Anti-inflammatory effects of compounds alpha-humulene and (−)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea

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Abstract

This study evaluated the anti-inflammatory properties of two sesquiterpenes isolated from Cordia verbenacea's essential oil, α-humulene and (−)-trans-caryophyllene. Our results revealed that oral treatment with both compounds displayed marked inhibitory effects in different inflammatory experimental models in mice and rats. α-humulene and (−)-trans-caryophyllene were effective in reducing platelet activating factor-, bradykinin- and ovoalbumin-induced mouse paw oedema, while only α-humulene was able to diminish the oedema formation caused by histamine injection. Also, both compounds had important inhibitory effects on the mouse and rat carrageenan-induced paw oedema. Systemic treatment with α-humulene largely prevented both tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) generation in carrageenan-injected rats, whereas (−)-trans-caryophyllene diminished only TNFα release. Furthermore, both compounds reduced the production of prostaglandin E2 (PGE2), as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) expression, induced by the intraplantar injection of carrageenan in rats. The anti-inflammatory effects of α-humulene and (−)-trans-caryophyllene were comparable to those observed in dexamethasone-treated animals, used as positive control drug. All these findings indicate that α-humulene and (−)-trans-caryophyllene, derived from the essential oil of C. verbenacea, might represent important tools for the management and/or treatment of inflammatory diseases.

Introduction

Cordia verbenacea D.C. (Boraginacea) is a bush distributed along the coastal regions of Brazil. The aerial parts of this plant are used in folk medicine for their anti-rheumatic, anti-inflammatory, analgesic and healing properties in the form of alcoholic extracts, decoctions and infusions (Akisue et al., 1983). C. verbenacea D.C. is popularly known in Brazil under several popular names including Erva Baleeira and Salicina, among others. It has also been referred to the following scientific names: Cordia salicina D.C., Cordia curassavica, Cordia cylindristachia, Lithocardium fresenii, Lithocardium salicinum and Lithocardium verbaceum (De Carvalho et al., 2004). Several compounds are found in the aerial parts of C. verbenacea including tannins, flavonoids and essential oils. The main components of the essential oil of C. verbenacea are α-pinene, β-felandrene, citronelol acetate, β-elemene, trans-caryophyllene, β-gurjunene, α-humulene, aloaromadendrene, bicyclogermacrene, δ-cadinene, espatulenol and epoxycariophyllene (De Carvalho et al., 2004).

It has been shown that extracts obtained from C. verbenacea exhibit important anti-inflammatory properties when administered orally or topically (Sertié et al., 1988, Sertié et al., 1991, Sertié et al., 2005, Basile et al., 1989, Oliveira et al., 1998, Ticli et al., 2005). Also, an important anti-inflammatory action was already described for artemetin, a flavone isolated from C. verbenacea (Sertié et al., 1990). Furthermore, C. verbenacea essential oil was found to be capable of inhibiting the growth of Gram-positive bacteria and yeast (De Carvalho et al., 2004). Additionally, our group have recently demonstrated for the first time that the essential oil of C. verbenacea displays marked oral anti-inflammatory actions in rodents, which are probably related to the presence of the sesquiterpenes α-humulene and (−)-trans-caryophyllene compounds in this plant (Passos et al., 2007).

In this study, we sought to assess the oral anti-inflammatory properties of the sesquiterpenes α-humulene and (−)-trans-caryophyllene (see their chemical structures, Fig. 1), attempting to establish some of the possible mechanisms involved in their actions.

Section snippets

Isolation and purification of active compounds

Compounds were separated from the essential oil from C. verbenacea on silica gel 60 F254 layers (Merck) eluted with toluene:ethyl acetate (93:7) or hexane:ethyl acetate (90:10) and visualised under UV 254 nm followed by anisaldehyde reagent. Analysis was carried out using a Hewlett-Packard (HP; Palo Alto, CA, USA) model HP 5890 series II chromatograph, equipped with an HP-5 capillary column (25 m × 0.2 mm i.d.; film thickness 0.33¼ m) and a split/splitless injector, interfaced to a model HP 5971

Results

As observed in Fig. 1, the single oral treatment of rats with α-humulene or (−)-trans-caryophyllene (5–50 mg/kg, p.o., 1 h) was capable of reducing the oedema formation induced by carrageenan (300 μg/paw), an effect observed at 30, 60, 120 and 240 min after the administration of this phlogistic agent. Likewise, dexamethasone (0.5 mg/kg, s.c., 4 h) also significantly inhibited the oedematogenic response evoked by carrageenan in rats, at all analysed time points. The percentages of inhibition for

Discussion

There is compelling evidence showing that many plants or its active principles used in traditional medicine might be useful for the treatment of inflammatory conditions (for review see: Calixto et al., 2003, Calixto et al., 2004). It has been demonstrated that the extracts of C. verbenacea or its essential oil display marked anti-inflammatory effects in several different models of inflammation (Sertié et al., 1988, Sertié et al., 1991, Sertié et al., 2005, Basile et al., 1989, Oliveira et al.,

Acknowledgements

This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the Programa de Apoio aos Núcleos de Excelência (PRONEX), the Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC) and Aché Laboratórios Farmacêuticos (Brazil). E.S.F. is a recipient of a post-doctoral grant from CNPq and G.F.P. and R.M. are post-graduate students in pharmacology receiving grants

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