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Extracts and constituents of Lavandula multifida with topical anti-inflammatory activity.

Abstract

The topical anti-inflammatory activity of the ethanol and aqueous extracts from the aerial parts of Lavandula multifida L. (Lamiaceae), used in the Moroccan traditional medicine, was investigated by inhibition of the Croton oil-induced ear edema in mice. The biological assay revealed a dose-dependent anti-inflammatory activity for the ethanol extract, while the aqueous one was less active. Bioassay-guided fractionation of the ethanol extract led to identify four triterpenic acids of oleanane series, four pimarane and one iso-pimarane diterpenes, as well as the phenolic monoterpene carvacrol and its glucoside. Some of these compounds revealed an anti-inflammatory activity comparable to that of indomethacin.

[c] 2004 Published by Elsevier GmbH.

Keywords: Lavandula multifida; Lamiaceae; Anti-inflammatory activity; Terpenoids; Croton oil ear test

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Introduction

The genus Lavandula (lavander; Lamiaceae) includes species which flower heads are traditionally used to treat headaches, depression, diabetes, and for their sedative properties (Gamez et al., 1987; Gilani et al., 2000). They are used also to obtain lavander essential oil, rich in monoterpenes and employed for its antimicrobial and carminative properties, to treat burns and for cosmetic purposes (Cavanagh and Wilkinson, 2002). Phytochemical studies revealed different secondary metabolites in Lavandula species, such as diterpenes (Politi et al., 2002), sesquiterpenes (Ulubelen et al., 1988; Shimizu et al., 1990), triterpenes (Topcu et al., 2001), coumarins (Shimizu et al., 1990), and phenolic compounds (Areias et al., 2000; Upson et al., 2000; Gabrieli and Kokkalou, 2003).

Lavandula multifida L. is a small semi-evergreen perennial shrub native of the South-Western Europe and North Africa (Pignatti, 1982). Its leaves and stems are used in the Moroccan folk medicine to prepare decoctions against rheumatism, chill and as digestive system benefic agent (El-Hilaly et al., 2003). However, no experimental studies supported these therapeutic properties, while the only documented pharmacological investigation on L. multifida evaluated its hypoglycemic action without evidencing any effect (Gamez et al., 1987). The few phytochemical studies on L. multifida showed luteolin 7-O-glycosides, hypolaetin-8-O-glycosides and isoscutellarin-8-O-glycosides as flavonoidic constituents of the leaves (Upson et al., 2000), whereas five diterpenes were isolated from the aerial parts of the plant (Politi et al., 2002).

Considering the traditional use of L. multifida against rheumatism (El-Hilali et al., 2003), an inflammatory-based disease, this study was undertaken to verify the anti-inflammatory activity of this species. To this aim, the aqueous and ethanol extracts of L. multifida aerial parts were evaluated for their ability to inhibit the Croton oil-induced ear edema in mice, after topical application. By a bioassay-guided fractionation, two monoterpenes, five diterpenes, and four triterpenes were identified in the ethanol extract. Their anti-inflammatory activity was evaluated in comparison to that of the non steroidal anti-inflammatory drug (NSAID) indomethacin.

Materials and methods

Plant material

L. multifida, collected in South Morocco in December 1999, was identified by Prof. P.E. Tomei of Dipartimento di Agronomia e Gestione dell'Agroecosistema, Universita di Pisa, where a voucher specimen was deposited.

Chemicals

Croton oil, indomethacin and ursolic and oleanolic acids were Sigma products (Sigma, Milan, Italy). Ketamine HCl was purchased from Virbac (Milan, Italy) and other reagents and solvents from Carlo Erba (Milan, Italy).

Extraction, fractionation and isolation procedures

Air-dried powdered aerial parts of L. multifida (20 g) were macerated with water or 90% ethanol. The extracts were filtered and lyophylized or dried in vacuum to give aqueous (0.8 g) and ethanol extracts (3.5 g), respectively. Ethanol extract (2 g) was chromatographed on Sephadex LH-20 to obtain 42 fractions of 8 ml that were pooled into 8 major fractions. Fraction 2 was purified by HPLC (LiChrospher 100 DIOL column, 25 X 1.5 cm, flow rate: 2.5 ml [min.sup.-1], eluent: chloroform) to obtain 2[alpha], 3[beta]-dihydroxy-olean-12-en-28-oic acid (maslinic acid; 1) ([t.sub.R] = 20 min, 4.0 mg). Fraction 3, purified as reported by Politi et al. (2002), yielded 15S, 16-dihydroxy-7-oxopimar-8(9)-ene (2, 5.1 mg), 15,16,17-trihydroxy-7-oxopimar-8(9)-ene (3, 1.2 mg), and carvacrol-3-glucoside (4, 3.0 mg). Preparative TLC of a subfraction from fraction 3 yielded 3[beta],19[alpha], 23-trihydroxy-urs-12-en-28-oic acid (5, 5.0 mg). HPLC separation of fraction 4 (Politi et al., 2002) afforded 15S,16-dihydroxyisopimar-8(9)-ene (glutinosin; 6, 4.0 mg), a mixture of oleanolic and ursolic acid (7 and 8) in the ratio 2:1, and three subfractions (C, D and E). Preparative TLC of subfraction C (eluent: chloroform) yielded carvacrol (9, 7.0 mg) while separation of subfractions D and E over RP-HPLC (Politi et al., 2002) gave 15,16-dihydroxy-7,11-dioxopimar-8(9)-ene (10, 2.0 mg) from subfraction D and 15,16,17-trihydroxypimar-8(9)-ene (11, 2.5 mg) from subfraction E. The structure of all compounds was determined spectroscopically by 1D- and 2D-NMR ([.sup.1]H-, [.sup.13]C-, [.sup.13]C-DEPT, 1D-TOCSY, DQF-COSY, HSQC, and HMBC experiments) and confirmed by comparison with literature data (Bohlmann et al., 1975; Skopp and Hoerster, 1976; Sendra and Cunat, 1980; Mahato and Kundo, 1994; Politi et al., 2002) and chromatographically by comparison with authentic samples.

Topical anti-inflammatory activity

Animal experiments complied with the Italian D.L. n. 116 of 27 January 1992 and associated guidelines in the European Communities Council Directive of 24 November 1986 (86/609 ECC). The topical anti-inflammatory activity was evaluated as inhibition of the Croton oil-induced ear edema in mice (Tubaro et al., 1985). Male CD-1 mice (28-32 g; Harlan-Italy, Udine, Italy) were kept at controlled temperature (21 [+ or -] 1 [degrees]C) and humidity (60-70%), with a fixed light cycle (7.00-19.00 h). Inflammation was induced in the morning (10.00-12.00 h), to avoid inflammatory response variations due to circadian fluctuations of endogenous corticosteroids (Soliman et al., 1983). Mice were anesthetised with ketamine HCl (145 mg [kg.sup.-1], intraperitoneally). Inflammation was induced on the inner surface (about 1 [cm.sup.2]) of the right ear applying 80 [micro]g of Croton oil dissolved in 42% aqueous ethanol (for extracts and the relevant controls) or acetone (for fractions, compounds and their controls). Control mice received only the irritant, while other mice received both the irritant and the test substances. At the maximum of edema, six hours later, mice were sacrificed and a plug (6 mm [empty set]) was excised from both the ears. Edema was quantified as the weight difference between the two plugs. The anti-inflammatory activity was expressed as percent edema reduction in treated mice compared to the controls.

Statistical analysis

Edema values were analysed by one-way analysis of variance followed by the Dunnett's test for multiple comparisons of unpaired data and a probability level lower than 0.05 was considered as significant. I[D.sub.50] values (dose giving 50% edema inhibition) were calculated by interpolation of the dose-effect curves.

Results

Anti-inflammatory activity of the extracts

Aqueous and ethanol extracts showed a dose-dependent anti-inflammatory effect, the ethanol one being the most active. At doses ranging from 100 to 1000 [micro]g [cm.sup.-2], the ethanol extract induced from 17% to 62% edema reduction. On the contrary, the aqueous extract exerted a significant activity only at 300 and 1000 [micro]g [cm.sup.-2] (24% and 33% edema reduction, respectively). Indomethacin induced from 16% to 81% edema reduction at doses ranging from 30 to 300 [micro]g [cm.sup.-2]. The ethanol extract was only five times less active than the reference drug, as their respective I[D.sub.50] values (dose giving 50% edema inhibition) were 510 and 93 [micro]g [cm.sup.-2] (data not shown).

Anti-inflammatory activity of the fractions from the ethanol extract

Separation of the ethanol extract (2 g) on Sephadex LH-20 gave 42 fractions. On the basis of their TLC profile, they were pooled into 8 fractions (1-8), obtaining 100.0, 310.4, 280.0, 730.0, 43.1, 12.2, 44.0 and 52.9 mg (5.0, 15.5, 14.0, 36.5, 2.2, 0.6, 2.2 and 2.6% of the parent extract, respectively). Each fraction was evaluated for its anti-inflammatory activity at the dose corresponding to 1000 [micro]g of the parent extract, on the basis of the fractionation yields. Fractions 1-5 induced a significant edema inhibition, ranging from 20% (fraction 5) to 68% (fraction 4). The most active were fractions 2, 3, and 4, and the last one accounted for all the activity of the ethanol extract, which induced 61% edema reduction at 1000 [micro]g [cm.sup.-2] (Table 1).

Phytochemical analysis of the purified fractions

The most active fractions (2, 3, and 4) were purified by HPLC to isolate their active principles. Fraction 2 yielded the triterpene 2[alpha], 3[beta]-dihydroxy-olean-12-en-28-oic acid (maslinic acid; 1) while fraction 3 afforded the pimarane diterpenes 15S,16-dihydroxy-7-oxopimar-8(9)-ene (2) and 15,16,17-trihydroxy-7-oxopimar-8(9)-ene (3), the monoterpene carvacrol-3-glucoside (4) and the triterpene 3[beta],19[alpha], 23-trihydroxy-urs-12-en-28-oic acid (5). Purification of fraction 4 yielded two pimarane and one iso-pimarane diterpenes [15S,16-dihydroxyisopimar-8(9)-ene (glutinosin; (6), 15,16-dihydroxy-7,11-dioxopimar-8(9)-ene (10) and 15,16,17-trihydroxypimar-8(9)-ene (11)], carvacrol (9), as well as a mixture of 3[beta]-hydroxy-olean-12-en-28-oic acid (oleanolic acid; (7) and 3[beta]-hydroxy-urs-12-en-28-oic acid (ursolic acid; (8) in the ratio 2:1 (Fig. 1).

Anti-inflammatory activity of the isolated compounds

Compounds isolated from fractions 2, 3, and 4 as well as pure ursolic and oleanolic acids were evaluated for their anti-inflammatory activity at the dose of 100 [micro]g [cm.sup.-2], in comparison to the same dose of indomethacin. Except carvacrol-3-glucoside (4), all the compounds induced a significant edema reduction: the monoterpene carvacrol (9) induced 26% edema reduction, the diterpenes (2, 3, 6, 10, 11) reduced the edematous response from 14% to 41% and the triterpene derivatives (1, 5, 7, 8) induced from 16% to 74% reduction. The activity of compounds 6, 7, and 8 was comparable or slightly lower to that of the reference NSAID, which induced 58% edema inhibition, at the same dose level (Table 2).

[FIGURE 1 OMITTED]

Discussion

The present study demonstrates the topical anti-inflammatory properties of L. multifida. In fact, the aqueous and ethanol extracts of L. multifida aerial parts were able to reduce the Croton oil-induced ear edema in mice, the ethanol extract being the most active. Although it was a raw extract in which the active principles were diluted by ballast substances, the ethanol extract exerted a dose-dependent anti-inflammatory activity and a potency only five times lower than that of the NSAID indomethacin (I[D.sub.50] = 510 and 93 [micro]g [cm.sup.-2], respectively).

A bioassay-guided fractionation concentrated the ethanol extract activity into fraction 4, which accounted for the total anti-inflammatory effect of the parent extract. Moreover, fractions 2 and 3 revealed an effect slightly lower than that of the extract. Phytochemical analysis of these fractions led to isolate two monoterpenes, five diterpenes, and four triterpene derivatives, some of which revealed an anti-inflammatory activity comparable to that of indomethacin. In particular, the triterpenes oleanolic and ursolic acids (7, 8) and the diterpene 15S, 16-dihydroxyisopimar-8(9)-ene (6) showed the highest antiphlogistic effect: at the dose of 100 [micro]g [cm.sup.-2] ursolic acid induced 74% edema inhibition while oleanolic acid and the diterpene exerted the same effect (41% edema inhibition). As reference, 100 [micro]g [cm.sup.-2] of indomethacin provoked 58% edema reduction. Among the other compounds, maslinic acid (1) induced 36% edema reduction, showing an effect slightly lower than that of oleanolic acid (7), devoid of the 2[alpha]-hydroxyl group. Similarly, the hydroxylated derivative of ursolic acid (3[beta],19[alpha], 23-trihydroxy-urs-12-en-28-oic acid, 5) induced 16% edema inhibition, being less active than ursolic acid (8). These observations are in agreement with previous results on the anti-inflammatory activity of ursolic and oleanolic acid derivatives, revealing an activity decrease consequent to hydroxylation of the two triterpenic acids (Sosa et al., 2002). Concerning the four pimarane diterpenes, characterised by the [beta] orientation of C-17 and possessing different oxygenation degree (2, 3, 10, 11), they induced from 14% to 26% edema inhibition. These compounds were less active than the iso-pimarane diterpene 15S,16-dihydroxy-isopimar-8(9)-ene (6) possessing a lower oxygenation degree and [alpha] orientation of C-17. It is noteworthy that the structural difference within the four pimarane diterpenes (2, 3, 10, and 11) was limited to their oxygenation pattern, which did not markedly influence the anti-inflammatory degree of these compounds. On the contrary, the iso-pimarane derivative (6) was characterised by [alpha] orientation of C-17, suggesting that its higher activity could be related to this molecular feature rather than to its oxygenation pattern. Among the monoterpene derivatives, carvacrol (9) induced 26% edema inhibition while its 3-glucoside (4) was almost inactive, probably as a consequence of its higher hydrophylicity that can influence the skin absorption and the pharmakokynetic of this compound.

Some triterpenes isolated from L. multifida, such as oleanolic, ursolic and maslinic acid were previously reported for their topical anti-inflammatory activity (Shimizu et al., 1985; Huang et al., 1994; Recio et al., 1995; Manez et al., 1997; Baricevic et al., 2001; Ismaili et al., 2001; Sosa et al., 2002). Ursolic and oleanolic acids were reported also for their systemic anti-inflammatory properties (Kosuge et al., 1985; Singh et al., 1992; Kapil and Sharma 1995; Recio et al., 1995). The in vivo antiphlogistic activity of these compounds was attributed to different actions, such as inhibition of histamine release, arachidonic acid metabolism, elastase activity, complement system, as well as nitric oxide production (Kapil and Sharma, 1995; Liu, 1995; Ringbom et al., 1998; Suh et al., 1998; Diaz et al., 2000; Ryu et al., 2000). On the contrary, an anti-inflammatory activity of the isolated diterpenes was not previously reported. Anyway, some structurally related pimarane and iso-pimarane derivatives are known for their antiphlogistic effects and for inhibitory actions on leukocytes, cyclo-oxygenase-2, inflammatory cytokines and/or nitric oxide production (Masuda et al., 1992; Suh et al., 2001; Awale et al., 2003a, b; Barrero et al., 2003; Cai et al., 2003), some of which could be exerted also by L. multifida diterpenes. Concerning the monoterpenes, carvacrol was reported to inhibit cyclooxygenase (Wagner et al., 1986) and to act as antioxidant and free radical scavenger (Halliwell et al., 1995; Burits and Bucar, 2000; Dapkevicius et al., 2002), an effect that could reduce the inflammatory oxidative stress and the phlogosis. Therefore, the terpenoids from L. multifida ethanol extract can exert multiple biological and biochemical actions, which could be involved in its anti-inflammatory effect.

In conclusion, the results demonstrated the anti-inflammatory properties of L. multifida aerial parts, supporting the traditional use of the plant as a remedy against inflammatory disorders, such as rheumatism. Furthermore, they demonstrate the presence of different anti-inflammatory terpenoids that can be extracted by ethanol. Therefore, this study provides evidence that Lavandula species, such as L. multifida, used mainly for their essential oil, can be important also as a natural source of non volatile anti-inflammatory compounds.
Table 1. Anti-inflammatory activity of fractions from the L. multifida
ethanol extract after 6 h induction of Croton oil mouse ear dermatitis

Substance Dose ([micro]g [cm.sup.-2]) No. of mice

Control -- 10
Ethanol extract 1000 10
Fraction 1 50 10
Fraction 2 155 9
Fraction 3 140 10
Fraction 4 365 10
Fraction 5 22 9
Fraction 6 6 10
Fraction 7 22 10
Fraction 8 26 10

Substance Edema (mg) mean [+ or -] S.E. Edema reduction (%)

Control 6.6 [+ or -] 0.3 --
Ethanol extract 2.6 [+ or -] 0.3* 61
Fraction 1 4.8 [+ or -] 0.2* 27
Fraction 2 3.8 [+ or -] 0.2* 42
Fraction 3 3.8 [+ or -] 0.3* 42
Fraction 4 2.1 [+ or -] 0.2* 68
Fraction 5 5.3 [+ or -] 0.2* 20
Fraction 6 6.1 [+ or -] 0.3 8
Fraction 7 6.0 [+ or -] 0.5 9
Fraction 8 6.0 [+ or -] 0.3 9

*p<0.05, at the analysis of variance, as compared with controls.

Table 2. Anti-inflammatory activity of pure compounds from L. multifida
after 6 h induction of Croton oil mouse ear dermatitis

 Dose ([micro]g
Substance [cm.sup.-2]) No. of mice

Control -- 30
Carvacrol (9) 100 10
Carvacrol-3-glucoside (4) 100 10
15,16-Dihydroxy-7,11-dioxopimar- 100 10
 8(9)-ene (10)
15S,16-Dihydroxy-7-oxopimar-8 100 10
 (9)-ene (2)
15,16,17-Trihydroxy-7-oxopimar- 100 10
 8(9)-ene (3)
15,16,17-Trihydroxypimar-8(9)- 100 10
 ene (11)
15S,16-Dihydroxyisopimar-8(9)- 100 10
 ene (6)
2[alpha],3[beta]-Dihydroxy- 100 10
 olean-12-en-28-oic acid (1)
3[beta],19[alpha], 23- 100 10
 Trihydroxy-urs-12-en-28-oic
 acid (5)
3[beta]-Hydroxy-olean-12-en-28- 100 10
 oic acid (7)
3[beta]-Hydroxy-urs-12-en-28-oic 100 10
 acid (8)
Indomethacin 100 10

 Edema (mg) Mean
Substance [+ or -] S.E. Edema reduction (%)

Control 6.9 [+ or -] 0.3 --
Carvacrol (9) 5.1 [+ or -] 0.3* 26
Carvacrol-3-glucoside (4) 6.2 [+ or -] 0.4 10
15,16-Dihydroxy-7,11-dioxopimar- 5.9 [+ or -] 0.3* 14
 8(9)-ene (10)
15S,16-Dihydroxy-7-oxopimar-8 5.2 [+ or -] 0.2* 25
 (9)-ene (2)
15,16,17-Trihydroxy-7-oxopimar- 5.1 [+ or -] 0.3* 26
 8(9)-ene (3)
15,16,17-Trihydroxypimar-8(9)- 5.7 [+ or -] 0.2* 17
 ene (11)
15S,16-Dihydroxyisopimar-8(9)- 4.1 [+ or -] 0.2* 41
 ene (6)
2[alpha],3[beta]-Dihydroxy- 4.4 [+ or -] 0.3* 36
 olean-12-en-28-oic acid (1)
3[beta],19[alpha], 23- 5.8 [+ or -] 0.3* 16
 Trihydroxy-urs-12-en-28-oic
 acid (5)
3[beta]-Hydroxy-olean-12-en-28- 3.8 [+ or -] 0.4* 45
 oic acid (7)
3[beta]-Hydroxy-urs-12-en-28-oic 1.8 [+ or -] 0.2* 74
 acid (8)
Indomethacin 2.9 [+ or -] 0.3* 58

*p<0.05, at the analysis of variance, as compared with controls.


Acknowledgements

This work was supported by a grant of the Italian Ministry of Instruction, University and Research.

Received 1 December 2003; accepted 2 February 2004

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S. Sosa (a), G. Altinier (a), M. Politi (b), A. Braca (b), I. Morelli (b), R. Della Loggia (a,*)

(a) Dipartimento di Economia e Merceologia, University of Trieste, Via A. Valerio 6, 34127 Trieste, Italy

(b) Dipartimento di Chimica Bioorganica e Biofarmacia, University of Pisa, Via Bonanno 33, 56126 Pisa, Italy

*Corresponding author. Tel.: + 39 040 558 3535; fax: + 39 040 558 3215.

E-mail address: roberto.della.loggia@econ.units.it (R. Della Loggia).
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Author:Sosa, S.; Altinier, G.; Politi, M.; Braca, A.; Morelli, I.; Loggia, R. Della
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:1USA
Date:Apr 1, 2005
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