation. Scientific Reports 6: 27530.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Katsukawa, M., R. Nakata, Y. Takizawa, K. Hori, S. Takashi, and H. Inoue. 2010. Citral, a component of lemongrass oil, activates PPARα and γ and suppresses COX-2 expression. Biochimica et Biophysica Acta 1801: 1214–1220.CrossRefPubMedGoogle Scholar
  14. 14.
    Kluger, M.J., D.H. Ringler, and M.R. Anver. 1975. Fever and survival. Science 188 (4184): 166–168.CrossRefPubMedGoogle Scholar
  15. 15.
    Kozak, W., C.A. Conn, J.J. Klir, G.H. Wong, and M.J. Kluger. 1995. TNF soluble receptor and antiserum against TNF enhance lipopolysaccharide fever in mice. American Journal Physiology Regul Integr Comp Physiol 269: R23–R29.Google Scholar
  16. 16.
    Lai, Y.S., W.C. Lee, Y.E. Lin, C.T. Ho, K.H. Lu, S. Panyod, Y.L. Chu, and L.Y. Sheen. 2016. Ginger essential oil ameliorates hepatic injury and lipid accumulation in high fat diet-induced nonalcoholic fatty liver disease. Journal of Agricultural and Food Chemistry 64: 2062–2071.CrossRefPubMedGoogle Scholar
  17. 17.
    Lee, H.J., H.S. Jeong, D.J. Kim, Y.H. Noh, D.Y. Yuk, and J.T. Hong. 2008. Inhibitory effect of citral on NO production by suppression of iNOS expression and NF-kappa B activation in RAW264.7 cells. Archives of Pharmacology Research 31: 342–349.CrossRefGoogle Scholar
  18. 18.
    Leon, L.R. 2002. Invited review: Cytokine regulation of fever: Studies using gene knockout mice. Journal of Applied Physiology 92: 2648–2655.CrossRefPubMedGoogle Scholar
  19. 19.
    Libert, C., P. Brouckaert, A. Shaw, and W. Fiers. 1990. Induction of interleukin 6 by human and murine recombinant interleukin 1 in mice. European Journal of Immunology 20: 691–614.CrossRefPubMedGoogle Scholar
  20. 20.
    Luheshi, G., A.J. Miller, S. Brouwer, M.J. Dascombe, N.J. Rothwell, and S.J. Hopkins. 1996. Interleukin-1 receptor antagonist inhibits endotoxin fever and systemic interleukin-6 induction in the rat. American Journal of Physiology 270: E91–E95.PubMedGoogle Scholar
  21. 21.
    Minihane, A.M., S. Vinoy, W.R. Russell, A. Baka, H.M. Roche, K.M. Tuohy, J.L. Teeling, E.E. Blaak, M. Fenech, D. Vauzour, H.J. McArdle, B.H. Kremer, L. Sterkman, K. Vafeiadou, M.M. Benedetti, C.M. Williams, and P.C. Calder. 2015. Low-grade inflammation, diet composition and health: Current research evidence and its translation. British Journal of Nutrition 114 (7): 999–1012.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nishijima, C.M., E.G. Ganev, L. Mazzardo-Martins, D.F. Martins, L.R.M. Rocha, A.R.S. Santo, and C.A. Hiruma-Lima. 2014. Citral: A monoterpene with prophylacticand therapeutic anti-nociceptive effects in experimental models of acute and chronic pain. European Journal of Pharmacology 736: 16–25.CrossRefPubMedGoogle Scholar
  23. 23.
    Nogueira, J.E., R.N. Soriano, R.A.R. Fernandez, H.D.C. Francescato, R.S. Saia, and T.M. Coimbra. 2017. Effect of physical exercise on the febrigenic signaling is modulated by preoptic hydrogen sulfide production. PloS One 12 (1): e0170468.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Saper, C.B., A.A. Romanovsky, and T.E. Scammell. 2012. Neural circuitry engaged by prostaglandins during the sickness syndrome. Nature Neurosciense 15: 1088–1095.CrossRefGoogle Scholar
  25. 25.
    Smith, B.K., and M.J. Kluger. 1992. Human IL-1 receptor antagonist partially suppresses LPS fever but not plasma levels of IL-6 in Fischer rats. American Journal of Physiology 263: R653–R655.PubMedGoogle Scholar
  26. 26.
    Stotz, S.C., J. Vriens, D. Martyn, J. Clardy, and D.E. Clapham. 2008. Citral sensing by transient receptor potential channels in dorsal root ganglion neurons. PloS One 3 (5): e2082.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Teeling, J.L., C. Cunningham, T.A. Newman, and V.H. Perry. 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, Behavior and Immunity 24: 409–419.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Maycon T. Emílio-Silva
    • 1
  • Clarissa M. D. Mota
    • 1
  • Clélia A. Hiruma-Lima
    • 2
  • José Antunes-Rodrigues
    • 1
  • Evelin C. Cárnio
    • 3
  • Luiz G. S. Branco
    • 4
    Email author
  1. 1.Medical School of Ribeirão PretoUniversity of São PauloSão PauloBrazil
  2. 2.Natural Products Laboratory, Department of Physiology, Bioscience InstituteUniversidade Estadual Paulista ‘Júlio de Mesquita Filho’São PauloBrazil
  3. 3.Nursing School of Ribeirão PretoUniversity of São PauloSão PauloBrazil
  4. 4.Department of Morphology, Physiology and Basic Pathology, Dental School of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil

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