Linalool and linalyl acetate are the principal components of many essential oils known to possess several biological activities, attributable to these monoterpene ...
Phytomedicine 9: 721-726, @ Urban & Fischer Verlag http://www.urbanfischer.de/jo
2002 umal s/phytomed
Anti-inflammatory activity of linalool and linalyl acetate constituents of essential oils A. T. Peana, P. S. D'Aquila, F. Panin, G. Serra, P. Pippia1, and M. D. L. Maretti Dipartimento di Scienze del Farmaco, Università degli Studi di Sassari, Sassari, Italy J
Dipartimentodi Scienze FisiologicheBiochimichee Cellulari,Università degli Studidi Sassari, Sassari,Italy
Summary Linalool and linalyl acetate are the principal components of many essential oils known to possess several biological activities, attributable to these monoterpene compounds. In this work, we evaluated individually the anti-inflammatory properties of (-) linalool, that is, the natural occurring enantiomer, and its racemate form, present in various amounts in distilled or extracted essenti al oils. Because in the linalool-containing essential oils, linalyl acetate, is frequently present, we also examined the anti-inflammatory action of this monoterpene estero Carrageenin-induced edema in rats was used as a model of inflammation. The experimental data indicate that both the pure enantiomer and its racemate induced, after systemic administration, a reduction of edema. Moreover, the pure enantiomer, at a dose of 25 mglkg, elicited a delayed and more prolonged effect, while the racemate form induced a significant reduction of the edema only one hour after carrageenin administration. At higher doses, no differences were observed between the (-) enantiomer and the racemate; a further increase in the dose of both forms did not resuIt in an increased effect at any time of observation. The effects of equi-molar doses of linalyl acetate on local edema were less relevant and more delayed than that of the corresponding alcohol. These finding suggest a typical pro-drug behavior of linalyl acetate. The results obtained indicate that linalool and the corresponding acetate play a major role in the anti-inflammatory activity displayed by the essential oils containing them, and provide further evidence suggesting that linalool and linalyl acetate-producing species are potentially anti-inflammatory agents. Key words: (-) Linalool, (I) linalool, linalyl acetate, essential oil, anti-inflammatory activity
Introduction Linalool and linalyl acetate are monoterpene compounds reported to be major volatile components of the essential oils of several aromatic species. A number of linalool- and linalyl acetate-producing species are used in traditional medicin systems to relieve symptoms and cure a variety of ailments, both acute and chronic. Their pharmacological activities are attributable to the content of alcohols like linalool and its corresponding ester (linal yl acetate) (Peana and
Moretti, 2002). Linalool was evaluated recently for its psychopharmacological activity in mice, revealing marked dose-dependent sedative effects on the centrai nervous system (CNS) (Jirovetz et al. 1991; Buchbauer et al. 1991), including protection against pentylenetetrazol (PTZ), picrotoxin and transcorneal electroshock-induced convulsions, hypnotic and hypothermic properties (Elisabetsky et al. 1995; Elisabetsky et al. 1999). It has also been reported that 0944-7113/02/09/08-721
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linalool modulates glutamate activation expression in vitro (competitive antagonism of L-[3H]glutamate binding) and in vivo (delayed subcutaneous N-methylD-aspartate-induced convulsions and blockade of intracerebroventricular quinolinic acid-induced convulsions) (Silva Brum et al. 2001; Brum et al. 2001). Anesthetic activity related to its effects on the nicotinic receptor-ion channel (Ghelardini et al. 1999; Re et al. 2000) and a spasmolytic effect (Lis-Balchin and Hart, 1999) were also reported, as well as antimicrobial activity against several bacteria and fungi (Carson and Riley, 1995; Pattnaik et al. 1997; Peana et al. 1999)0 Moreover, linalool, as well as some terpenes and terpenoids, could enhance the permeability of a number of drugs through biological tissues like skin or mucus membranes (Kunta et al. 1997; Kommuru et al. 1998; Ceschel et al. 2000)0 Among the many papers on linalool, no data about its anti-inflammatory activity have been reported, although some linalool-producing species have been reported to possess good anti-inflammatory activity and
a peripheralanalgesicaction(Moretti et al. 1997; Peana and Moretti, 2002). The aim of the present study was to test the anti-inflammatory activity of linalool and linalyl acetateo IndividuaI dose curves of (-) linalool, the natural occurring enantiomer, and its racemate form, present in various amounts in distilled or extracted essential oils, were examined. The anti-inflammatory effect of equimolar doses of linalyl acetate, frequently present in linalool-containing essential oils, was also evaluatedo Carrageenin-induced edema in rats was used as a model of local inflammationo
Materials and Methods The present study was carried out in accordance with Italian law, which allows experiments on laboratory animals only after submission of a research project to the competent authorities, and in accordance with the "Principles of laboratory animaI care" (NIH publica-
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Fig.!. Anti-inflammatory activity of (-) linalool. Differences of means of edema volume (mi) between basai and treatment values at different times :t S.Eo % Variation compared to the control animalso ANOVA followed by F-test for contrasts comparing each group versus control. **p < 0001; ***p < 0.005; ****p < 0.001.
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Anti-inflammatory activity of linalool and linalyl acetate tion no. 85-23, revised 1985). According to these principles, with the aim to reduce the number of experimental animals, positive control tests were not performed. Animals The experiments were performed on male albino Wistar filts weighing 150 170 g each (Rarlan, Italy). They were housed in groups of three per cage and maintained under controlled environmental conditions (temperature 22 :t 2°C; humidity 60-65%; 12-h lightdark cycle). All animals were given standard laboratory diet and aquafontis, available ad libitum. Drugs and treatments
(:t) Linalool (Sigma) was purified by steam distillation before use; (-) linalool and linalyl acetate (Sigma) were used as received. All compounds were tested on six rats, with six animals as controi. Aspirin (ASA) was used as positive controi. (-) Linalool was administered at doses of 25, 50 and 75 mg/kg body wl., the racemate at doses of 12.5, 25, 50 and 75 mg/kg body wl., while linalyl acetate was administered at doses equivalent to the molar content of (-) linalool (32, 64 and 96 mg/kg body wl.). ASA was utilized at the dose of 150 mg/kg
body wl. AlI compounds tested were administered by abdominal subcutaneous injection after their dissolution in PEG-200 (vehicle). The control groups received only the vehicle, injected in the same site of administration, which did not cause any effect per se. All experiments were performed between 09.00 and 15.00 h. Anti-inflammatoryactivity Anti-inflammatory activity was evaluated on the basis of inhibition of carrageenin-induced hind paw edema (Winter et al. 1962; Dolara et al. 1989). Thirty min after dosing with the compounds of interest, 0.05 mI of a 1% carrageenin À suspension in saline (0.9% NaCl) was injected into the pIantar surface of the hind paw. Paw volumes were determined using a water plethysmometer (Basile, Italy), at time zero (basaI) and at the 1st, 3rd and 5th hour after carrageenin injection. The results are expressed as the difference in mean paw volumes (mI) between basaI and treatment values at different times :t S.E. The activity was evaluated according to edema inhibition at the 1st, 3rd and 5th hour after carrageenin injection, using the folIowing ratio: (Vt-Vo) control- (Vt-Vo) treated x 100/(Vt-Vo) control where Vt is the average volume at each time point after carrageenin injection and Vo is the average basaI volume.
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Fig. 2. Anti-inflammatory activity of (i:) linalool. Differences of means of edema volume (mI) between basai and treatment values at ditIerent times i: S.E. % Variation compared to the control animals. ANOVA followed by F-test for contrasts comparing each group Yersus contro!. *P"" 0.05; **P"" 0,01.
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Fig. 3. Anti-inflammatory activity oflinalyl acetate. Differences of means of edema volume (mI) between basaI and treatment values at different times :!:S.E. % Variation compared to the control animals. ANOVA followed by F-test for contrasts comparing each group versus controi. *P
