Inhibitory Effects of Citronellol and Geraniol on Nitric Oxide and Prostaglandin E₂ Production in Macrophages

Abstract

Geranium oil has been used traditionally for diarrhea, dermatitis, and intestinal inflammation in East Asia. The aim of this study was to determine the effects of geranium oil's characteristic components, citronellol and geraniol, on lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E₂ (PGE₂) production in RAW 264.7 macrophages. Citronellol and geraniol suppressed NO and PGE₂ production in a dose-dependent manner. The inhibitory efficacy of geraniol was concomitant with decreases in protein and mRNA expression levels of inducible nitric oxide synthase (iNOS), whereas citronellol inhibited only iNOS enzymatic activity. By adding citronellol and geraniol, the LPS-induced cyclooxygenase-2 (COX-2) protein and mRNA expression levels were significantly attenuated, whereas cytosolic degradation of IκBα and upregulation of NF-κB p65 in the nucleus were reversed. These results suggested that citronellol and geraniol exhibit anti-inflammatory activities, supporting their common use and demonstrating their therapeutic potential for inflammation-associated disorders.

geraniol - citronellol - anti‐inflammatory - nitric oxide - prostaglandin E₂ - macrophage

References

• 1 Pikarsky E, Porat R M, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer.  Nature. 2004;  431 461-466
• 2 Kutuk O, Basaga H. Inflammation meets oxidation: NF-kappaB as a mediator of initial lesion development in atherosclerosis.  Trends Mol Med. 2003;  9 549-557
• 3 Shim J U, Oh P S, Lim K T. Anti-inflammatory activity of ethanol extract from Geranium sibiricum Linne.  J Ethnopharmacol. 2009;  126 90-95
• 4 Maruyama N, Sekimoto Y, Ishibashi H, Inouye S, Oshima H, Yamaguchi H, Abe S. Suppression of neutrophil accumulation in mice by cutaneous application of geranium essential oil.  J Inflamm. 2005;  2 1-11
• 5 Abe S, Maruyama N, Hayama K, Inouye S, Oshima H, Yamaguchi H. Suppression of neutrophil recruitment in mice by geranium essential oil.  Mediators Inflamm. 2004;  13 21-24
• 6 Abe S, Maruyama N, Hayama K, Ishibashi H, Inoue S, Oshima H, Yamaguchi H. Suppression of tumor necrosis factor-alpha-induced neutrophil adherence responses by essential oils.  Mediators Inflamm. 2003;  12 323-328
• 7 Kupeli E, Tatli I I, Akdemir Z S, Yesilada E. Estimation of antinociceptive and anti-inflammatory activity on Geranium pratense subsp. finitimum and its phenolic compounds.  J Ethnopharmacol. 2007;  114 234-240
• 8 Sokmen M, Angelova M, Krumova E, Pashova S, Ivancheva S, Sokmen A, Serkedjieva J. In vitro antioxidant activity of polyphenol extracts with antiviral properties from Geranium sanguineum L.  Life Sci. 2005;  76 2981-2993
• 9 Stuehr D J, Kwon N S, Gross S S, Thiel B A, Levi R, Nathan C F. Synthesis of nitrogen oxides from L-arginine by macrophage cytosol: requirement for inducible and constitutive components.  Biochem Biophys Res Commun. 1989;  161 420-426
• 10 Lin C Y, Shen Y H, Wu S H, Lin C H, Hwang S M, Tsai Y C. Effect of bismuth subgallate on nitric oxide and prostaglandin E2 production by macrophages.  Biochem Biophys Res Commun. 2004;  315 830-835
• 11 Zhang L, Wu C, Zhao S, Yuan D, Lian G, Wang X, Wang L, Yang J. Demethoxycurcumin, a natural derivative of curcumin attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-kappaB signaling pathways in N9 microglia induced by lipopolysaccharide.  Int Immunopharmacol. 2010;  10 331-338
• 12 Harris S G, Padilla J, Koumas L, Ray D, Phipps R P. Prostaglandins as modulators of immunity.  Trends Immunol. 2002;  23 144-150
• 13 Huntjens D R, Danhof M, Della Pasqua O E. Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors.  Rheumatology (Oxford). 2005;  44 846-859
• 14 Hemmrich K, Kroncke K D, Suschek C V, Kolb-Bachofen V. What sense lies in antisense inhibition of inducible nitric oxide synthase expression?.  Nitric Oxide. 2005;  12 183-199
• 15 Knowles R G, Moncada S. Nitric oxide synthases in mammals.  Biochem J. 1994;  298 249-258
• 16 Aktan F. iNOS-mediated nitric oxide production and its regulation.  Life Sci. 2004;  75 639-653
• 17 Tanabe T, Tohnai N. Cyclooxygenase isozymes and their gene structures and expression.  Prostaglandins Other Lipid Mediat. 2002;  68–69 95-114
• 18 Ward S G, O'Neill L A. Spotlight on new anti-inflammatory drug targets in the immune system.  Curr Opin Pharmacol. 2003;  3 391-395
• 19 Chainy G B, Manna S K, Chaturvedi M M, Aggarwal B B. Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis.  Oncogene. 2000;  19 2943-2950
• 20 Korhonen R, Lahti A, Kankaanranta H, Moilanen E. Nitric oxide production and signaling in inflammation.  Curr Drug Targets Inflamm Allergy. 2005;  4 471-479
• 21 Lo A H, Liang Y C, Lin-Shiau S Y, Ho C T, Lin J K. Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages.  Carcinogenesis. 2002;  23 983-991
• 22 Wang J, Mazza G. Inhibitory effects of anthocyanins and other phenolic compounds on nitric oxide production in LPS/IFN-gamma-activated RAW 264.7 macrophages.  J Agric Food Chem. 2002;  50 850-857
• 23 Radwan M A, El-Zemity S R, Mohamed S A, Sherby S M. Potential of some monoterpenoids and their new N-methyl carbamate derivatives against Schistosomiasis snail vector, Biomphalaria alexandrina.  Ecotoxicol Environ Saf. 2008;  71 889-894
• 24 Cal K, Sznitowska M. Cutaneous absorption and elimination of three acyclic terpenes – in vitro studies.  J Control Release. 2003;  93 369-376
• 25 El-Kattan A F, Asbill C S, Michniak B B. The effect of terpene enhancer lipophilicity on the percutaneous permeation of hydrocortisone formulated in HPMC gel systems.  Int J Pharm. 2000;  198 179-189
• 26 Godwin D A, Michniak B B. Influence of drug lipophilicity on terpenes as transdermal penetration enhancers.  Drug Dev Ind Pharm. 1999;  25 905-915