Pharmacology 11 The Biologicalpharmacological Activity Of The Salvia Genus

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DEA BARICEVIC AND TOMAZ BARTOL

Slovenian National AGRIS Centre, Biotechnical Faculty University of Ljubljana, Jamnikarjeva 101, 1111 Ljubljana, Slovenia

INTRODUCTION

Sage (Salvia species) has been used as a herb with beneficial healing properties for millennia. The name itself comes from the Latin word for health (salvare or heal). Ancient authors called it elelisphakon. This term most likely refers to several species, such as Salvia fruticosa Mill., Salvia officinalis L. and Salvia pomifera L. (Rivera et al., 1994). A tenth century Salerno School called it Salvia salviatrix, whereas the Spanish call it ierba buena or "good herb". Both terms admire feats attributed to sage. A proverb assures us, that a man who has sage in his garden needs no doctor. Sage became very popular also in China in the eighteenth century where the merchants would exchange two crates of best tea for a crate of sage (Toussaint-Samat, 1996).

Until the discovery of antibiotics, sage was a frequent component of herbal tea mixtures, recommended in patients with tuberculosis to prevent sudation. The essential oil of sage is still employed in flavouring condiments, cured meats, liqueurs and bitters. Besides the usage as a flavouring and antioxidant agent, sage (S. officinalis L.) leaves exhibit a range of biological activities, i.e. antibacterial, micostatic, virustatic, astringent and antihidrotic (Anonymus, 1994). Sage was found to be an active ingredient in combined plant preparations for treatment of acute and chronic bronchitis. Animal studies show hypotensive activity and central nervous system (CNS) depressant action of sage extracts (Newall et al., 1996). Because of antimicrobial effects (Dobrynin et al., 1976; Cherevatyi et al., 1980; Farag et al., 1986) and tannin-based astringent activities of sage this is used as an active ingredient of dental-care preparations. It reduces growth of plaques, inhibits gingival inflammation, and has beneficial effects on caries prophylaxis (Willershausen et al., 1991).

The traditional Chinese herbal drug Dan-Shen (Tan-shen, S. miltiorrkiza Bge.) is described to have sedative, antimicrobial, antispasmodic, anti-inflammatory and antioxidant properties. Tan-shen is mentioned in Chinese Pharmacopoeia as a drug that treats problems associated with heart and circulatory system (oral preparations: decoction or tablet with Panax notoginseng) insomnia (dry, oral preparation: decoction with Polygala tenuifolia and Zizyphus spinosa) and as a drug used in the

treatment of acute arthritic pain in patients with rheumatism (Xiao, 1989). Also, use of the decoction of tan-shen together with other herbs such as Angelica sinensis and Curcuma zedoaria, is recommended in the treatment of amenorrhea, dysmenorrhea and other menstrual disorders. When studying the effects of S. miltiorrhiza on endocrine function of ovary-uterus in immature rats, increased level of estradiol (E2) in plasma, weight of uterus and ovarian PGF2 alpha content were observed by Li et al. (1992). S. Miltiorrhiza stimulated ovulation in immature mice, inhibited function of corpus luteum in pseudopregnant rats and decreased concentration of progesterone in plasma.

S. haematodes Wall., known as red sage, was found to posses significant CNS depressant (anticonvulsant) properties (Akbar et al., 1985). Further pharmacological screening revealed a broad variety of pharmacological effects. When tested in animal models, the ethanolic extract of red sage showed anti-inflammatory and analgesic effects, hypothermic response in non-pyretic rats and enhancement of the wound healing process (Akbar, 1989). The ethanolic extract of S. haematodes had significant inotropic and chronotropic effects on isolated rabbit hearts. It also had a parasympathomimetic effect on isolated rabbit duodenum. Unfortunately, active substances responsible for these effects have been so far unknown, although different constituents are probably involved.

S. desoleana Atzei & Picci, an indigenous Sardinian species, is used in folk medicine to treat menstrual and digestive disorders and diseases of the central nervous system. Peana and Satta (1992) reported that the essential oil from the leaves of S. desoleana had a dose dependent central nervous-depressant effect in mice. In further pharmacological screening, the essential oil was tested also for its choleretic effects in rats and was found to significantly increase bile flux at 1 h after administration of essential oil at 250 mg/kg i.p. or its alcoholic (linalool and alpha-terpineol) fraction at 62 mg/kg i.p. (Peana et al., 1994). Intraperitoneal administration of essential oil produced stronger choleretic effects than subcutaneous administration. The amount of dry bile residue of essential oil treated rats was higher than that of control values at 1 and at 2 h after treatment. Linalool and alpha-terpineol fractions of the essential oil fractions showed the strongest choleretic activity.

A wide variety of species (900 known species) of the Salvia genus shows also much variety in bioactivity. There are, however, many differences in pharmacol ogical effects amongst these species. Aerial parts of these plants usually contain flavonoids and triterpenoids as well as essential oils with volatile compounds such as monoterpenoids. Diterpenoids are the main compounds in roots. Some of these compounds have been isolated and their structures elucidated, however, many compounds are still scientifically challenging. Many more studies on structure-activity relationship within the Salvia species are needed in order to explain mechanisms of biological activity.

ANTIMICROBIAL AND ANTIVIRAL ACTIVITIES

Extensive literature on the antimicrobial potency of the Salvia genus reveals a broad variability with regard to microorganisms sensitivity as well as to the efficiency

(measured as minimal inhibitory concentration, MIC) of tested compounds, when different species are considered. Most frequently, essential oils with volatile monoterpenoids as their major constituents are reported to be antibacterially active in those Salvia species that are rich in essential oil (S. officinalis L., S. lavandulifolia Vahl., S. triloba L.=S. fruticosa Mill.).

Less evidence exists on the antifungal potency of these essential oils. Generally, Gram-negative bacteria are not sensitive or are less sensitive for sage essential oil when compared with the sensitivity of Gram-positive bacteria. This is in agreement with observations of Maruzella and Henry (1958) and of Yousef and Tawil (1980), while some authors report that there is no relationship between susceptibility of tested bacteria to essential oils and their Gram reaction (Deans and Ritchie, 1987, Shapiro et al., 1994).

When compared with some other species from Labiatae family (especially Thymus spp. and Origanum spp.), essential oils of Salvia species show relatively low antibacterial and/or antifungal activity (Thompson et al., 1986).

Sage oil turned out to exhibit inhibitory effects on many of oral bacteria, such as obligate anaerobes (Fusobacterium nucleatum, Peptostreptococcus anaerobius, Porphyromonas gingivalis, Treponema denticola, Treponema vincentii) and capnophilic microaerophiles (Actinobacillus actinomycetemcomitans, Capnocytophaga spp., Eikenella corrodens) at concentrations between 0.06 % (w/v) and 0.2 % (w/v). When compared to obligate anaerobes, the facultative anaerobe group of oral bacteria (Actinomyces viscosus, Strepococcus sanguis, Streptococcus sobrinus) was generally less sensitive to administered sage oil. Sage oil inhibited the growth of the facultative group at concentrations between 0.3% (w/v) and 0.6 % (w/ v) (Shapiro et al., 1994).

The Egyptian sage essential oil, composed mostly of thujone (41.5%) and of limonene (14.7%), shows antibacterial activity against Gram-positive Sarcina spp. (MIC=2.0 mg/ml), Staphylococcus aureus (MIC =1.0 mg/ml), Bacillus subtilis (MIC=0.75 mg/ml) and against yeast Saccharomyces cerevisiae (MIC 2.0 mg/1) (Farag et al., 1989a). According to Kustrak and Pepeljnjak (1989), the antimicrobial activity (against Bacillus subtilis) of sage oil depended on composition, i.e. contents of 1, 8-cineole, p-cymene, a- and ^-thujone and camphor as well as on the relationship between 1, 8-cineole, p-cymene and ketonic compounds. The antimicrobial activity of Dalmatian sage oil, was attributed to its thujone contents (Jalsenjak et al., 1987). Antibacterial activity was not reduced even when essential oil was microencapsulated into gelatin-acacia capsules (although a certain time lag in achieving full activity was observed), microencapsulation, however, inhibited antifungal activity of sage oil.

According to Deans and Ritchie (1987), who tested 50 essential oils against 25 genera of bacteria, sage (S. officinalis L.) essential oil (undiluted) was moderately effective against the growth of Bacillus subtilis, Brevibacterium linens, Micrococcus luteus, Seratia marcescens bacteria. When tested against eight bacteria (Bacillus subtilis, Escherichia coli, Hafnia alvei, Micrococcus luteus, Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis) and five fungi (Aspergillus niger, Aspergillus terreus, two strains of Candida albicans,

Fusarium spp.) commercial sage essential oil (probably issued from a mixture of S. triloba L. and of S. lavandulifolia Vahl.) had almost no effect (Biondi et al., 1993). Similarly, the essential oil from S. triloba showed no fungistatic activity against soil-borne pathogens (Fusarium oxysporum, Macrophomina phaseolina) or against foliar plant pathogens (Botrytis cinerea, Exserohilum turcicum) (Shimoni et al., 1993). Ground sage (2%), as a component of Malt Extract Agar (MEA) medium, showed no fungistatic activity against food-contaminating fungi (Trichoderma harzianum, Alternaria alternata, Fusarium oxysporum, Mucor circinelloides f. griseo-cyanus, Rhizopus stolonifer, Cladosporium cladosporioides, Fusarium culmorum, Aspergillus versi-color, Penicillium citrinum) (Schmitz et al., 1993).

Contrary to this, by measuring the antifungal property of sage essential oil against Alternaria alternata and against Aspergillus parasiticus, a strong fungistatic effect was observed (Crisan and Hodisan, 1975; Farag et al., 1989b). Volatile oils showed much stronger fungistatic properties than tested extracts (Crisan and Hodisan, 1975).

Concentration of 2.0 mg/ml sage oil reduced Aspergillus parasiticus mould growth by 87.6% and inhibited total aflatoxin (B and G groups) production by more than 96% (Farag et al., 1989b). Like antibacterial activity, the mould growth inhibitory effect of sage oil was mainly due to thujone as a major component in essential oil. According to Farag et al. (1989a, 1989b), a relationship between the chemical structures of the most prevalent compounds in essential oils and antimicrobial activity was observed. The antimicrobial activity of sage essential oil was lower than that of essential oils (thyme oil, clove oil) containing thymol or other phenolic-OH structure compounds (eugenol). A well known inductive effect of polar functional groups (e.g. hydroxyl or isopropyl) on aromatic nucleus seems of great importance in explaining the correlation between structure and antimicrobial activity of the essential oil compound.

The essential oil of S. plebeia is also reported to have fungitoxic potential, inhibiting the growth of storage fungus Aspergillus flavus by 54% (at a concentration of 5000 ppm) (Mishra and Dubey, 1990).

Much emphasis has also been placed on the investigation of compounds (i.e. diterpenoids, flavonoids) in extracts of different Salvia species, which show significant inhibitory activity against bacteria (G-negative and/or G-positive) and fungi.

Significant antibacterial (towards gram-negative Klebsiella pneumoniae at a concentration 400 pg/ml and against gram-positive Bacillus subtilis at 300 pg/ml and Staphylocoecus aureus (200 pg/ml) and antifungal (towards Candida albicans at concentration of 200 pg/ml) compounds (carnosic acid, 16-hydroxycarnosic acid and their derivatives) were found in the diterpene acid fraction of extract of S. apiana, whereas its essential oil (composed primarily of 1, 8-cineole and camphor) as well as a mixture of oleanolic and ursolic acid were inactive even at 1000 pg/ml against tested organisms (Dentali and Hoffmann, 1992). Antibacterial activity (against Staphylococcus aureus) of carnosic acid (referred to as salvin) has been reported already by Dobrynin et al. (1976) and Pavlenko et al. (1989). The dry methanolic extract of S. officinalis, dissolved in DMSO (50 mg/ml DMSO) inhibited the growth of Gram-positive Staphylococcus aureus at a concentration 100 pg/ml, while no

antibacterial activity against Gram-negative bacteria E. coli or Pseudomonas aeruginosa strains was observed (Baricevic et al., 1996). An abietane diterpene galdosol (structure 1) with antibacterial properties against Bacillus subtilis, Micrococcus luteus and Staphylococcus aureus was isolated from the aerial parts of S. canariensis L., a plant endemic to Canary Islands (Gonzalez et al., 1989a; Gonzalez et al., 1989b; Darias et al., 1990). This shrub has been used in folk medicine as an antispasmodic, febrifuge and hypoglycemiant. Abietane diterpenes, sugiol (structure 2) and 15-hydroxy-7-oxo-abiet-8,11,13-triene (structure 3), were isolated from S. albocaerulea Lindl., a species, which is native to the south-eastern intertropical region of Mexico. These two diterpenes are responsible for antimicrobial activity against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus, MIC 50 pg/ml) and for a moderate activity against Candida albicans (at 100 pg/ml), but are inactive against Gram-negative bacteria (Pereda-Miranda et al., 1992). Another abietane diterpene, forskalinone (structure 4) isolated from roots of S. forskahlei L., showed slight antimicrobial activity against Enterococcus faecalis (168 pg/ml) (Ulubelen et al., 1996). Free catechol grouping (or

Structure 2.

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