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Pharmacological activity of Salvia lavandulifolia and chemical components of its essential oil. A review/Actividad farmacologica de Salvia lavandulifolia Valh y los componentes quimicos de su aceite esencial.

INTRODUCTION

The genus Salvia of Lamiaceae is widely distributed and it is used extensively as ethnomedicinal plant. The Lamiaceae family is compound by 200 genus and 3000 species (Topcu, 2006). Salvia L. (sage), belongs to Mentheae Tribe, is the largest and more diverse genus of this family and it is represented by 900 recognized species, native of Mediterranean. Nevertheless, widespread almost all around the world, abundantly located in three areas: through Europe around the Mediterranean, to South-East Asia and more than half of species across Central and South America (GALI-MUHTASIB & al., 2000; WALKER & al., 2004).

The genus name Salvia is derived from Latin word 'salvare' meaning 'to heal or to be safe and unharmed' referring to the medicinal properties of some of the species (BLUMENTHAL & al., 2000). For centuries Salvia species are used as folk medicine for its curative properties. Sage has a historical reputation in Greek, Egyptian, indigenous American Indian, Roman ceremonies as a sacred herb and especially by traditional Chinese medicines, for promotion of health and treatment of illness, and as an herb for longevity. A proverb assures that "How can man die that has sage in the garden?" (FONT-QUER, 1999). Pliny the Elder (23-79 AD) reported the properties of sage as enhancer of memory functions and the importance of this plant in traditional medicine (RAMOS & al., 2010). Whereas the Greek physician Dioscorides reported sage stop bleeding wounds and sores besides clean ulcers after aqueous decoction of the plant. Besides, juice warm water is used for hoarseness and cough (BLUMENTHAL & al., 2000). Several species of Salvia genus present therapeutic activity due to their essential oils. Salvia was used in folk medicine all around the world from epilepsy, treat colds, bronchitis, tuberculosis, hemorrhage, and menstrual disorders (DWECK, 2000; TOPCU, 2006; TILDESLEY & al., 2005) and as antiseptic, astringent, depurative, digestive, expectorant, febrifuge and tonic, and also externally as insecticide, skin and month or throat infections (JIROVETZ & al., 2007; GONZALEZ & al., 2012). Moreover, species belonging to this genus are also known for other biological activities, such as anti-inflammatory, antidiabetic, antimicrobial, antitumor or anxiolytic activities (LOIZZO & al., 2009; KELEN & TEPE, 2008) or antispasmodic, antimalarial, anticancer or antifungal. Furthermore, it also preserves food due its antioxidant properties, as well as spice for its natural flavor (GUILLEN & IBARCOITIA, 1995; TOPCU, 2006).

About 25% of modern drugs are originated from plants either directly or indirectly. Phytochemical and pharmacological researches carried out during last years confirm many traditional uses of Salvia genus in central nervous system disorders (IMANSHAHIDI & HOSSEINZADEH, 2006). It is necessary therapeutic agents for nervous system disorders with reduce toxicity and side effects and with safety and acceptability. Salvia lavandulifolia present no reported adverse effects from its long use as flavoring in food (PERRY & al., 2001). Sage genus, including Salvia lavandulifolia (Figure 1), has been used by humans for more than two millennia in the treatment of different age related cognitive disorders associated with ageing to enhance cognitive function and attenuate cognitive decline (KENNEDY & WIGHTMAN, 2011). In addition beneficial effects on disorders of central nervous systems as cognitive disorders, depression and cerebral ischemia have been demonstrated (AKHONDZADEH & al., 2003; HOWES & al., 2003). In recent controlled trials, administration of sage extracts, with known cholinergic characteristic improve behavioral and cognitive function in healthy young adults humans, and also improve memory and attention in healthy older volunteers by its anticholinesterase properties relevant to Alzheimer's disease therapy (Wake & al., 2000; SCHOLEY & al., 2008; LOIZZO & al., 2009). Cholinesterase inhibiting from botanical origin, used to the treatment of these diseases modifies the progress and symptoms of the diseases (ABASCAL & YARNELL, 2004a; KENNEDY & SCHOLEY, 2006; Adams & al., 2007). In Alzheimer's disease the biological mechanism underlying dementia is: neuronal damage caused by oxidative stress and inflammatory reactions; disrupted cholinergic transmission; and beta-amyloid formation or toxicity (PERRY & al., 1999). Most of current treatments increase the availability of neurotransmitter acetylcholine through the inhibition of cholinesterase enzymes (KENNEDY & SCHOLEY, 2006).

Aromatic plants are important as food-flavouring agent and spice, in cosmetic or perfumes but also for their pharmaceutical and therapeutical properties with less adverse effects than synthetic drugs. The use of essential oils for healing purposes has been known in folk medicine since ancient times, however the pharmacology studies on whole essential oil and their constituents are very little (PERRY & PERRY, 2006; FRANZ, 2010). There are several studies on analyses of quantitative and qualitative changes in essential oils of sage, and genetic and morphological variations are observed according to their geographical origin and growth stage (AMIRI, 2007). The greatest use of essential oil is in food as flavorings, perfumes as fragrances, pharmaceuticals (BURT, 2004) and as ornamental (CLEBSCH, 2003; PEURAT & al., 2012). S. lavandulifolia essential oil inhibits the enzyme acethylcholinesterase; and present antioxidant, anti-inflammatory and estrogenic activity. Therefore, the plant has notable reputation for its potentially relevant activities in brain function as cognition enhancing, beneficial effects on behavioral, for treatment of depression, memory disorder, and preventive and symptomatic treatment of age-related memory decline (PERRY & al., 1998).

TAXONOMICAL, GEOGRAPHICAL AND ECOLOGICAL FEATURES

Salvia lavandulifolia Valh. is native from the Iberian Peninsula (Figura 2), which is the reason of its common name "Spanish sage". It was considered as an medicinal species from ancient times (CANIGUERAL & al., 1998). The geographical distribution is similar to actual one however it is thought that the species most probably arrive to Iberian Peninsula through North of Africa. Different factors such as historic, geographic, geologic, and climatic could have influenced on its present-day distribution. The isolation of populations makes possible the microevolution of the species (ROSUA & BLANCA, 1990). This species is widely spread over the Mediterranean area, mainly in East of Spain (especially in Andalucia, Murcia and Castilla), just extending into western Mediterranean: South East France, North West Africa (Morocco and Algeria) (Jordan & al., 2009; SAEZ, 2010). Salvia lavandulifolia is very adapted to the semiarid Mediterranean climate, growing in rocky soil in sandy-calcareous mountains. This plant can be found in altitudes from 350 to 2000 m above the sea level. The species grows on types of soil, preferably on slightly deep and basic soils, on limestone substrate, loamy or gypsum (MARCOS & al., 1988; SAEZ, 2010). While it commonly grows wild, the cultivated plots are also shown. Salvia grows optimally in full sun and needs well-drained soil (CRESPO & al., 1986; PAGES & al., 1992).

Salvia lavandulifolia Vahl. is characterized by a small sub-shrub or herb up to 17-100 cm, stems branched, erect and pubescent, tector hairs sometimes glandular. The leaves grow opposite each other on the stem and appear to grow in bunches. They are green or gray-white, simple and petiolate with hair protectors, limbo from, elliptic to linear-lanceolate and petiole 5-54 mm. The inflorescence, 5-71 cm, simple or branched, with 2-8 flowers. Bracts are ovate, lanceolate, green or violet color. Flowers present pedicels and calyx of 8-14 mm, regular, tubular or campanulate, usually green or violet-purple, pubescent. Its corolla of 15-40 mm in size, pink, purple or blue violet, straight, laterally compressed. The blooming develops for about one month in late spring and early summer (HEDGE, 1972; SAEZ, 2010). The leaf presents seasonally dimorphic (PALACIOS & al., 2008). The different subspecies of Salvia lavandulifolia has been studied in diverse geographical regions of Spain by different authors (VALDES-BERMEJO & LOPEZ, 1977; ROSUA & BLANCA, 1985, 1988; FERNANDEZ-GONZALEZ & AL., 1986; FIGUEROLA, 1987; DONAIRE & al., 1992; HERVAS-SERRANO & al., 1997; SOLANAS & CRESPO, 1998; SALHI & al., 2010; LAZARO BELLO, 2011). Till date five different subspecies have been described: S. lavandulifolia subsp. lavandulifolia, S. lavandulifolia subsp. vellerea, S. lavandulifolia subsp. mariolensis, S. lavandulifolia subsp. blancoana and S. lavandulifolia subsp. oxyodon (Saez, 2010).

ETHNOPHARMACOLOGY

Salvia species have been widely used since the Middle Ages. The English herbalist John Gerard (1545-1607) wrote about sage in 1597, "It is singularly good for the head and brain and quickened the nerves and memory." About 50 years later, English physician Nicholas Culpeper (1616-1654) wrote in 1652, "It also heals the memory, warming and quickening the senses." John Hill (1714-1775), in 1756, said "Sage will retard that rapid progress of decay that treads upon our heels so fast in later years of life, will preserve faculties and memory more valuable to the rational mind than life itself". Salvia tea is described by Grieve in 1980 as a "highly serviceable stimulant tonic in debility of the nervous system" (HOUGTON & al., 2004; PERRY & al., 2000b).

Salvia has been considered as a 'panacea' throughout the world. The traditional uses recorded for this plant, are numerous and mainly medicinal. This aromatic species is frequently used as folk remedies to treat some diseases and several of these pharmacological effects have been demonstrated in controlled laboratory studies (CRESPO & al., 1986). It is a common food supplement (THACKERAY & al., 2010). But also play an important role in preservation of foods due organoleptic properties of terpenes, sesquiterpenes and oxygenated derivates (GUILLEN & MANZANOS, 1999) and cosmetic industry for its fragrance (cosmetic and perfumes). It is used in perfumes and for flavoring because it is not irritant, sensitizing to human skin and non-phototoxic (DWECK, 2000). Since ancient Greek, sage has a history as a cognition enhancer and treatment of memory decline. Several chemical and pharmacological studies of this aromatic plant are described in the literature, as sources of natural antioxidant with health benefits. Indications have traditionally included beneficial effects on central nervous system, mainly in mood and memory enhancement age-related because of their anticholinesterase activity, depression or epilepsy might hence be due to a combination of actions (PERRY & al., 2000b; TILDESLEY & al., 2003)

S. lavandulifolia has been used in traditional medicine for its therapeutic properties as spasmolytic, antiseptic (bactericidal, virucidal and fungicidal), analgesic, sedative, anti-inflammatory and locally anesthetic remedies. This herbal medicine has been utilized for their psychoactive and psychotropic properties. The leaves of S. lavandulifolia are traditionally used as a choleretic, astringent, cicatrizing and antiseptic drug (Canigueral & al., 1989; ZRIRA & al., 2004), and also antiperspirant effect for menopause symptoms. Aqueous extract present hypoglycemic activity (ZARZUELO & al., 1991), and is used as folk remedies to treat diabetic hyperglycemia. The essential oil of the plant is rich of compounds not only with antimicrobial and antiviral activities but also with antioxidant properties. Others notable ailments for which this plant has been used includes depression (PERRY & al., 2000b).

PHYTOCHEMISTRY

Besides its morphological complexity, S. lavandulifolia shows a well-known variability in its chemical constituents, many of them have been identified, and also present many physical characteristics. The main secondary metabolites are flavonoids and terpenoids. JOHNSTON & BEART (2004) suggest that flavonoids have the potential to manage several psychiatric and neurological disorders. Flavonoids, triterpenoids and monoterpenes (present in volatile compounds) are usual components of aerial parts found in flowers and leaves, whereas diterpenoids are the main compounds of roots (ESCUDERO & al., 1983; ULUBELEN & al., 2000; BARICEVIC & BARTOL, 2000; Topcu, 2006). The herb presents phenolic monoterpenoid, flavones and the phenolic rosmarinic acid. Salvia is also a rich source of polyphenols (ZARZUELO & al., 1995; Canigueral & al., 1989; LU & FOO, 2002).

ESSENTIAL OIL

At room temperature, much of them are a chemically complex mixture of aromatic oily liquids, insoluble in water and soluble in organic solvents, whose constituents of secondary metabolism are biosynthesized from aromatic plants (e.g. flowers, leaves, herbs, fruits, roots or wood). Essential oil of plant is a mixture of great number of terpenic components synthesizes in the cells of the leaf trichomes and stored in the glandular hairs of aerial parts (GIANNOULI & al., 2000). Monoterpenes incorporate 2 isoprene units (C10) and are the most representative molecules of essential oils (WANG & al., 2010). Volatile oils of Salvia usually present more than 100 individual components at different concentrations. Several authors have published the phytochemical analysis showing the presence of many compounds on the essential oil composition of this species (LAWRENCE & al., 1970; JORDAN & al., 2009; GUILLEN & al., 1999; CARDILE & al., 2009; HERRAIZ & al., 2010).Most of these studies concern the variations of a few major essential oil constituents, without study the high number of minor compounds. The essential oil percentage composition gives an important characteristic to classify each plant (SANTOS-GOMES & FERNANDES-FERREIRA, 2001).

Their components are volatile monoterpenoids whose main common active compounds which define the chemotype of the essential oil include 1,8-cineole (GUILLEN & IBARGOITIA, 1995; SAVELEV & al., 2003; PERRY & al., 2000a) and camphor. The chromatographic profile are: 1,8-cineole or eucalyptol (11-25%), camphor (11-36%), [alpha]-pinene (4-11%), sabinene (0.1-3%), limonene (25%), linalool (0,5-9%), borneol (1-8%), linalil acetate (<5%) and terpin-1-en-4-ol (<2%). [beta]-caryophyllene is a non-steroidal anti-inflamatory sesquiterpene with gastric cytoprotection activity (TAMBE & al., 1996). The Chromatographic profile according to the standard UNE 84310:2001 (AENOR, 2001) for Salvia lavandulifolia essential oil is shown in Table 1.

The gas chromatography analyses allowed the identification and relative quantification of components of this sage species after the isolation of essential oil by hydro-distillation usually. This essential oil is obtained from the dried parts of the plant using a Clevenger apparatus for 4 h (ANON., 2004). After the extraction, the oil is colorless to slightly yellow with fine fragrance oil, camphoraceous and cineole-like (VERNIN & METZGER, 1986). Volatile constituents of the essential oil probably cross the blood-brain barrier by their lipophilicity and small molecular size (SAVELEV & al., 2004).

PHARMACOLOGICAL ACTIVITIES

Plenty of investigations indicated that Salvia genus has been popular in phytochemical and ethnobotanical research, revealing important pharmacological properties, in vitro as well as in vivo, with fewer side effects. There are several studies of S. lavandulifolia extracts and constituents that investigate their traditional, central nervous system related use. Its antioxidant, anticholinesterase, anti-inflammatory, oestrogenic and central nervous system depressant effects are relevant to the treatment of some neurodegenerative problems as Alzheimer's disease (MANTLE & al., 2000; HOUGHTON & HOWES, 2005; KENNEDY, 2009). Several studies relate with neurodegenerative problems are explain in Table 2. The activity properties on central nervous system (CNS) of this plant are attributable to the presence of potentially active secondary metabolites constituents (PANAGIOTOPOULOS & al., 2000). These chemicals, that may improve brain function, are synthesized to increase the suitability of the plant to survive to pathogens or environment and potential effectiveness as nootropics (KENNEDY & WIGHTMAN, 2011). Terpenoids present biological activities, some of them very relevant as neuroprotective, important for the treatment of several diseases (CHANG & al., 2007) and in protection against pathological or stress conditions (BAKKALI & al., 2008). The main disadvantage of natural products is the small quantity that can be extracted from each plant. Numerous literatures have recently reported the chemical composition, biological properties, and possible applications of essential oils as a source of pharmaceutical natural products. Synergistic or antagonistic interactions among the components increase the potency, and also the activity of compound in minor percentage of essential oil mixture has to be considered (BURT, 2004).

ANTIOXIDANT ACTIVITY

Many diseases of the nervous system involve free radical damage due to an excess of reactive oxygen species. The cellular damage to lipid, protein and DNA is associated with a number of diseases, as neurodegenerative disorders. Antioxidant activity limiting free radical damage of sage oil was correlated with diterpenes and oxygenated sesquiterpenes concentration (PAPAGEORGIOU & al., 2008). The activity in enzyme-dependent and enzyme independent systems of lipid peroxidation (ZUPKO & al., 2001); carvacrol, luteolin and rosmarinic acid with potent scavenging activity in herb, and 1.8-cineole, linalool, [alpha] and [beta]-pinene in essential oil by inhibition of bovine brain liposome peroxidation by the ARUOMA & al. method (1996). Thujone and geraniol present lower effect (Perry & al., 2001) as well as eugenol and thymol, and other methylisopropylphenols (GUILLEN & MANZANOS, 1999). The potential antioxidant activity depends on concentration and systems used (PERRY & al., 2003). Camphor instead presents pro-oxidant properties in a liposome peroxidation preparation, but this activity may not have effect in the whole essential oil (PERRY & al., 2001) and its association with neurotoxicity (convulsive) at high doses. Salvia lavandulifolia water extracts protects DNA against [H.sub.2][O.sub.2] induced damage in HeLa cells by acting on reactive species or by stimulating endogenous defense systems, only 21% due its low levels of phenolics compounds (RAMOS & al., 2010).

ANTI-INFLAMMATORY ACTIVITY

Inflammation is associated with effects in disorders of nervous system. There are many studies regarding the anti-inflammatory activity of plants is produced by phenolics and flavonoids as carvacrol, the flavones genkwarin and luteolin and the 6-hydroxy flavones cirsimaritin and salvigenin and polyphenolics as rosmarinic acid, and the monoterpenoid present in the essential oil: [alpha]-pinene (that inhibit the enzyme cycloxygenase and weak selectivity for eicosanoid, leukotriene B4 [LTB4] that was measured by radio immunoassay) and geraniol show weak selectivity for the thromboxane B2 [TXB2]. Both of them present significant inhibition of synthesis of pro-inflamatory eicosanoid in rat leucocytes stimulated by calcium-ionophore method (PERRY & al., 2001; PERRY & al., 2003).

OESTROGENIC ACTIVITY

Oestrogenic activity has been suggested to play a role in the prevention or deletion of neurodegeneration perhaps by protection against neuronal loss. Oestrogenic activity and no dose-dependent activity were demonstrated in essential oil of S. lavandulifolia, maybe for the volatility of its components (PERRY & al., 2001). The essential oil and their monoterpenoid constituent geraniol, with hydroxyl group, present a weak oestrogenic activity by induction of [beta]-galactosidase activity in yeast cells (Saccharomyces cerevisiae) (PERRY & al., 2003).

CHOLINESTERASE INHIBITORY ACTIVITY

Increasing levels of the neurotransmitter acethylcholine and their synaptic availability are due to a delay in the catabolism of acethylcholine (ACh) (HOUGHTON & al., 2006). Acetylcholine (ACh) transmitted electrical impulses, by nerve cells to another nerve cell or to muscles. The receptors sensitive to ACh usually are muscarinic or nicotinic. The enzymes acetylcholinesterase (AChE) hydrolyses the ACh and produces a loss of stimulatory activity. Inhibit the cholinesterase group of enzymes results in a prolongation of the activity of ACh. Colorimetric method developed by ELLMAN & al., (1961) is widely used to detection of AChE inhibition (MIYAZAWA & YAMAFUJI, 2005). This is very important in the treatment of diseases associated with low levels of Ach in the brain as in Alzheimer's disease by improving cognitive function (HOUGHTON & al., 2006). Sage has previously been shown to improve cognitive function and to inhibit cholinesterase. Acetylcholine has an important role in cognitive functions such as memory, learning and attention (TILDESLEY & al., 2003) and for problems associated with aging such as memory loss (PERRY & al., 1999). Several studies show that Salvia species present properties relevant to the attenuation of cognitive declination by the inhibition of the brain enzymes in vitro butyrylcholinesterase and acethylcholinesterase (PERRY & al., 1996; SAVELEV & al., 2004). S. lavandulifolia essential oil inhibits human brain AChE in vitro in human postmortem brain tissue at quite low concentration. The inhibition is more effective when synaptic acetylcholine levels are low as happens in Alzheimer's disease, suggesting that the inhibition is competitive. Furthermore, AChE is more inhibited than butyrylcholinesterase by essential oil. In addition, it interacts with nicotinic and muscarinic receptors (PERRY & al., 1996) and bovine erythrocyte AChE in vitro (PERRY & al., 2000a). And this AChE inhibition in selected brain areas was confirmed in vivo after oral administration of essential oil to young rats. Compared with control group, there was a significant decrease in AChE activity in the striatum but not in the hippocampus at lower dose. At higher dose the decrease is in both places (PERRY & al., 1996; PERRY & al., 2002). 1,8-cineole and [alpha]-pinene present the most inhibition of the enzyme, against bovine erythrocyte AChE (PERRY & al., 2000a) and synergistic effects between them (Savelev & al., 2003). However, other main monoterpenoid constituents are responsible for antiChE activity of the whole essential oil as camphor and bornyl acetate with weak activity (Perry & al., 2000a) or borneol, [alpha] and [beta]-pinene. Spanish sage essential oil may be relevant in the treatment of Alzheimer's disease (ABASCAL & YARNELL, 2004a). The neuronal systems affected present a cholinergic system where essential oil and its constituents demonstrated dose dependent inhibition of erythrocytes human bovine AChE in vitro. Specific monoterpenes, such as [alpha]-pinene, the most potent inhibitors tested, followed by 1,8-cineole and camphor after as weaker inhibitor, are responsible for the in vitro effect. All of them present uncompetitive reversible inhibitor dose-dependent activity. No single component is particularly potent, suggesting a synergistic relationship. Then, monoterpenes were less active than the alkaloidal AChE inhibitors such as physostigmine (PERRY & al., 2000a).

CENTRAL NERVOUS SYSTEM DEPRESSANT ACTIVITY

This action has been shown by monoterpenoids linalool and terpineol in vivo through glutamatergic systems. Salvia species has been frequently used as anxiolytic and sedative (PERRY & al., 2003).

ANTIFUNGAL ACTIVITY

In a study against pathogenic Candida albicans, S. lavandulifolia possess the strongest antifungal activity compared with other species of Salvia. Usually the chemical composition of the oil has influential properties; probably its main components (1,8-cineole and camphor) have antifungal activity (JIROVETZ & al., 2007).

ANTIMICROBIAL ACTIVITY

Antimicrobial activity has long been recognized. In vitro essential oil of S. lavandulifolia is used for the control of growth and survival of pathogenic microorganisms by the determination of MIC and MBC, which inhibit the growth of Listeria monocytogenes (ROTA & al., 2004). There has been observed synergism between carvacrol and pcymene, its precursor, and between cinnamaldehyde and eugenol. And also it has been observed synergism between the components of essential oil and methods of mild preservation. There is some evidence that minor components have an important role in this activity, possibly by producing a synergistic effect between other components. Generally, essential oils produced from plants harvested during or immediately after flowering present the strongest activity (Burt, 2004). Phenolic components are the most active and usually act as membrane permeabilisers. Gram-positive organism is generally more sensitive to essential oil than gram-negative. Antimicrobial activity of essential oils has been mainly attributed to the presence of 1, 8-cineole, [beta]-thujone, camphor, borneol and p-cymene (PIEROZAN & al., 2009).

CYTOTOXIC ACTIVITY

In some studies, the cytotoxic activities of oil were tested on cultures of different human tumor cell compared to doxorubicin and anticancer agent. The tumor cells used were from human promyelocytic leukemia, human chronic myelogenous leukemia, human breast adenocarcinoma and human ovarian adenocarcinoma. S. lavandulifolia essential oil were less active than the control antineoplasic doxorubicin against tumor cells, however unless weak cytotoxic activity of oil is present (FORAY & al., 1999). The cytotoxic capacity of the essential oils is based on a prooxidant activity by damage the cell wall and membrane and lysis cell finally or also by reducing local tumor size or its proliferation by apoptotic. For example, geraniol inhibits colon cancer cell proliferation by membrane depolarisation and ionic canals of signaling pathways (BAKKALI & al., 2008).

BIOACTIVITY OF ESSENTIAL OIL'S COMPONENTS

Essential oils and their constituents have been used since ancient times to prevent and treat many diseases because of their pharmaceutical properties (EDRIS, 2007). They have been used as antimicrobial, fungicidal, antiparasitical, medicinal and cosmetic applications. Nowadays, they are frequently used in pharmaceutical, cosmetic, agricultural and food industries (BAKKALI & al., 2008). Essential oils are complex mixtures of compounds with beneficial or adverse effects. Some studies show that the interaction between whole essential oil have a greater activity than some mixed components, which suggest that even minor components are critical to the activity. Synergism effect is observed when the effect of the combined substances is greater than the individual effects. In contrast, antagonism is observed when the effect of one or both components is less when they are applied together than individually (Burt, 2004). S. lavandulifolia essential oil activity is attributed to the behavior of several components simultaneously, not individually (CRESPO & al., 1986). Volatile constituents of the essential oil likely cross the blood-brain barrier for their lipophilicity and small molecular size (SAVELEV & al., 2004). S. lavandulifolia essential oil produces some significant effects on cognition. S. lavandulifolia essential oil inhibit acethylcholinesterase enzyme and its monoterpenoids alone produce this effect with different potency (SAVELEV & al., 2003; Perry & al., 2000a; PERRY & al., 2002). These activities may be particularly important in degeneration associated with age, such as dementia. Therefore effects of S. lavandulifolia essential oil are really relevant to potential treatment of central nervous system disorders such as Alzheimer's disease. Many secondary metabolites from plants are used in phytotherapy, cosmetics or aromatherapy. The components activity of essential oil of S. lavandulifolia identified by different studies is summarized in Table 3.

SAFETY: TOXICOLOGY AND SIDE EFFECTS

Only trace of the convulsant thujone, (a terpenoid ketone), could be detected at any time in vegetative cycle of Spanish sage. Ph. <0.5% (BRUNETON, 2001; BARICEVIC & BARTOL, 2000). S. lavandulifolia is closely related to S. officinalis sharing similar composition, with the exception of potentially toxic thujone. Its concentration (1.30-22.82% [alpha]-thujone and 0.01-4.32% [beta]-thujone) makes the difference with S. officinalis, where it is higher (1.20-45.80% [alpha]-thujone and 1.02-40.10 [beta]-thujone). Thujone in large doses is toxic (Tildesley & al., 2003; abascal & al., 2004b). For this reason S. lavandulifolia is more suitable species to investigate comparison with S. officinalis (GIANNOULI & KINTZIOS, 2000; Perry & al., 2000a). The [alpha]-thujone, the known GABA-a receptor antagonist monoterpenoid (JOHNSTON & BEART, 2004; KENNEDY & al., 2011), present genotoxicity, reproductive toxicity, chronic toxicity, neurotoxicity and carcinogenicity testing in rats and mice (HOLD & al., 2001). Most of the commercial samples present the terpenoid sabinyl acetate (0.1-24% according to the subspecies, the chemotype and their origin) (AFNOR norm: NFT 75-212). This shows potential teratogenicity activity and dose-dependent abortifacient effect; while it does not present fetotoxicity in mice. For these reasons its use should be avoided in pregnant women (PAGES & al., 1992; FOURNIER & al., 1993). The most important proportions of sabinyl acetate are from S. lavandulifolia subsp. vellerea (MARCOS & al., 1988). There are potential adverse effects associated with the overdose of essential oils. High percentage of ketones in essential oils (camphor or thujone) are contraindicate in patients with epilepsy for the epileptiform activity of these compounds. Camphor poisoning, produces gastrointestinal and CNS irritation after toxic ingestion and it is associated with hepatotoxicity and toxicity in kidney (MILLET & al., 1981; SCHNITZLER & al., 2008). For these reasons, Salvia are not considered poisonous (unless at very high dosage) (PERRY & al., 1998).

CONCLUSIONS AND FUTURE APPLICATIONS

Since immemorial times, several plants have been used not only in diet but also for the therapy of diseases. Although Salvia species are well known to be used in folk medicine, the experimental studies to support their use are largely lacking. Many of these species possess activity on the central nervous system, traditionally used to support memory. Sage can be used in the treatment of Alzheimer's disease symptoms (PERRY & al., 2003). The inhibition of AChE activity by bycyclic monoterpenoids ([alpha]--and [beta]-pinene, camphor and borneol) was studied by the colorimetric method of ELLMAN (1961). In the last years, the essential oils of plants have been great interest as a source of natural products, and an alternative treatment of some diseases, due to the presence of secondary metabolites. Essential oils of Lamiaceae family present high biological activities as antimicrobial, antibacterial, antiinflamatory and antioxidant. They have been recognized by its curative, nutritional and cosmetic properties. This is due to its secondary metabolites. Currently, they are widely used in aromatheraphy; however they cannot be applied to human skin in a pure form, in food, cosmetic and pharmaceutical industries. Several studies have shown that Salvia lavandulifolia present properties to attenuate the cognitive decline in natural aging and dementia. The improvement mood and cognition-enhancing effects of sage also exhibit anti-oxidant, antiinflammatory and oestrogenic properties (PERRY & al., 2003), relevant to brain function (KENNEDY & SCHOLEY, 2006). These results demonstrate that Salvia lavandulifolia, its essential oil and some constituents have properties relevant to the treatment of neurodegenerative disorders due to its reported memory-enhancing properties. S. lavandulifolia has shown to possess not only properties to the treatment of cognitive decline associated with Alzheimer's disease, but also in the general cognitive enhancement of healthy people. Salvia is well tolerated and without side effects of some treatment. S. lavandulifolia essential oil was a potent inhibitor of human cholinesterase (AChE) but BuChE was weakly inhibited. This cholinesterase inhibition may explain its traditional use for ailing memory, for example it is relevant to the treatment of Alzheimer's disease (SAVELEV & al., 2004). Although evidence indicates that S. lavandulifolia may be appropriate to the treatment of neurodegenerative disorders as Alzheimer's disease, further investigation in vitro and in vivo are necessary to determinate structure, pharmacological activity relationship, the interaction of their compounds,--since monoterpenoids have demonstrated to inhibit enzymes of the cytochrome P-450 2B subfamily--, and to exploring the potential clinical value of S. lavandulifolia. Salvia is potentially a novel therapeutic treatment for neurodegenerative disorders as Alzheimer's disease. Studies on identification of active S. lavandulifolia constituents are important in the search for new therapeutic compounds. The activity of essential oil can be the result of complex interactions between its different constituents, which may produce even at low concentrations additive, synergistic or antagonistic effects of some compounds in the mixture of oil composition. Mixture --might present a very active compound which should be determined and purified. Subsequently, the effects of the oil would be better than isolated monoterpenes (BAKKALI & al., 2008). These finding reveal that the monoterpenoids may present synergistic and antagonistic complex interactions between the components to produce different activities, such as inhibitory activity of enzyme acetilcholinesterase. The inhibitory activity of essential oil results from a complex interaction between its components, that present synergic and antagonic activities between the monoterpenoids. For example, minor synergy between 1,8 cineole and [alpha]-pinene, and 1,8 cineole and caryophyllene epoxide, and antagonism between 1,8-cineole and camphor. Then, high concentration of 1,8-cineole and low camphor contents in essential oil may increase its anticholinesterase activity. The 1,8-cineole is a selective inhibitor for AChE but not for butyrylChE (SAVELEV & al., 2003). It was reported positive effects on three mood dimensions: alertness, contentedness and calmness in a dose-dependent manner, modulating mood and cognition evaluated by Cognitive Drug Research test. Specifically, following oral administration of essential oil the immediate and delayed verbal memory was improved.

In the light of these findings, further research is required to determinate the bioactive constituents of plants and elucidate their molecular mechanism of action to therapeutic application. Because, due their low cost and commercial availability might be interesting candidates to the development of dietary or pharmaceutical products.

doi: 10.5209/rev_LAZA.2013.v34.n1.43298

Received: 16 September 2013

Accepted: 31 October 2013

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Maria Porres-Martinez, Ma Emilia Carretero Accame & Ma Pilar Gomez-Serranillos (*)

(*) Department of Pharmacology. Faculty of Pharmacy. Universidad Complutense de Madrid. E-28040 Madrid, Spain. E-mail: m.porres@farm.ucm.es, meca@farm.ucm.es, pserra@farm.ucm.es

Table 1
Chromatographic profile for Salvia lavandulifolia
essential oil (AENOR, 2001)

Components                  Min. (%)    Max. (%)

[alpha]-pinene                  4          11
sabinene                       0.1          3
limonene                        2           5
1,8-cineole                    11          30
linalool                       0.3          4
camphor                        15          36
borneol                         1           5
terpinen-4-ol                              <2
linalil acetate                0.1          5
[alpha]-terpenil acetate       0.5          9
sabinil acetate                0.5          9

Table 2
Pharmacological studies of Salvia lavandulifolia

Assay            Ref.             Characteristics          Plant parts
type                                                          used

in Vitro    Perry &          Human brain tissue           Essential
            al., 1996        (post-mortem) 42-83          oil of leaf
                             years.

in Vitro    Perry &          Ellman                       Essential
            al., 2000 (a)    spectrophotometric           oil and
                             method                       terpenes

in Vitro    Perry &          Antioxidant assay by         Essential
            al., 2001        inhibition of bovine         oil and
                             brain liposome               terpenes.
                             peroxidation.

in Vivo     Perry &          Decrease AChE                Essential
            al., 2002        activity in striatum         oil
                             and in hippocampus
                             compared with
                             control rats.

in Vitro    Savelev &        Method of Ellman             Essential
            al., 2003                                     oils of
                                                          aerial parts

Clinical    Tildesley        Healthy young                Essential
trial       & al., 2003      volunteers. Double-          oil
                             blind, placebo-
                             controlled,
                             randomized.

Clinical    Perry &          11 patient, aged 76-         Essential
trial       al., 2003        95 years, diagnoses of       oil
                             mild to moderate
                             Alzheimer's disease.

in Vitro    Savelev          Method of Ellman.            Essential
            & al., 2004                                   oils of
                                                          aerial parts

Clinical    Tildesley        Double-blind,                Essential
trial       & al., 2005      placebo-controlled,          oil
                             randomised, balanced-
                             crossover studies in 24
                             healthy young adults.

Clinical    Thackeray        Double-blind, placebo-       Essential
trial       & al., 2010      controlled, randomised,      oil
                             balanced-crossover
                             design. 40 healthy
                             male and female

Clinical    Kennedy          volunteers. Double-blind,    Essential
trial       & al., 2010      placebo-controlled,          oil
                             balanced crossover
                             study. 36 health young
                             adults [+ or -] 24 years

Clinical    Moss &           Healthy adults. 36           Essential
trial       al., 2010        females and 9 males'         oil's aroma
                             aroma and no aroma
                             (Control) age 21-24

Assay                              Objetive
type

in Vitro    Dose-dependent measure inhibitory
            effects on the AChE activity

in Vitro    Dose-dependent inhibition of human
            erytrocyte acetylcholinesterase

in Vitro    Lipid peroxidation in bovine brain
            tissue, eicosanoid production in rat
            leucocytes and binding to estradiol
            receptors in yeast
            Activity relevant to the treatment of
            Alzheimer's disease (antioxidant, anti-
            inflammatory and estrogenic)

in Vivo     Oral administration (20 and 50/[micro]L)
            once daily for 5 days to rats,
            inhibition AChE

in Vitro    8 terpenoids constituents of Salvia
            lavandulifolia essential oil (1,8-cineole,
            camphor, [alpha]-pinene, [beta]-pinene, borneol,
            caryophyllene oxide, linalool and bornyl
            acetate) AChE inhibitory activity

Clinical    Single doses of Spanish sage essential
trial       oil and placebo oral administration.
            Enhance memory, cognitive and mood
            effects with confirmed AChE-inhibiting
            properties.

Clinical    Capsules of 50 [micro]l essential oil plus 50[micro]l
trial       of sunflower oil. Tolerability of oral
            administration of essential oil in patients
            with Alzheimer's disease.

in Vitro    Dose dependent BuChE and AChE
            inhibition by essential oil.

Clinical    25 and 50 [micro]l of the essential oil mixed
trial       with sunflower oil in 7-day washout
            period. Tested at 1, 2.5, 4 and 6 hours
            after the administration. Improved
            memory and mood. AChE-inhibiting
            properties

Clinical    50 [micro]l Salvia essential oil or placebo.
trial       Sensitivity of a range of cognitive and
            mood measures.

Clinical    Capsules with 50 [micro]l of essential oil or
trial       placebo with a separation of 7days.
            Effects on cognitive performance and
            mood.

Clinical    Potential aromas of Salvia lavandulifolia
trial       affect cognition and mood.

Assay                                Results
type

in Vitro    Inhibitory effects on brain AChE (63.1%, [IC.sub.50]
            <0,1[micro]g/ml) and interaction with nicotinic receptor,
            inhibiting nicotine binding with an [IC.sub.50] value <
            0.67[micro]g/ml and muscarinic at 6.7 mg/ml.

in Vitro    Inhibition of acetylcholinesterase by essential oil
            ([IC.sub.50]=0.03 [micro]g-ml), 1,8-cineole,
            [alpha]-pinene and camphor ([IC.sub.50]=0,67mM, 0.63 a
            nd >10mM). No single constituent was particularly potent,
            suggesting a synergistic relationship.

in Vitro    Antioxidant properties, with reduced lipid peroxidation as
            a consequence of application of extract and monoterpenoids
            ([alpha] and [beta] pinene, geraniol, 1,8-cineol and
            thujone). Camphor present pro-oxidant properties.
            Antiinflamatory actions by an ethanolic extract and
            geraniol and [alpha]-pinene constituents. Weak oestrogenic
            activity of essential oil and geraniol.

in Vivo     Dose-dependent decreases in AChE activity in selected
            brain regions following oral administration. Components of
            the essential oil or its components are capable of
            surviving digestion, and traversing the blood brain
            barrier for delivery to therapeutically relevant sites.

in Vitro    AChE inhibitory activity of the essential oil resulted
            from a complex synergistic and antagonistic interactions
            between the terpenoids. Minor synergy 1,8/cineole with
            [alpha]-pinene or caryophillene. Antagonism 1,8 cineol and
            camphor. Mixtures of terpenoids were less potent than the
            whole essential oil. 1,8/cineole has been shown to be the
            most potent single ([IC.sub.50]=0.06 mg/ml).

Clinical    Inhibition of AChE ([IC.sub.50] =0.07mg/ml). Trial 1:
trial       mnemonic effect of encapsulated essential oil, 1, 2.5, 4
            and 6 h after administration. Result showed significant
            improvements in immediate and delayed word recall.

Clinical    Improvements in memory and attention. Patients presented
trial       excellent tolerability of the oil and no adverse effects.
            Although, two patients with hypertension had increase in
            blood pressure with highest dose of sage oil.

in Vitro    Inhibit human erythrocyte AChE (by [beta]-caryophyllene,
            3-carene, 1,8-cineole, [alpha]-pinene and [beta]-pinene)
            and butyryl cholinesterase dose-dependent inhibition.

Clinical    Improved cognitive performance, significantly increased
trial       ratings of "contentedness" and "calmness". Significantly
            improved accuracy of memory with enhanced speed of

            retrieval.

Clinical    S. lavandulifolia was associated with a strong reduction
trial       in subjective mental fatigue at post-dose time points.
            Improvement in alertness at 4h, improved speed of reaction
            time and in delayed memory at the 1h post-dose time-
            point. Effects on memory and on cognition.

Clinical    Essential oil with high levels of 1,8-cineole and an
trial       [IC.sub.50] (0.003 mg-ml) for AChE inhibition. Single
            doses show to improve performance of attention and
            secondary memory 1-h post dose testing session. And reduce
            mental fatigue and increase subjective alertness more at 4
            h post-dose.

Clinical    No significant effect for S. lavandulifolia aroma on any
trial       of the cognitive performance factors. Small increases in
            self-reported alertness.
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Title Annotation:articulo en ingles
Author:Porres-Martinez, Maria; Accame, Ma Emilia Carretero; Gomez-Serranillos, Ma Pilar
Publication:Lazaroa
Date:Jan 1, 2013
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