Pharmacological Activity of Salvia Lavandulifolia and Chemical Components of Its Essential Oil

LAZAROA 34: 237-254. 2013 doi: 10.5209/rev_LAZA.2013.v34.n1.43298 ISSN: 0210-9778

Pharmacological activity of Salvia lavandulifolia and chemical components of its essential oil. A review María Porres-Martínez, Mª Emilia Carretero Accame & Mª Pilar Gómez-Serranillos (*)

Abstract: porres-Martínez, M., Carretero M.E. & Gómez-Serranillos, M.p. Pharmacological activity of Salvia lavan - dulifolia Vahl. and chemical components of its essential oil. Lazaroa 34: 237-254 (2013).

Salvia lavandulifolia Vahl. is a plant from the Iberian peninsula whose phytochemical evaluation indicated the presence of flavonoids, triterpenoids, diterpenoids and monoterpenes. It has an essential oil rich in various bioactive compounds (like 1,8-cineole or α- pinene). It has been traditionally used for its spasmolytic, antiseptic, analgesic, sedative and anesthesic activities. pharmacological studies of the plant have demonstrated its reputation as aromatic plant to enhance memory and anti-dementia drug by the inhibition of cholinesterase enzyme. The species also possesses a wide range of pharmacological uses including: antioxidant, anti-inflammatory, estrogenic and central nervous system depressant properties, relevant to the treatment of Alzheimer´s disease. The present review summarizes the information concerning the taxonomy ecological and biogeographical features, ethnopharmacology, phytochemistry, pharmacological activities and toxicity of the Salvia lavandulifolia because these findings suggest the need for further research on this species.

Keywords: Salvia lavandulifolia Vahl, botanic, chemical composition, essential oil, traditional uses, pharmacological activities.

Resumen: porres-Martínez, M., Carretero M.E. & Gómez-Serranillos, M.p. Actividad farmacológica de Salvia lavan - dulifolia Valh y los componentes químicos de su aceite esencial. Lazaroa 34: 237-254 (2013).

Salvia lavandulifolia Vahl. es un taxon Ibérico cuya evaluación fitoquímica indica la presencia de flavonoides, triter - penos, diterpenos y monoterpenos. Su aceite esencial es rico en varios compuestos bioactivos (como 1,8-cineol o α- pineno). Esta especie se ha utilizado tradicionalmente para sus actividad espasmolítica, antiséptica, analgésica, sedante y anestésica. Los estudios farmacológicos sobre la misma han demostrado su reputación como planta aromática para mejorar la memoria y contra la demencia por la inhibición de la enzima colinesterasa. La especie también posee un amplia actividad farmaco - lógica, incluyendo: antioxidante, antiinflamatoria, estrogénica y depresora del sistema nervioso central, propiedades rele - vantes para el tratamiento de la enfermedad Alzheimer. Esta revisión resume la información taxonómica, biogeográfica, ecológica y también la referente a la etnofarmacología, fitoquímica, actividades farmacológicas y toxicidad de la planta Salvia lavandulifolia , y sugieren la necesidad de investigaciones adicionales sobre esta planta.

Palabras clave: Salvia lavandulifolia Vahl, botánica, composición química, aceite esencial, usos tradicionales, activi - dades farmacológicas.

INTRODUCTION and more diverse genus of this family and it is represented by 900 recognized species, native of The genus Salvia of Lamiaceae is widely dis - Mediterranean. Nevertheless, widespread almost tributed and it is used extensively as ethnomedici - all around the world, abundantly located in three nal plant. The Lamiaceae family is compound by areas: through Europe around the Mediterra - 200 genus and 3000 species ( TOpCU , 2006). Salvia nean, to South-East Asia and more than half of L. (sage), belongs to Men theae Tribe, is the larg est species across Central and South America

* Department of Pharmacology. Faculty of Pharmacy. Universidad Complutense de Madrid. E-28040 Madrid, Spain. E-mail: [email protected], [email protected], [email protected]

237 LAZAROA 34: 237-254. 2013 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia

(GALI -M UhTASIb & 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, indi - genous American Indian, Roman ceremonies as a sacred herb and especially by traditional Chi - nese medicines, for promotion of health and tre - atment of illness, and as an herb for longevity. A proverb assures that “how can man die that has sage in the garden?” ( FONT -Q UER , 1999). pliny Figure 1. – Salvia lavandulifolia Vahl. the Elder (23-79 AD) reported the properties of sage as enhancer of memory functions and the importance of this plant in traditional medicine sorders ( IMANShAhIDI & h OSSEINzADEh , 2006). It (RAMOS & al. , 2010). Whereas the Greek physi - is necessary therapeutic agents for nervous cian Dioscorides reported sage stop bleeding system disorders with reduce toxicity and side ef - wounds and sores besides clean ulcers after fects and with safety and acceptability. Salvia la - aqueous decoction of the plant. besides, juice vandulifolia present no reported adverse effects warm water is used for hoarseness and cough from its long use as flavoring in food ( pERRy & (bLUMENThAL & al. , 2000). Several species of al. , 2001). Sage genus, including Salvia lavandu - Salvia genus present therapeutic activity due to lifolia (Figure 1), has been used by humans for their essential oils. Salvia was used in folk medi - more than two millennia in the treatment of dif - cine all around the world from epilepsy, treat ferent age related cognitive disorders associated colds, bronchitis, tuberculosis, hemorrhage, and with ageing to enhance cognitive function and at - menstrual disorders ( DWECk , 2000; TOpCU , 2006; tenuate cognitive decline ( kENNEDy & W IGhT - TILDESLEy & al. , 2005) and as antiseptic, astrin - MAN , 2011). In addition beneficial effects on gent, depurative, digestive, expectorant, febrifuge disorders of central nervous systems as cognitive and tonic, and also externally as insecticide, skin disorders, depression and cerebral ischemia have and month or throat infections ( JIROVETz & al. , been demonstrated ( AkhONDzADEh & al. , 2003; 2007; GONzáLEz & al. , 2012). Moreover, species hOWES & al. , 2003). In recent controlled trials, belonging to this genus are also known for other administration of sage extracts, with known cho - biological activities, such as anti-inflammatory, linergic characteristic improve behavioral and antidiabetic, antimicrobial, antitumor or anxioly - cognitive function in healthy young adults hu - tic activities ( LOIzzO & al. , 2009; kELEN & TEpE , mans, and also improve memory and attention in 2008) or antispasmodic, antimalarial, anticancer healthy older volunteers by its anticholinesterase or antifungal. Furthermore, it also preserves food properties relevant to Alzheimer´s disease therapy due its antioxidant properties, as well as spice for (WAkE & al. , 2000; SChOLEy & al. , 2008; LOIzzO its natural flavor ( GUILLéN & I bARCOITIA , 1995; & al. , 2009). Cholinesterase inhibiting from bo - TOpCU , 2006). tanical origin, used to the treatment of these di - About 25% of modern drugs are originated seases modifies the progress and symptoms of the from plants either directly or indirectly. phyto - diseases ( AbASCAL & y ARNELL , 2004a; kENNEDy chemical and pharmacological researches carried & S ChOLEy , 2006; ADAMS & al. , 2007). In Alz - out during last years confirm many traditional heimer’s disease the biological mechanism un - uses of Salvia genus in central nervous system di - derlying dementia is: neuronal damage caused by

LAZAROA 34: 237-254. 2013 238 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia oxidative stress and inflammatory reactions; dis - gic, and climatic could have influenced on its pre - rupted cholinergic transmission; and beta-amy - sent-day distribution. The isolation of populations loid formation or toxicity ( pERRy & al. , 1999). makes possible the microevolution of the species Most of current treatments increase the availabi - (ROSUA & b LANCA , 1990). This species is widely lity of neurotransmitter acetylcholine through the spread over the Mediterranean area, mainly in inhibition of cholinesterase enzymes ( kENNEDy East of Spain (especially in Andalucia, Murcia & SChOLEy , 2006). and Castilla), just extending into western Medi - Aromatic plants are important as food-flavou - terranean: South East France, North West Africa ring agent and spice, in cosmetic or perfumes but (Morocco and Algeria) ( JORDAN & al. , 2009; also for their pharmaceutical and therapeutical SáEz , 2010). Salvia lavandulifolia is very adapted properties with less adverse effects than synthetic to the semiarid Mediterranean climate, growing drugs. The use of essential oils for healing pur - in rocky soil in sandy-calcareous mountains. This poses has been known in folk medicine since an - plant can be found in altitudes from 350 to 2000 cient times, however the pharmacology studies m above the sea level. The species grows on types on whole essential oil and their constituents are of soil, preferably on slightly deep and basic soils, very little ( pERRy & pERRy , 2006; FRANz , 2010). on limestone substrate, loamy or gypsum ( MAR - There are several studies on analyses of quantita - COS & al. , 1988; SáEz , 2010). While it commonly tive and qualitative changes in essential oils of grows wild, the cultivated plots are also shown. sage, and genetic and morphological variations Salvia grows optimally in full sun and needs well- are observed according to their geographical ori - drained soil ( CRESpO & al. , 1986; pAGES & al. , gin and growth stage ( AMIRI , 2007). The greatest 1992). use of essential oil is in food as flavorings, per - Salvia lavandulifolia Vahl. is characterized by fumes as fragrances, pharmaceuticals ( bURT , a small sub-shrub or herb up to 17-100 cm, stems 2004) and as ornamental ( CLEbSCh , 2003; pEURAT branched, erect and pubescent, tector hairs some - & al. , 2012). S. lavandulifolia essential oil inhi - times glandular. The leaves grow opposite each bits the enzyme acethylcholinesterase; and pre - other on the stem and appear to grow in bunches. sent antioxidant, anti-inflammatory and They are green or gray-white, simple and petio - estrogenic activity. Therefore, the plant has nota - late with hair protectors, limbo from, elliptic to ble reputation for its potentially relevant activities linear-lanceolate and petiole 5-54 mm. The inflo - in brain function as cognition enhancing, benefi - rescence, 5-71 cm, simple or branched, with 2-8 cial effects on behavioral, for treatment of depres - flowers. bracts are ovate, lanceolate, green or sion, memory disorder, and preventive and violet color. Flowers present pedicels and calyx symptomatic treatment of age-related memory of 8-14 mm, regular, tubular or campanulate, 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 con - sidered as an medicinal species from ancient times ( CAñIGUERAL & al. , 1998). The geographi - cal distribution is similar to actual one however it is thought that the species most probably arrive to Iberian peninsula through North of Africa. Dif - Figure 2. – Distribution of Salvia lavandulifolia in Wes - ferent factors such as historic, geographic, geolo - tern Mediterranean basin.

239 LAZAROA 34: 237-254. 2013 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia usually green or violet-purple, pubescent. Its co - an important role in preservation of foods due or - rolla of 15-40 mm in size, pink, purple or blue ganoleptic properties of terpenes, sesquiterpenes violet, straight, laterally compressed. The bloo - and oxygenated derivates ( GUILL éN & M ANzA - ming develops for about one month in late spring NOS , 1999) and cosmetic industry for its fragrance and early summer ( hEDGE , 1972; SáEz , 2010). (cosmetic and perfumes). It is used in perfumes The leaf presents seasonally dimorphic ( pALACIOS and for flavoring because it is not irritant, sensi - & al. , 2008). The different subspecies of Salvia tizing to human skin and non-phototoxic ( DWECk , lavandulifolia has been studied in diverse geogra - 2000). Since ancient Greek, sage has a history as phical regions of Spain by different authors ( VAL - a cognition enhancer and treatment of memory DéS -b ERMEJO & LópEz , 1977; ROSUA & b LANCA , decline. Several chemical and pharmacological 1985, 1988; FERN áNDEz -G ONz áLEz & al. , 1986; studies of this aromatic plant are described in the FIG UEROLA , 1987; DONAIRE & al. , 1992; hERV áS - literature, as sources of natural antioxidant with SERRANO & al. , 1997; SOLANAS & CRESpO , 1998; health benefits. Indications have traditionally in - SALhI & al. , 2010; LAzARO bELLO , 2011). Till date cluded beneficial effects on central nervous five different subspecies have been described: S. system, mainly in mood and memory enhance - lavandulifolia subsp. lavandulifolia, S. lavanduli - ment age-related because of their anticholineste - folia subsp. vellerea, S. lavandulifolia subsp. ma - rase activity, depression or epilepsy might hence riolensis, S. lavandulifolia subsp. blancoana and be due to a combination of actions ( pERRy & al. , S. lavandulifolia subsp. oxyodon (SáEz , 2010). 2000b; TILDESLEy & al. , 2003) S. lavandulifolia has been used in traditional medicine for its therapeutic properties as spas - EThNOphARMACOLOGy molytic, antiseptic (bactericidal, virucidal and fungicidal), analgesic, sedative, anti-inflamma - Salvia species have been widely used since the tory and locally anesthetic remedies. This herbal Middle Ages. The English herbalist John Gerard medicine has been utilized for their psychoactive (1545-1607) wrote about sage in 1597, "It is sin - and psychotropic properties. The leaves of S. la - gularly good for the head and brain and quicke - vandulifolia are traditionally used as a choleretic, ned the nerves and memory." About 50 years astringent, cicatrizing and antiseptic drug ( CAñI - later, English physician Nicholas Culpeper (1616- GUERAL & al. , 1989; zRIRA & al. , 2004), and also 1654) wrote in 1652, "It also heals the memory, antiperspirant effect for menopause symptoms. warming and quickening the senses." John hill Aqueous extract present hypoglycemic activity (1714-1775), in 1756, said “Sage will retard that (zARzUELO & al. , 1991), and is used as folk re - rapid progress of decay that treads upon our heels medies to treat diabetic hyperglycemia. The es - so fast in later years of life, will preserve faculties sential oil of the plant is rich of compounds not and memory more valuable to the rational mind only with antimicrobial and antiviral activities but than life itself”. Salvia tea is described by Grieve also with antioxidant properties. Others notable in 1980 as a “highly serviceable stimulant tonic ailments for which this plant has been used inclu - in debility of the nervous system” ( hOUGTON & des depression ( pERRy & al. , 2000b). al. , 2004; pERRy & al. , 2000b). Salvia has been considered as a ‘panacea’ throughout the world. The traditional uses recor - phyTOChEMISTRy ded for this plant, are numerous and mainly me - dicinal. This aromatic species is frequently used besides its morphological complexity, S. la - as folk remedies to treat some diseases and seve - vandulifolia shows a well-known variability in its ral of these pharmacological effects have been de - chemical constituents, many of them have been monstrated in controlled laboratory studies identified, and also present many physical cha - (CRESpO & al. , 1986). It is a common food sup - racteristics. The main secondary metabolites are plement ( ThACkERAy & al. , 2010). but also play flavonoids and terpenoids. JOhNSTON & b EART

LAZAROA 34: 237-254. 2013 240 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia

(2004) suggest that flavonoids have the potential phor. The chromatographic profile are: 1,8-cineole to manage several psychiatric and neurological or eucalyptol (11-25%), camphor (11-36%), α- pi - disorders. Flavonoids, triterpenoids and monoter - nene (4-11%), sabinene (0.1-3%), limonene (2- penes (present in volatile compounds) are usual 5%), linalool (0,5-9%), borneol (1-8%), linalil components of aerial parts found in flowers and acetate (<5%) and terpin-1-en-4-ol (<2%). β- car - leaves, whereas diterpenoids are the main com - yophyllene is a non-steroidal anti-inflamatory ses - pounds of roots ( ESCUDERO & al. , 1983; ULUbE - quiterpene with gastric cytoprotection activity LEN & al. , 2000; bARICEVIC & b ARTOL , 2000; (TAMbE & al. , 1996). The Chromatographic pro - TOpCU , 2006). The herb presents phenolic mono - file according to the standard UNE 84310:2001 terpenoid, flavones and the phenolic rosmarinic (AENOR , 2001) for Salvia lavandulifolia essential acid. Salvia is also a rich source of polyphenols oil is shown in Table 1. (zARzUELO & al. , 1995; CAñIGUERAL & al. , 1989; U OO L & F , 2002). Table 1 Chromatographic profile for Salvia lavandulifolia ESSENTIAL OIL essential oil (AENOR, 2001) Components Min. (%) Max. (%) At room temperature, much of them are a che - mically complex mixture of aromatic oily liquids, α- pinene 4 11 sabinene 0.1 3 insoluble in water and soluble in organic solvents, limonene 25 whose constituents of secondary metabolism are 1,8-cineole 11 30 biosynthesized from aromatic plants (e.g. flo - linalool 0.3 4 wers, leaves, herbs, fruits, roots or wood). Essen - camphor 15 36 tial oil of plant is a mixture of great number of borneol 15 terpenic components synthesizes in the cells of terpinen-4-ol <2 the leaf trichomes and stored in the glandular linalil acetate 0.1 5 α- terpenil acetate 0.5 9 IANNOULI hairs of aerial parts ( G & al. , 2000). Mo - sabinil acetate 0.5 9 noterpenes incorporate 2 isoprene units (C10) and are the most representative molecules of essential oils ( WANG & al. , 2010). Volatile oils of Salvia The gas chromatography analyses allowed the usually present more than 100 individual compo - identification and relative quantification of com - nents at different concentrations. Several authors ponents of this sage species after the isolation of have published the phytochemical analysis sho - essential oil by hydro-distillation usually. This es - wing the presence of many compounds on the es - sential oil is obtained from the dried parts of the sential oil composition of this species ( LAWRENCE plant using a Clevenger apparatus for 4 h & al. , 1970; JORDAN & al. , 2009; GUILLEN & al. , (ANON ., 2004). After the extraction, the oil is co - 1999; CARDILE & al. , 2009; hERRAIz & al. , lorless to slightly yellow with fine fragrance oil, 2010).Most of these studies concern the varia - camphoraceous and cineole-like ( VERNIN & tions of a few major essential oil constituents, wi - METzGER , 1986). Volatile constituents of the es - thout study the high number of minor sential oil probably cross the blood-brain barrier compounds. The essential oil percentage compo - by their lipophilicity and small molecular size sition gives an important characteristic to classify (SAVELEV & al. , 2004). each plant ( SANTOS -G OMES & F ERNANDES -F E- RREIRA , 2001). Their components are volatile monoterpenoids phARMACOLOGICAL ACTIVITIES wh ose main common active compounds which define the chemotype of the essential oil include plenty of investigations indicated that Salvia 1,8-cineole ( GUILLEN & I bARGOITIA , 1995; SAVE - genus has been popular in phytochemical and eth - LEV & al. , 2003; pERRy & al. , 2000a) and cam - nobotanical research, revealing important phar -

241 LAZAROA 34: 237-254. 2013 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia macological properties, in vitro as well as in vivo , enzyme independent systems of lipid peroxidation with fewer side effects. There are several studies (zUpkO & al. , 2001); carvacrol, luteolin and ros - of S. lavandulifolia extracts and constituents that marinic acid with potent scavenging activity in investigate their traditional, central nervous herb, and 1.8-cineole, linalool, α and β- pinene in system related use. Its antioxidant, anticholines - essential oil by inhibition of bovine brain lipo - terase, anti-inflammatory, oestrogenic and central some peroxidation by the ARUOMA & al. method nervous system depressant effects are relevant to (1996). Thujone and geraniol present lower effect the treatment of some neurodegenerative pro - (pERRy & al. , 2001) as well as eugenol and blems as Alzheimer´s disease ( MANTLE & al. , thymol, and other methylisopropylphenols ( GUI - 2000; hOUGhTON & h OWES , 2005; kENNEDy , LLEN & M ANzANOS , 1999). The potential antioxi - 2009). Several studies relate with neurodegene - dant activity depends on concentration and rative problems are explain in Table 2. The acti - systems used ( pERRy & al. , 2003). Camphor ins - vity properties on central nervous system (CNS) tead presents pro-oxidant properties in a liposome of this plant are attributable to the presence of po - peroxidation preparation, but this activity may not tentially active secondary metabolites consti - have effect in the whole essential oil ( pERRy & tuents ( pANAGIOTOpOULOS & al. , 2000). These al. , 2001) and its association with neurotoxicity chemicals, that may improve brain function, are (convulsive) at high doses. Salvia lavandulifolia synthesized to increase the suitability of the plant water extracts protects DNA against h 2O2 indu - to survive to pathogens or environment and po - ced damage in heLa cells by acting on reactive tential effectiveness as nootropics ( kENNEDy & species or by stimulating endogenous defense WIGhTMAN , 2011). Terpenoids present biologi - systems, only 21% due its low levels of phenolics cal activities, some of them very relevant as neu - compounds ( RAMOS & al. , 2010). roprotective, important for the treatment of several diseases ( ChANG & al. , 2007) and in pro - ANTI -INFLAMMATORy ACTIVITy tection against pathological or stress conditions (bAkkALI & al. , 2008). The main disadvantage Inflammation is associated with effects in di - of na tural products is the small quantity that can sorders of nervous system. There are many stu - be extracted from each plant. Numerous literatu - dies regarding the anti-inflammatory activity of res hav e recently reported the chemical composi - plants is produced by phenolics and flavonoids as tion, biological properties, and possible applications carvacrol, the flavones genkwarin and luteolin of essential oils as a source of pharmaceutical na - and the 6-hydroxy flavones cirsimaritin and sal - tural products. Synergistic or antagonistic interac - vigenin and polyphenolics as rosmarinic acid, and tions among the components increase the potency, the monoterpenoid present in the essential oil: α- and also the activity of compound in minor percen - pinene (that inhibit the enzyme cycloxygenase tage of essential oil mixture has to be considered and weak selectivity for eicosanoid, leukotriene (bURT , 2004). b4 [LTb4] that was measured by radio immuno - assay) and geraniol show weak selectivity for the ANTIOXIDANT ACTIVITy thromboxane b2 [TXb2]. both of them present significant inhibition of synthesis of pro-inflama - Many diseases of the nervous system involve tory eicosanoid in rat leucocytes stimulated by free radical damage due to an excess of reactive calcium-ionophore method ( pERRy & al. , 2001; oxygen species. The cellular damage to lipid, pro - pERRy & al. , 2003). tein and DNA is associated with a number of dise - ases, as neurodegenerative disorders. Antioxidant OESTROGENIC ACTIVITy activity limiting free radical damage of sage oil was correlated with diterpenes and oxygenated ses - Oestrogenic activity has been suggested to play quiterpenes concentration ( pApAGEORGIOU & al. , a role in the prevention or deletion of neurodegene - 2008). The activity in enzyme-dependent and ration perhaps by protection against neuronal loss.

LAZAROA 34: 237-254. 2013 242 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia

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243 LAZAROA 34: 237-254. 2013 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia d .

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LAZAROA 34: 237-254. 2013 244 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia

Oestrogenic activity and no dose-dependent activity nicotinic and muscarinic receptors ( pERRy & al. , were demonstrated in essential oil of S. lavanduli - 1996) and bovine erythrocyte AChE in vitro folia , maybe for the volatility of its components (pERRy & al. , 2000a). And this AChE inhibition (pERRy & al. , 2001). The essential oil and their mo - in selected brain areas was confirmed in vivo after noterpenoid constituent geraniol, with hydroxyl oral administration of essential oil to young rats. group, present a weak oestrogenic activity by induc - Compared with control group, there was a signi - tion of β- galactosidase activity in yeast cells ( Sac - ficant decrease in AChE activity in the striatum charomyces cerevisiae ) ( pERRy & al. , 2003). but not in the hippocampus at lower dose. At hig - her dose the decrease is in both places ( pERRy & ChOLINESTERASE INhIbITORy ACTIVITy al. , 1996; pERRy & al. , 2002). 1,8-cineole and α- pinene present the most inhibition of the enzyme, Increasing levels of the neurotransmitter against bovine erythrocyte AChE ( pERRy & al. , acethylcholine and their synaptic availability are 2000a) and synergistic effects between them ( SA- due to a delay in the catabolism of acethylcholine VELEV & al. , 2003). however, other main mono - (ACh) ( hOUGhTON & al. , 2006). Acetylcholine terpenoid constituents are responsible for antiChE (ACh) transmitted electrical impulses, by nerve activity of the whole essential oil as camphor and cells to another nerve cell or to muscles. The re - bornyl acetate with weak activity ( pERRy & al. , ceptors sensitive to ACh usually are muscarinic 2000a) or borneol, α and β- pinene. Spanish sage or nicotinic. The enzymes acetylcholinesterase essential oil may be relevant in the treatment of (AChE) hydrolyses the ACh and produces a loss Alzheimer´s disease ( AbASCAL & y ARNELL , of stimulatory activity. Inhibit the cholinesterase 2004a). The neuronal systems affected present a group of enzymes results in a prolongation of the cholinergic system where essential oil and its activity of ACh. Colorimetric method developed constituents demonstrated dose dependent inhi - by ELLMAN & al. , (1961) is widely used to detec - bition of erythrocytes human bovine AChE in tion of AChE inhibition ( MIyAzAWA & y AMAFUJI , vitro. Specific monoterpenes, such as α- pinene, 2005). This is very important in the treatment of the most potent inhibitors tested, followed by 1,8- diseases associated with low levels of Ach in the cineole and camphor after as weaker inhibitor, are brain as in Alzheimer’s disease by improving responsible for the in vitro effect. All of them pre - cognitive function ( hOUGhTON & al. , 2006). Sage sent un competitive reversible inhibitor dose-depen - has previously been shown to improve cognitive dent activity. No single component is particularly function and to inhibit cholinesterase. Acetylcho - potent, suggesting a synergistic relationship. Then, line has an important role in cognitive functions monoterpenes were less active than the alkaloidal such as memory, learning and attention ( TILDES - AChE inhibitors such as physostigmine ( pERRy & LEy & al. , 2003) and for problems associated with al. , 2000a). aging such as memory loss ( pERRy & al. , 1999). Several studies show that Salvia species present CENTRAL NERVOUS SySTEM DEpRESSANT ACTIVITy properties relevant to the attenuation of cognitive declination by the inhibition of the brain enzymes This action has been shown by monoterpe - in vitro butyrylcholinesterase and acethylcholines - noids linalool and terpineol in vivo through glu - terase ( pERRy & al. , 1996; SAVELEV & al. , 2004). tamatergic systems. Salvia species has been S. l avandulifolia essential oil inhibits human brain frequently used as anxiolytic and sedative ( pERRy AChE in vitro in human postmortem brain tissue & al. , 2003). at quite low concentratio n. The inhibition is more effective when synaptic acetylcholine levels are ANTIFUNGAL ACTIVITy low as happens in Alzheimer´s disease, suggesting that the inhibition is competitive. Furthermore, In a study against pathogenic Candida albi - AChE is more inhibited than butyrylcholineste - cans, S. lavandulifolia possess the strongest anti - rase by essential oil. In addition , it interacts with fungal activity compared with other species of

245 LAZAROA 34: 237-254. 2013 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia

Salvia . Usually the chemical composition of the proliferation by apoptotic. For example, geraniol oil has influential properties; probably its main inhibits colon cancer cell proliferation by mem - components (1,8-cineole and camphor) have an - brane depolarisation and ionic canals of signaling tifungal activity ( JIROVETz & al. , 2007). pathways ( bAkkALI & al. , 2008).

ANTIMICRObIAL ACTIVITy bIOACTIVITy OF ESSENTIAL OIL´S COMpONENTS Antimicrobial activity has long been recogni - zed. In vitro essential oil of S. lavandulifolia is used Essential oils and their constituents have been for the control of growth and survival of pathoge - used since ancient times to prevent and treat many nic microorganisms by the determination of MIC diseases because of their pharmaceutical properties and MbC, which inhibit the growth of Listeria mo - (EDRIS , 2007). They have been used as antimicro - nocytogenes (ROTA & al. , 2004). There has been bial, fungicidal, antiparasitical, medicinal and cos - observed synergism between carvacrol and p- metic applications. Nowadays, they are frequently cymene, its precursor, and between cinnamal - used in pharmaceutical, cosmetic, agricultural and dehyde and eugenol. And also it has been observed food industries ( bAkkALI & al. , 2008). Essential synergism between the components of essential oil oils are complex mixtures of compounds with be - and methods of mild preservation. There is some neficial or adverse effects. Some studies show that evidence that minor components have an important the interaction between whole essential oil have a role in this activity, possibly by producing a syner - greater activity than some mixed components, gistic effect between other components. Generally, which suggest that even minor components are cri - essential oils produced from plants harvested du - tical to the activity. Synergism effect is observed ring or immediately after flowering present the when the effect of the combined substances is gre - strongest activity ( bURT , 2004). phenolic compo - ater than the individual effects. In contrast, anta - nents are the most active and usually act as mem - gonism is observed when the effect of one or both brane permeabilisers. Gram-positive organism is components is less when they are applied together generally more sensitive to essential oil than gram- than individually ( bURT , 2004). S. lavandulifolia negative. Antimicrobial activity of essential oils essential oil activity is attributed to the behavior of has been mainly attributed to the presence of 1, 8- several components simultaneously, not indivi - cineole, β- thujone, camphor, borneol and p- dually ( CRESpO & al. , 1986). Volatile constituents cymene ( pIEROzAN & al. , 2009). of the essential oil likely cross the blood-brain ba - rrier for their lipophilicity and small molecular size CyTOTOXIC ACTIVITy (SAVELEV & al. , 2004). S. lavandulifolia essential oil produces some significant effects on cognition. In some studies, the cytotoxic activities of oil S. lavandulifolia essential oil inhibit acethylcholi - were tested on cultures of different human tumor nesterase enzyme and its monoterpenoids alone cell compared to doxorubicin and anticancer agent. produce this effect with different potency ( SAVE - The tumor cells used were from human promye - LEV & al. , 2003; pERRy & al. , 2000a; pERRy & al. , locytic leukemia, human chronic myelogenous 2002). These activities may be particularly impor - leukemia, human breast adenocarcinoma and tant in degeneration associated with age, such as human ovarian adenocarcinoma. S. lavandulifolia dementia. Therefore effects of S. lavandulifolia es - essential oil were less active than the control anti - sential oil are really relevant to potential treatment neoplasic doxorubicin against tumor cells, howe - of central nervous system disorders such as Alz - ver unless weak cytotoxic activity of oil is present heimer´s disease. Many secondary metabolites (FORAy & al. , 1999). The cytotoxic capacity of the from plants are used in phytotherapy, cosmetics or essential oils is based on a prooxidant activity by aromatherapy. The components activity of essen - damage the cell wall and membrane and lysis cell tial oil of S. lavandulifolia identified by different finally or also by reducing local tumor size or its studies is summarized in Table 3.

LAZAROA 34: 237-254. 2013 246 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia y ; R 3

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247 LAZAROA 34: 237-254. 2013 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia

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LAZAROA 34: 237-254. 2013 248 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia

SAFETy: TOXICOLOGy AND SIDE EFFECTS CONCLUSIONS AND FUTURE AppLICATIONS Only trace of the convulsant thujone, (a ter - penoid ketone), could be detected at any time Since immemorial times, several plants have in vegetative cycle of Spanish sage. ph. <0.5% been used not only in diet but also for the therapy (bRUNETON , 2001; bARICEVIC & bARTOL , of diseases. Although Salvia species are well 2000). S. lavandulifolia is closely related to S. known to be used in folk medicine, the experi - officinalis sharing similar composition, with mental studies to support their use are largely lac - the exception of potentially toxic thujone. Its king. Many of these species possess activity on concentration (1.30-22.82% α- thujone and the central nervous system, traditionally used to 0.01-4.32% β- thujone) makes the difference support memory. Sage can be used in the treat - with S. officinalis , where it is higher (1.20- ment of Alzheimer’s disease symptoms ( pERRy & 45.80% α- thujone and 1.02-40.10 β- thujone). al. , 2003). The inhibition of AChE activity by Thujone in large doses is toxic (Tildesley & bycyclic monoterpenoids ( α- and β- pinene, cam - al. , 2003; abascal & al. , 2004b). For this rea - phor and borneol) was studied by the colorimetric son S. lavandulifolia is more suitable species method of ELLMAN (1961). In the last years, the to investigate comparison with S. officinalis essential oils of plants have been great interest as (GIANNOULI & k INTzIOS , 2000; pERRy & al. , a source of natural products, and an alternative 2000a). The α- thujone, the known GAbA-a re - treatment of some diseases, due to the presence ceptor antagonist monoterpenoid ( JOhNSTON & of secondary metabolites. Essential oils of Lamia - bEART , 2004; k ENNEDy & al. , 2011), present ceae family present high biological activities as genotoxicity, reproductive toxicity, chronic to - antimicrobial, antibacterial, antiinflamatory and xicity, neurotoxicity and carcinogenicity tes - antioxidant. They have been recognized by its cu - ting in rats and mice ( höLD & al. , 2001). Most rative, nutritional and cosmetic properties. This of the commercial samples present the terpe - is due to its secondary metabolites. Currently, noid sabinyl acetate (0.1-24% according to the they are widely used in aromatheraphy; however subspecies, the chemotype and their origin) they cannot be applied to human skin in a pure (AFNOR norm: NFT 75-212). This shows po - form, in food, cosmetic and pharmaceutical in - tential teratogenicity activity and dose-depen - dustries. Several studies have shown that Salvia dent abortifacient effect; while it does not lavandulifolia present properties to attenuate the present fetotoxicity in mice. For these reasons cognitive decline in natural aging and dementia. its use should be avoided in pregnant women The improvement mood and cognition-enhancing (pAGES & al. , 1992; FOURNIER & al. , 1993). effects of sage also exhibit anti-oxidant, antiin - The most important proportions of sabinyl ace - flammatory and oestrogenic properties ( pERRy & tate are from S. lavandulifolia subsp. vellerea al. , 2003), relevant to brain function ( kENNEDy (MARCOS & al. , 1988). There are potential ad - & SChOLEy , 2006). These results demonstrate verse effects associated with the overdose of that Salvia lavandulifolia , its essential oil and essential oils. high percentage of ketones in some constituents have properties relevant to the essential oils (camphor or thujone) are con - treatment of neurodegenerative disorders due to traindicate in patients with epilepsy for the its reported me mory-enhancing properties. S. la - epileptiform activity of these compounds. vandulifolia has shown to possess not only proper - Camphor poisoning, produces gastrointestinal ties to the treatment of cognitive decline associated and CNS irritation after toxic ingestion and it with Alzheimer´s disease, but also i n the general is associated with hepatotoxicity and toxicity cognitive enhancement of healthy people. Salvia in kidney ( MILLET & al. , 1981; SChNITzLER & is well tolerated and without side effects of some al., 2008). For these reasons, Salvia are not treatment. S. lavandulifolia essential oil was a po - considered poisonous (unless at very high do - tent inhibitor of human cholinesterase (AChE) sage) ( pERRy & al. , 1998). but buChE was weakly inhibited. This cholines -

249 LAZAROA 34: 237-254. 2013 María Porres-Martínez & al. pharmacological activity of Salvia lavandulifolia terase inhibition may explain its traditional use betwe en the components to produce different acti - for ailing memory, for example it is relevant to vities, such as inhibitory activity of enzyme acetil - the treatment of Alzheimer´s disease ( SAVELEV & cholinesterase. The inhibitory activity of essential al. , 2004). Although evidence indicates that S. la - oil results from a complex interaction between its vandulifolia may be appropriate to the treatment components, that present synergic and antagonic of neurodegenerative disorders as Alzheimer´s di - activities between the monoterpenoids. For exam - sease, further investigation in vitro and in vivo are ple, minor synergy between 1,8 cineole and α- pi - necessary to determinate structure, pharmacolo - nene, and 1,8 cineole and caryophyllene epoxide, gical activity relationship, the interaction of their and antagonism between 1,8-cineole and cam - compounds, -since monoterpenoids have de - phor. Then, high concentration of 1,8-cineole and monstrated to inhibit enzymes of the cytochrome low camphor contents in essential oil may incre - p-450 2b subfamily-, and to exploring the poten - ase its anticholinesterase activity. The 1,8-cineole tial clinical value of S. lavandulifolia. Salvia is is a selective inhibitor for AChE but not for potentially a novel therapeutic treatment for neu - butyrylChE ( SAVELEV & al. , 2003). It was repor - rodegenerative disorders as Alzheimer´s disease. ted positive effects on three mood dimensions: Studies on identification of active S. lavandulifo - alertness, contentedness and calmness in a dose- lia constituents are important in the search for dependent manner, modulating mood and cogni - new therapeutic compounds. The activity of es - tion evaluated by Cognitive Drug Research test. sential oil can be the result of complex interac - Specifically, following oral administration of es - tions between its different constituents, which sential oil the immediate and delayed verbal me - may produce even at low concentrations additive, mory was improved. synergistic or antagonistic effects of some com - In the light of these findings, further research pounds in the mixture of oil composition. Mixture is required to determinate the bioactive consti - - might present a very active compound which tuents of plants and elucidate their molecular me - should be determined and purified. Subsequently, chanism of action to therapeutic application. the effects of the oil would be better than isolated because, due their low cost and commercial monoterpenes ( bAkkALI & al. , 2008). These fin - availability might be interesting candidates to the ding reveal that the monoterpenoids may present development of dietary or pharmaceutical pro - synergistic and antagonistic complex interactions ducts.

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Received: 16 September 2013 Accepted: 31 October 2013

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