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Antipyretic Effects of Citral and Possible Mechanisms of Action

Inflammation volume 40, pages 1735–1741 (2017)Cite this article

Abstract

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.

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References

  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.

    Article  PubMed  Google Scholar 

  2. Blatteis, C.M. 2006. Endotoxic fever: New concepts of its regulation suggest new approaches to its management. Pharmacology & Therapeutics 111: 194–223.

    CAS  Article  Google Scholar 

  3. Blatteis, C.M., and E. Sehic. 1998. Cytokines and fever. Annals of the New York Academy of Sciences 840: 608–618.

    CAS  Article  PubMed  Google Scholar 

  4. Branco, L.G., R.N. Soriano, and A.A. Steiner. 2014. Gaseous mediators in temperature regulation. Comprehensive Physiology 4: 1301–1338.

    Article  PubMed  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  Google Scholar 

  7. Dinarello, C.A. 2004. Infection, fever, and exogenous and endogenous pyrogens: Some concepts have changed. Journal of Endotoxin Research 10: 201–222.

    CAS  PubMed  Google Scholar 

  8. Dinarello, C.A. 2009. Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology 27: 519–550.

    CAS  Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  14. Kluger, M.J., D.H. Ringler, and M.R. Anver. 1975. Fever and survival. Science 188 (4184): 166–168.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  18. Leon, L.R. 2002. Invited review: Cytokine regulation of fever: Studies using gene knockout mice. Journal of Applied Physiology 92: 2648–2655.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Article  Google Scholar 

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Affiliations

  1. Medical School of Ribeirão Preto, University of São Paulo, 14049-900, Ribeirão Preto, São Paulo, Brazil

    Maycon T. Emílio-Silva, Clarissa M. D. Mota & José Antunes-Rodrigues

  2. Natural Products Laboratory, Department of Physiology, Bioscience Institute, Universidade Estadual Paulista ‘Júlio de Mesquita Filho’, Botucatu, São Paulo, 18618-970, Brazil

    Clélia A. Hiruma-Lima

  3. Nursing School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14040-902, Brazil

    Evelin C. Cárnio

  4. Department of Morphology, Physiology and Basic Pathology, Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, 14040-904, Brazil

    Luiz G. S. Branco

Authors
  1. Maycon T. Emílio-Silva
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  2. Clarissa M. D. Mota
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  3. Clélia A. Hiruma-Lima
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  4. José Antunes-Rodrigues
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  5. Evelin C. Cárnio
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  6. Luiz G. S. Branco
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Corresponding author

Correspondence to Luiz G. S. Branco.

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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.

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The authors declare that they have no conflict of interest.

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Emílio-Silva, M.T., Mota, C.M.D., Hiruma-Lima, C.A. et al. Antipyretic Effects of Citral and Possible Mechanisms of Action. Inflammation 40, 1735–1741 (2017). https://doi.org/10.1007/s10753-017-0615-4

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  • DOI: https://doi.org/10.1007/s10753-017-0615-4

KEY WORDS

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