Antipyretic Effects of Citral and Possible Mechanisms of Action


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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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).

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