ReviewArticle

MEDICINALUSESANDPHARMACOLOGICALPROPERTIESOFCROCUSSATIVUSLINN(SAFFRON)

VIJAYABHARGAVAK

KrupanidhiCollegeofPharmacy,Bangalore,India.Email:vijayabhargava.k@gmail.com

Received:05March2011,RevisedandAccepted:08April2011

ABSTRACT

CrocussativusLinn(Iridaceae)isusedwidelyintropicalandsubtropicalcountriesforavarietyofpurposesinbothhouseholdandformedicinalpurposes.Thestigmasoftheplantareusedfortheycontainavarietyofchemicalconstituentslikethecrocetin,crocinandotherflavanoidswhichmake them suitable to possess diversifiedmedicinal properties for treating various ailments. In countries like India and otherAsian countries,saffronisbeenusedintheirtraditionalmedicinefromtheprehistoricages.Chemicalconstituentswerestudiedfortheirdiversifiedpropertiesandthisreviewfocusonthedetailedchemicalconstituentsalongwiththepharmacologicalpropertiestestedwiththeplant.

Keywords:crocussativus,crocetin.

INTRODUCTION

Crocus sativus Linn (family: Iridaceae) is a flowering plant in thecrocusfamilyandiscommonlyknownassaffron.Itiswidelyusedasspiceandasacoloringandflavoringagentinthepreparationofvarious foods and cosmetics. It is native to Iran and Greece. It isnow cultivated largely in Southern Europe, Tibet and othercountries. In India, it is mainly cultivated in Kashmir andUttranchal. The stigmas of the plant are mainly used fortherapeutic purposes1. The stigmas of Crocus sativus Linn.(Saffron) are used as coloring and flavoring agents in thepreparationof food indifferentpartsof theworld.Apartfromitsuseinpreparationoffood,thestigmasoftheplantareusedforthetreatment of a variety of disorders traditionally. The medicinalpropertiesattributedtosaffronareextensive.

Description

Crocus sativus Linn is a grass like tuber plantwith purple or lilaccolored flowers. The flower stalk rises from a bulb, and is a long,white,slender tube; the flower itselfbeing large,andofabeautifullilac color. Leaves radical, linear, dark green above, pale greenbelow, enclosed in a membranous sheath, sometimes remainingfresh nearly the whole winter. Corolla in two segments, betweenwhich the longstyleshangout.Stigmas three, large,nearlyan inchlong,rolledat theedges,brightorange1.Thestigmasofsaffronaretheparts that have been used inmedicine. They have apleasantlybitterandsomewhatwarmingtaste.Theycontainalargeportionofextractive matter, and a portion of volatile oil. Age and exposureimpairthem2.

Medicinaluses

Thestigmasoftheplantaremainlyusedforitsmedicinalpropertiesextensively in traditional medicine for various purposes, as anaphrodisiac, antispasmodic, expectorant, for treatment of stomachailments,reducingstomachacheandforrelievingtension.InPersiantraditionalmedicine,itisusedfordepression.Itisalsousedtotreatinsomniaand in the treatment of themeasles, dysentery, jaundice,choleraetc:Topicallyit isappliedintheformofpastetotreatskindiseases like acne. It is also used inweaving industry as a dyeingagentandinthepreparationofvariousperfumesandincensesticks.It is considered as a tonic for heart and nervous system1 and forsmoothingmenstruation23.

Charaka used the powdered stigmas as one of the drugs in thetreatment of cataracts, night blindness and poor vision. Sushrutauseditasabloodpurifierandtotreatskineruptionsinternally.Itisalso used as an antibacterial agent, antiseptic, antifungal andantiflatulenttraditionally4.

Saffron was also used as a nervine sedative, emmenogogue, intreatment of fever,melancholia and enlargement of the liver. It isalso used as analgesic,diuretic, immune stimulant, interferoninducer,andfor inhibitingthethrombinformation.At lowdoses, itcausesthestimulationofthepregnantuterusandinlargeramountsitcancauseconstrictionandspasm5.

Saffron is also a protective agent against chromosomal damage, amodulator of lipid peroxidation, and an anti seizure, for reducingbloodpressureandalsousedintreatmentofpsoriasis6.

Chemicalconstituents

Chemical studies on Crocus sativus stigmas reported that itpossesses carotenoids like crocetin (also called crocetin orcrocetinI), its glycosidic forms are digentiobioside (crocin),gentiobioside,glucoside,gentioglucosideanddiglucoside.

Crocetin (monomethyl ester), crocetin (dimethylester), transcrocetin isomer, 13ciscrocetin; carotene,carotene, lycopene,zeaxanthin and mangicrocin, a xanthonecarotenoid glycosidicconjugate7.

The colouring components of saffron were crocins, which areunusualwatersoluble carotenoids (cis and transglucosylestersofcrocetin). The monoterpene aldehydes picrocrocin and itsdeglycosylated derivative safranal (dehydrocyclocitral), formedin saffron during drying and storage by the hydrolysis of thepicrocrocin, are also important components of saffron, responsibleofitsbitterflavourandaroma,respectively.Saffronsgoldenyelloworangecolorisprimarilytheresultofcrocinpigments7.

Anthocyanins, flavonoids, vitamins (especially riboflavin andthiamine), amino acids, proteins, starch,mineralmatter, gums andother chemical compounds presence were also described tomaketheirpresenceinsaffron6.Amongtheconstituentsofsaffronextract,crocetinismainlyresponsibleforitspharmacologicalactivities8.

Other than these Monoterpene aldehydes and isophoronerelatedcompounds like: 2,6,6trimethyl4hydroxy1cyclohexen1carboxaldehyde,2,4,4trimethyl3formyl6hydroxy2,5cylohexadien1one,isophorone, 3,5,5trimethyl4hydroxy1cyclohexanon2ene, 3,5,5trimethyl1,4cyclohexadione, 3,5,5trimethyl1,4cyclohexadion2ene, and 3,5,5trimethyl2hydroxy1,4cyclohexadion2ene are isolated from the volatile constituentsofsaffronandstudiedwithIR,UV,NMRandmassspectroscopy9.

Apart from these they also contain 5 to 8% fat andwax, 12 to 13percent protein with a few essential oil that constitutes for thestrongsmellofsaffron10.

International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 3, Suppl 3, 2011

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SaffronConstituents

Pharmacologicalactivities

A.AntiAlzheimers:

The main carotenoid constituent, transcrocin4, the digentibiosylester of crocetin, inhibited Abeta fibrillogenesis formed byoxidationof theamyloidbetapeptide fibrils inAlzheimersdisease.Thewater:methanol (50:50, v/v) extract ofCrocus sativusstigmasinhibited Abeta fibrillogenesis in a concentration and timedependent manner at lower concentrations than its anotherconstituentdimethylcrocetin11.

B.Antitussiveactivity:

Theethanolic extract ofCrocus sativusand its constituent safranal,was found to reduce the number of cough in guinea pigs wheninjected intraperitoneallywhereanebulizedsolutionof citricacid(20%)wasusedtoinducecough12.

C.Hypolipidemicactivity:

Crocin, one of the constituents of saffron was shown to producehypolipidemic effect in the dose range of 25mg/kg to 100mg/kgbody weight in dietinduced hyperlipidemic rats by inhibitingpancreatic lipase thereby leading to malabsorbtion of fat andcholesterolproducinghypolipidemiceffect13.

D.Anticonvulsantactivity:

Safranal,thecoloringagentofsaffron,onperipheraladministrationto rats was found to induce a dosedependent decrease in theincidence of both minimal clonic seizures and generalized tonicclonic seizures following pentylene tetrazole administration. Thiseffect of safranal was thought to be mediated atleast in part,through GABA (A)benzodiazepine receptor complex14. Anothercomponent of saffron, crocin did not showed any effect inpentylenetetrazoleinducedconvulsionsinmice15.

E.AntipruriticandEmmolienteffects:

Crocus sativus in a topical formulation at a concentration of0.025%v/w was found to have beneficial effects, with atopicdermatitis, ichthyosis vulgaris, and other xerotic diseases of mildseverity16.

F.AntinociceptiveandAntiinflammatoryactivity:

The aqueous and ethanolic extracts of saffron stigmas and petalswere reported to posses anti nociceptive and antiinflammatoryactivity both of, acute and chronic as evidenced by effects inwrithing test, xylene induced ear oedema in mice and formalininducededemaintheratpaw.Thissupportsitstraditionaluseas,anantiedematogenicremedy8.

G.Antioxidantactivity:

ThemethanolicextractofCrocussativusanditscomponentssuchassafranal, crocin etc. were reported to possess radical scavengingactivity, suggesting its use as a cosmetic to treat age relateddisorders,asafoodsupplementetc17.

Crocinwasfoundtopossessgreaterantioxidantcapacitythanalphatocopherol in neuronally differentiated pheochromocytoma cellsdeprivedofglucose,whoseabsencecausedperoxidationoftheircellmembrane lipidsanddecreased intercellularsuperoxidedismutaseactivity. These effects were reversed by crocin, promising it as aunique and potent antioxidant that combats oxidative stress inneurons18.Further itwasalsosaidto increasethe levelsofvariousenzymes such as the glutathione reductase, glutathioneStransferase and also maintains the functional levels of otherantioxidantssuggestingitasapotentialantioxidant.

H.protectionformgenotoxicity:

Theaqueousextractofsaffronpreventedthegenotoxicityproducedbycertaindrugssuchascisplatin,urethane,cyclophosphamideandmitomycinCinmicebonemarrowmicronucleustest.Furthertherewas an increase of hepatic enzymes such as the glutathionestransferase in those animals pretreated with saffron. It was alsoreported to prevent the oxidative stress induced by these drugsthrough attenuation of the lipid peroxidation with a simultaneousincreaseofliverenzymessuchasthesuperoxidedismutase,catalaseand nonenzymatic antioxidants suggesting that thechemopreventive effects of saffron are mediated throughmodulation of lipid peroxidation, antioxidants and detoxificationsystems19.

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I.Preventionofacetaldehydeinduced inhibitionofLongTermpotentiationinrat:

The alcoholic extract of Crocus sativus prevented ethanol andacetaldehyde induced inhibition of hippocampal longtermpotentiationinthedentategyrusofanesthetizedratssuggestingitsusetopreventaversiveeffectsinducedbyethanolandacetaldehyde,itsprimarymetabolite20.

J.Cardioprotection:

Crocetin, the main active constituent of saffron was found todecreasethelevelofcardiacmarkerlactatedehydrogenaseactivityand also increase mitochondrion potential in a cardiac myocytetreatedwithnoradrenaline,suggestingitscardioprotectiveaction21.

Saffron was also showed to possess calcium antagonistic activity.ThisantagonisticactivitywasthroughtheblockadeofextracellularCa (2+) influx through receptoroperated Ca (2+) channels andpotentialdependentCa(2+)channels22.

Inanotherstudy,crocetinbyvirtueofitsstrongantioxidantactivityprevented the cardiac hypertrophy induced by norepinephrine byincreasingthelevelsoftheantioxidantenzymessuchasmyocardialsuperoxide dismutase, catalase, glutathione peroxidase and alsosignificantly improved the myocardial pathological histologicalchangesinducedbynorepinephrine23.

K.Antidiabeticactivity:

Crocetin,theactiveconstituentofsaffronwasfoundtopossessantidiabetic activity in fructosefed rats as it alleviated free fatty acidinduced insulin insensitivityanddysregulatedmRNAexpression ofadiponectin, TNFalpha and leptin in primary cultured ratadipocytes suggesting the possibility of crocetin treatment as apreventivestrategyofinsulinresistanceandrelateddiseases24.

Advancedglycationendproductsareknowntocause theoxidativereaction that usually results in endothelial cell apoptosis and thusresult in diabetic vascular complications. Crocetin by virtue of itsgood antioxidant capacity and calcium antagonistic activity orstabilization may be a good remedy for diabetic vascularcomplications25.

L.InRespiratorydisorders:

TherelaxanteffectofCrocussativusonsmoothmusclewasevidentas shown in guinea pig tracheal chain experiment. The relaxationproduced with the aqueousethanolic extract and safranal incomparison with saline as negative control, and theophylline, wascomparable to or even higher than that relaxation produced withtheophylline suggesting its use in the treatment of variousrespiratorydisorderslikeasthmaetc.26,27.

M.Effectsonocularbloodflowandretinalfunction:

Crocinanalogs isolated fromCrocus sativuswere found to increaseblood flowbyvasodilation to the retinaand choroid, also facilitateretinal functionrecoverytherebypreventing ischeamicretinopathyandagerelatedmaculardegenerationthatresultsinblindness28.

N.AntiParkinsonsactivity:

In a model of middle cerebral artery occlusion (model of acutecerebral ischemia) in rats, the decrease in the activity of enzymessuch as superoxide dismutase, Na+K+ATPase, catalase etc: wascounteredbypretreatingtheanimalswithcrocetin,whichsuggeststheusageofCrocussativusinfocalischeamia29.

Parkinsons disease, a neurodegenerative disorder is mainlycharacterizedbythedegenerationofneuronsinthesubstantianigrabyreactiveoxygenspeciesorbyinjectionofcertainchemicalslike6hydroxydopamineleadingtothedeathofneurons.Inexperimentalrats, pretreated with crocetin, there was an increase in theantioxidant capacities of enzymes followed by protection from thedeleteriouseffectsof6hydroxydopaminethuspresentingitselfasagoodtreatmenttocombatthisdevastatingdisorder30.

O.Effectonlearningandmemorybehaviour:

Behavioural and electrophysiological studies have demonstratedthat saffron extract affects learning and memory in experimentalanimals. Aqueous extract of saffron was reported to improveethanolinduced impairments of learning behavior in mice andethanolinducedinhibitionofhippocampallongtermpotentiation,aform of activitydependent synaptic plasticity that may underlaylearning and memory. These effects of saffron extract wereattributedtocrocin(crocetindigentiobioseester),butnotcrocetin.Saffronextractoritsactiveconstituents,crocetinandcrocin,maybeuseful for the treatment for neurodegenerative disordersaccompanying memory impairment31. Crocin was also showed toprevent the death of neurons provoked by internal and externalapoptoticstimulibysuppressingtheTNFinducedcelldeath32.

P.Effectsonbloodpressure:

TheaqueousandethanolicextractsofCrocussativuspetalsshowedadecrease in blood pressure in a dose dependent manner inanaesthetisedrats,inisolatedratvasdeferens,guineapigileumetc.where responses were initiated by electrical stimulation. Thisdecrease in blood pressure was proposed to be mediatedpostsynaptically3334.

Q.Antidepressantactivity:

Crocus sativus petals and hydro alcoholic extracts of the stigmashaveshowntopossessantidepressantactivity in a6weekdoubleblind,randomizedandplacebocontrolledtrialandinanimalbasedpreclinical studies. This antidepressant activitywas similar to theactivityofstandarddrugsimipramineandfluoxetine3537.

R.Effectsonuterus:

In traditional medicine, the herb is used for promoting andregulating menstrual periods. It also soothes lumber pains, whichaccompanymenstruation.Saffronisalsobeneficialinthetreatmentof other ailments concerning women such as leucorrhoea andhysteria.Pessariesofsaffronwereusedinpainfulconditionsoftheuterus38.

Apolyherbalformulationcontainingsaffronwhenusedatthedosesof 1000 and 2000mg/kgwas reported to produce contractions ofuterusinrats39.

S.Anticancerandantitumouractivity:

EthanolicextractsofCrocussativus increased the lifespanofSwissalbino mice, which were intraperitoneally transplanted withsarcoma180cells,EhrlichascitescarcinomaorDaltonslymphomaascites tumours. Saffron in the presence of the T cell mitogenphytohemagglutinin stimulated a nonspecific proliferation of Tlymphocytesinvitro.Thissuggeststhatsaffronsantitumouractivitymightbeimmunologicallymediated40.

Theuseof crocetin in lungcancerwas foundtodecrease the lipidperoxidation,glutathionemetabolizingenzymesandalsorevert thehistopathologicalchangesrelevanttotumourincidenceprovingitasapotentialantitumouragent41.

Crocetin was found to exert a small inhibitory effect on thedevelopment of skin tumours induced in nude mice by theapplication of 9, 10dimethyl1,2benzanthracene, 712 dimethylbenz[]anthracinandcrotonoil42.Inrats,crocinsrevealedagreatprotective effect against hepatocarcinogenic compounds such asaflatoxinB1anddimethylnitrosamine,partiallysuppressingchronichepaticdamage.Crocetinhasbeenfoundtobeapotentinhibitorofskin tumour promotion induced by 12Otetradecanoylphorbol13acetateinmice43.

Topical administration of saffron extracts inhibited theinitiation/promotionof7,12dimethylbenz []anthraceneinducedskintumoursinmice,delayingtheonsetofpapilomaformationandreducingthemeannumberofpapillomaspermouse.

This antitumour effect of saffronwas attributed to the increase inthe levels of carotene and vitamin A in the serum of theexperimental animals receiving saffron. The study demonstrated

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thatcrocetinhadnocytotoxiceffectoncolonyformationofdifferenttumor cells, but had a dosedependent inhibitory effect on DNA,RNA,andproteinsynthesisinthesehumanmalignantcells.Furtheranovelglucoconjugateisolatedfromcormsandcallusofsaffronwasshowed to possess cytotoxic activity against different tumor cellsderived from fibrosarcoma, cervical epithelioid carcinoma, andbreastcarcinoma17.

Crocin and diglucosylcrocetin inhibited early tumor antigenexpression of adenovirus infected cells crocetin esters were lesspotentthancrocinitselfinthisconcern67.

T.Cellularandmoleculareffects:

Ithasbeendemonstratedthatcrocinpossesesantiapoptoticeffectson noncancerous cells. Crocin suppresses cell death induced bytumournecrosisfactoralpha

(TNF),cysteineproteasemRNAsandsimultaneouslyrestoresthecytokineinducedreductionofTNFandmRNAexpression6.

U.Crocetinandhaemorrahagicshock:

Crocetin, a saffronderived carotenoid,was shown to improvepostshock recovery of cellular adenosine triphosphate and to increaseoverallsurvival inanexperimentalmodelofhemorrhagicshock. Inthis model, crocetin caused the suppression and subsequentexpressionofmessengerribonucleicacidfortumornecrosisfactor,interleukin1andinduciblenitricoxidesynthase44.

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