Review Article Medicinal Herbals with Antiplatelet ...

Review ArticleMedicinal Herbals with Antiplatelet Properties Benefit inCoronary Atherothrombotic Diseases

Nurul Huda Mohd Nor1 Fauziah Othman1

Eusni Rahayu Mohd Tohit2 and Sabariah Md Noor2

1Department of Human Anatomy Faculty of Medicine and Health Sciences Universiti Putra Malaysia43000 Serdang Selangor Malaysia2Department of Pathology Faculty of Medicine and Health Sciences Universiti Putra Malaysia 43400 Serdang Selangor Malaysia

Correspondence should be addressed to Sabariah Md Noor md sabariahupmedumy

Received 7 December 2015 Revised 10 February 2016 Accepted 17 February 2016

Academic Editor Giovanni de Gaetano

Copyright copy 2016 Nurul Huda Mohd Nor et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Coronary atherothrombotic diseases such as coronary artery disease peripheral vascular disease cerebrovascular disease and heartfailure are the serious concerns of the thrombus formed in blood vessels Anticoagulant and antiplatelet drugs are the cornerstonesof the management of these diseases To prevent the recurrence of these diseases double antiplatelet drugs such as aspirin andclopidogrel has been the standardmanagement inmost hospitals However aspirin resistance and clopidogrel inefficient effects dueto noncompliance with double drugs regimen can cause a sinister effect on patients Medicinal plants serve as a greater resource fornew medication and their potential currently became a topic of interest to the researchers all over the world Traditionally certainherbs have been used as a treatment for heart diseases but have been investigated for their antiplatelet properties This currentreview explained few traditional antithrombotic herbals and their antiplatelet properties in vitro and in vivo and this is to be deeplydiscussed in further research

1 Introduction

Coronary atherothrombotic diseases (CADs) are the leadingcauses of death and disabilities in the world Globally itis estimated that about 173 million people had died fromCADs in 2008 and by 2030 approximately 236 million ofthe world population might die from CADs [1] CADs con-sist of coronary artery disease peripheral vascular diseasecerebrovascular disease and heart failure The risk factor ofCADs is mainly due to atherosclerosis that leads to arterialthrombosis The pathogenesis process encompasses chronicprogressive atherosclerosis punctuated by acute processesthat is (1) plaque rupture and (2) platelet thrombus formationin the areas of progressive stenosis The final pathway toarterial thrombosis is atherosclerosis plaque rupture thusthe effective way to treat or to prevent this occurrenceis by limiting or eradicating platelet-dependent thrombusformation

Oral antiplatelet drugs are the cornerstone of the therapyof CADs that consist of primary and secondary preventionstrategies to manage these diseases Patients with efficientantiplatelet therapy can reduce stroke and death rates byabout 25 [2] Currently the standard practice in a clinicalsetting to prevent adverse events of CADs is a combinationof aspirin and clopidogrel which inhibits cyclooxygenaseand antagonizes P2Y

12 respectively Despite their proven

effectiveness there are cases of recurrent cardiovasculardiseases among thosewho take double antiplatelet drugsThismight be due to incompliancy and the adverse effect facedby the patients Gastrointestinal bleeding and gastric ulcersare the most common adverse effects reported [3] There arethree points of argument of aspirin resistance that include thefollowing no evidence of antithrombotic effect being aspirindosage related ability to generate thromboxane A2 despitethe usual aspirin dosage and low dose of aspirin causingblocking of more than 95 of platelet cyclooxygenase-1

Hindawi Publishing CorporationrombosisVolume 2016 Article ID 5952910 7 pageshttpdxdoiorg10115520165952910

2 Thrombosis

activity Thus inability to benefit from regular aspirin dosageleads to the failure of aspirin as an antiplatelet therapy [4]

Medicinal plants serve as a greater resource for newmedication and their potential currently became a topic ofinterest to the researchers all over the world The WorldHealth Organisation (WHO) has recommended medicinalplants to be used more effectively in healthcare system [1]Recently there is a trend of studies on the development ofnatural compound present in traditional medicinal herbsdemonstrating antiplatelet properties The currently knownmechanisms of action that can be used to interfere with theprimary haemostatic system that regulates receptors suchas catecholamine collagen thrombin prostacyclin ADPPGD2 PGE

2 and serotonin TXA

2 cAMP cGMP and

calcium have been identified to be the effective target ofantiplatelet therapy [5] In order to have a wider variety oftreatments screening of medicinal herbs that is postulated tohave high potential of antiplatelet properties was performed

2 Methods

The information about medicinal plants that are traditionallyused in the management of coronary atherothrombotic dis-ease was obtained from published papers and texts on eth-nobotanical studies as well as those investigating the effects ofplant(s) used with anticoagulation effect A literature searchon electronic databases such as Google Scholar PubMedand Scopus up to 2015 was carried out using ldquoantiplateletrdquoand ldquoherbalrdquo as the keywords for primary search and thenldquoplant name ndash accepted or synonymsrdquo ldquoconstituentsrdquo andorldquomechanismrdquo for the secondary search

In order to highlight the medicinal plants traditionallyused in CADs management with the potential of integrationin the healthcare system not all identified plants wereincluded in this paperTherefore this review was not exhaus-tive of all plants used traditionally for treating CADs

3 Results and Discussions

CADcan be prevented or treated by interferingwith itsmech-anism of thrombosis The primary goal of antithrombotictherapy is to inhibit platelet activation (primary haemostasis)and fibrin formation via cascade (secondary haemostasis)from happening There are four steps in platelet activa-tion pathways which are adhesion aggregation secretionand procoagulation which lead to secondary haemostasisHowever this review focuses on primary haemostasis andthe main method used in these various studies was lightimpedance aggregometry either in vivo or in vitro Thereare a lot of plants that exhibit antiplatelet properties Tenplants from various families and regions are discussed asthey possibly contain the compound responsible for thoseproperties as listed in Table 1

31 Curcuma longa (Turmeric) Turmeric is derived from therhizomes of Curcuma longa and has been used in SoutheastAsia for a long time as an Indian spice and treatmentfor several conditions such as stomachache wounds and

joint problems in Ayurvedic medicine [6] Turmeric itselfhas been extensively used for its antioxidant antimicrobialanti-inflammatory and antiproliferative propertiesThemostlipophilic component of Curcuma longa extracted calledCurcuma oil (C oil) has been utilized as antimicrobialantifungal antiviral and anti-inflammatory agent and alsoused for wound healing activity

A fraction of C oil namely ar-turmerone has beenshown to inhibit collagen- (10 120583gml) adenosine-51015840-diphosphate- (ADP- (10 120583M)) and thrombin- (064Uml)induced platelet aggregation The effect of C oil on plateletaggregation (in vivo) in rats significantly reduced collagen-(28) ADP- (31) and thrombin- (34) induced plateletaggregation in comparison to aspirin (50 to 75)While thesethree agonists had significantly inhibitory effect calciumionophore PAF and arachidonic acid were not affectedat all [6] This study is supported by another study doneon ar-turmerone that showed that ar-turmerone inhibitedplatelet activation induced by collagen (2 120583gml) gave 100inhibition at concentration of 100 120583gml and 80 and60 inhibition at concentration of 10 120583gml and 5 120583gmlrespectively [7] In a study that used curcumin (500120583M)a major ingredient of Curcuma longa showed effectiveinhibition against AA-induced platelet aggregation (10mM)A further study has noted that an increase in lipoxygenase-(LOX-) derived products was observed in curcumin-treatedplatelets [8] These could be due to the redirection of AA toLOX pathway orand potentiation of the enzyme AA is amembrane-derived fatty acid metabolized by cyclooxygenaseto prostaglandin (PG) endoperoxide intermediates such asPGH2 In platelets endoperoxides are further metabolized

to thromboxane A2and PGs [9] This suggests that the

antiplatelet effect of C oil possibly affects the cyclooxygenase(COX) pathway in platelet at membranereceptor level

32 Berberis vulgaris Scientifically named as Berberis vul-garis the herb known as ldquobarberryrdquo is a native herb in Europeand Asia and is wildly grown in Canada to Pennsylvania Intraditional Chinese medicine barberry was mentioned morethan 3000 years ago to have diverse medicinal propertiesincluding antimicrobial antiemetic antipyretic and antipru-ritic properties Scientifically barberry may offer healthcarebenefits as an antihypertensive and vasodilator agent [10]and play a prominent role in apoptosis in the treatment ofhepatocarcinogenic rats [11]

A study has been done to investigate the antiplateleteffects of Berberis vulgaris on alkaloid component namedberberine (BR) towards rabbits as in vivo model In thestudy platelet aggregation induced by adenosine diphosphate(ADP) collagen AA and calcium ionophore A23187 wasdifferentially inhibited in which collagen-induced platelet ag-gregationwasmost potently inhibited and calcium ionophoreA23187-induced platelet aggregation was least inhibited Theinhibition of platelet aggregation is dose dependent from10 to 30mgkg giving the maximum inhibition of 525[12] There is also another report of inhibitory effects on AAmetabolism and calcium influx partial agonist activity onplatelet 1205722-adrenoceptors using Berberis vulgaris extract [13]

Thrombosis 3

Table1Summaryof

inhibitio

nof

platele

tactivationby

medicinalherbs

Reference

Plants

Com

poun

dDoseo

fplantsrsquoextract

Agonistanddo

sage

Postu

latedantip

latelet

prop

ertie

sIn

vivo

orin

vitro

[6ndash8]

Turm

eric(Curcumalonga)

Ar-turm

eron

ecurcum

in100120583

gml500120583

MCollagen(2120583gml)

ADP(10120583

M)and

thrombin(064U

ml)

Adhesio

nIn

vivo

[1213]

Barberry

(Berberis

vulga

ris)

Berberine

30mgkg

Collagen

Adhesio

nIn

vivo

[14]

Osm

anthus

fragran

s28m

gml

Collagen(1mgml)andADP(5mM)

Adhesio

nsecretion

Invitro

[15]

Magno

lia(M

agnolia

officin

alis)

Magno

lolho

nokiol

Collagen(10120583gml)

Adhesio

nIn

vitro

[16]

CudraniatricuspidataBu

reau

Cudratric

usxantho

neA

10120583M

Thrombin(3Um

l)Aggregatio

nIn

vitro

[1718]

Don

gqu

ai(Angelica

sinensis)

Z-Ligustilid

e40

mgkg

ADP(5120583M)

Secretion

Invivo

[19ndash22]

Ginger(Zingiberoffi

cinale)

Gingerolparado

l25120583M

AA(20m

M)a

ndAA(2120583M)

Secretion

Invitro

[2324]

Garlic

(Allium

sativ

um)

Methano

lextract

48ndash9

5gkg

ADP(10120583

M)epinephrine(10120583gml)

collagen(2120583gml)

thrombin(01Um

l)AA

(11mM)andPA

F(10120583

M)

Adhesio

nsecretion

and

aggregation

Invitro

invivo

[25ndash27]

Scutellariabaica

lensis

Georgi

Baicalinw

ogon

oside

456120583M30120583

MTh

rombin(3Um

l)collagen(1120583gml)

and

ADP(5120583M)

Adhesio

nsecretion

Invitro

[28ndash30]

Fructusgardenia

Iridoidglycosidesgenipin

100m

gk


Adhesio

nvasoconstrictio

nIn

vivo

4 Thrombosis

33 Osmanthus fragrans This plant has been used as anadditive in beverage and also in perfumes as it has intensefragrance [31] Besides it had been used traditionally astreatmentrsquos constituent for stomachache rheumatism andhalitosis [14] Osmanthus fragrans (OF) has high amount ofphenolic acid which has been used as a natural source ofantioxidant for controlling probing free radicals related tovarious diseases including chronic inflammation cataractsand atherosclerosis and other cardiovascular diseases [32]

One novel study on phytochemical investigation on OFseed the purple-brown ripe fruit of OF extracted usingethyl acetate and n-butyl alcohol showed the greatest effecton inhibition of collagen-induced platelet aggregation atconcentration of 14mgml and 28mgml Further studyusing the same extracts but using ADP showed equal effectcompared to a positive drug at 28mgml [14]These findingssuggest that OF seeds may have the potential to be developedas a novel inhibitor of platelet aggregation

34 Magnolia officinalis This traditional Chinese and Jap-anesemedicinal herb comes fromMagnoliaceae family and isbeing used for the treatment of thrombotic stroke headacheand typhus fever [15] It is believed to have multifunc-tional health benefits including general antioxidative effectsthrough scavenging hydroxyl radicals that are generated byultraviolet (UV) irradiation [33] and anticancer propertiesinduced by apoptosis of HER2 overexpressed in breast cancercells [34] They are also capable of controlling pain [35]Besides thatmagnolol has an antiapoptotic effect through theregulation of bcl-XL gene and suppression of bcl-xS gene [36]

It contains two bioactive isomers called magnolol andhonokiol As for the cardiovascular protection effects theherbs through magnolol suppress the platelet activationin aggregation step via inhibition of intracellular calciummobilization and thromboxane formation [15 37] Studyon inhibition potential of honokiol and magnolol againstcollagen (10 120583gml) showed that honokiol is 5 to 10 timesmore potent than magnolol at even very low concentrationand it is concentration dependent Honokiol and magnololpossess 80 and 55 inhibition on collagen-induced plateletaggregation at the highest concentration Further test ontreated platelets with magnolol and honokiol showed thatboth had reversible action from collagen-induced plateletaggregation After conducting the centrifugation of plateletsuspension it is found that there is no presence of lactatedehydrogenase which confirms that both compounds did notcause breakdown of platelets [15]

35 Cudrania tricuspidata Bureau This plant is also knownas Maclura tricuspidata Bureau It is a plant from theMoraceae family It is a tree native to East Asia and the roothas been used as a traditional Chinese medicine for treat-ing dysmenorrhea rheumatism and jaundice The wealthysource of flavonoids and xanthones enhances this plant tobe explored It has been reported to possess antioxidant[38] anti-inflammatory anticancer [39] antihepatoprotec-tive [40] and anticoagulant properties

The bioactive compound used which exhibits theantiplatelet properties obtained from the roots of Cudrania

tricuspidata is called cudratricusxanthone A (CTXA) Stud-ies done usingmouse platelet showed thatCTXAsignificantlyprevented the platelet aggregation induced by thrombin(3Uml) in a concentration-dependent manner At concen-tration of 10 120583M platelet aggregation reduced to 35 com-pared to control (80) CTXA inhibited thrombin-catalyzedfibrin polymerization resulting in a reduction of plasminogenactivator inhibitor type 1 (PAI-1) and platelet aggregation [16]

36 Angelica sinensis Angelica sinensis is a type of herb fromthe family Apiaceae that grows inmountains of China Koreaand Japan Angelica sinensis is a Chinese traditional herbused for treating dysmenorrhea and it is also used as a foodsupplement in Korea Radix Angelica sinensis is also officiallylisted in the Chinese pharmacopoeia The health benefits arewell documented [41] Conventionally this plant had beenused in the treatment and prevention of thrombosis

An arterial thrombus is mainly composed of plateletaggregation hence the platelets play a vital role in bothinitiation and growth of thrombi An initial study hasexamined the effect of herbs extract named Z-ligustilidecharacterized by 3-n-alkylphthalide constituents on atrial-type thrombus formation on a rat arteriovenous shuntmodelAfter administration of the extract (40mgkg) for 3 con-secutive days orally thrombus formation was significantlyreduced Further tests on the treated rats showed that themaximumplatelet aggregation by ADP (5120583M) had decreasedand the result was 3 times greater than aspirin at a dose of40mgkg [17] Another study done on rabbit showed the sameinhibition of ADP-induced platelet aggregation at 10 120583M andit was comparable to aspirin at the same dosage The possiblemechanism of action is due to the inhibition of thromboxaneA2 formation or Ca2+ activation in platelet [18]

37 Zingiber officinale (Ginger) Zingiber officinale from Zin-giberaceae family is a medicinal herb that is used in our dailyfood especially in Asian countries The benefit of this herb iswell known for its antiulcer [42] and antibacterial properties[43] The common name for this plant is ginger a traditionalmedicine with a carminative effect

This herb has been investigated for its antiplatelet prop-erties An initial study done on aqueous extract of gingerhad shown that it inhibits platelet aggregation induced byAA adenosine diphosphate and collagen [19] A researchdone on a compound of [8]-gingerol showed that selectivelyinhibited AA-induced platelet aggregation in washed plateletpreparation started at 1mM up to 20mM AA concentrationIt gave partial inhibition against collagen-induced plateletaggregation at 10 120583gml [20 21] Further studies on [6]- and[8]-gingerol have shown inhibition activity towards COX-1in human platelet at 075mM AA concentration and usingrat basophilic leukemia (RBL-2H3) cells gingerols at ICmaxapproximately 20 to 25120583Minhibit COXactivity bymeasuringthe product of AA metabolism by COX prostaglandin D2[3] These suggest the inhibition mechanism of gingerolspossibly due to effect on AA-induced platelet activationBesides that another phenolic compound [8]-paradol anatural constituent of ginger also has been found to be the

Thrombosis 5

most potent inhibitor against AA-induced platelet aggre-gation at very low concentration (2120583M) Further test oninhibitory activity of this compound against COX-1 showedthe strongest inhibitory activity with IC

50values of 4 120583M[22]

Overall studies exhibited that ginger mechanism of plateletinhibition through cyclooxygenase-1thromboxane synthaseactivity compared to aspirin activity

38 Allium sativum Allium sativum is also known as garlicThis medicinal herb had been narratively used by veter-inarians to treat peripheral venous thrombosis in horses inthe French literature a long time ago

Study on cooked blanched garlic leaves juices on rabbitplatelets aggregation induced by ADP and collagen showedsignificant inhibition with maximum ratio of 8737 and8624 respectively in vitro and in vivo The inhibitionof aggregation pathway mainly blocks the combination offibrinogen with 120583Fib-R which finally results in the inhibitionof platelet aggregation proved by the amount of plateletfibrinogen binding detected by flow cytometry [23] Besidesstudy on the effect of methanol extract of garlic bulbs(EOG) and three pure components isolated from it (F1 F2and F3) on human platelet aggregation induced by ADP(10 120583M) epinephrine (10 120583gml) collagen (2 120583gml) throm-bin (01 Uml) arachidonate (11mM) and PAF (10 120583M) wasconducted The incubation of platelet rich plasma with EOGinhibits 100 platelet aggregation induced by all of theabovementioned agonists at 68 plusmn 5 gml 48 plusmn 2 gml 52 plusmn7 gml 95plusmn7 gml 55plusmn3 gml and 60plusmn3 gml concentrationrespectively However for 3 other fractions isolated from itF3 was shown to have about four times more potency thanothers using listed agonists at 120 plusmn 9 gml 60 plusmn 8 gml75 plusmn 11 gml 100 plusmn 12 gml 30 plusmn 1 gml and 65 plusmn 7 gmland is also able to induce ADP-rapid deaggregation whenadded to aggregated platelet This can indicate the possiblemechanism of antiplatelet maybe on the plasma membraneproperties Thrombin-induced release of ATP from plateletalso was inhibited by 75ndash80 after F3 treatment [24]

39 Scutellaria baicalensis Georgi It is one of the importantherbs used in traditional Chinese medicine for treatment offebrile cough and liver problem Its roots have been used fortheir anti-inflammatory and anticancer effects for treatingbacterial and viral infections and for reducing the totalcholesterol level and hypertension [44] Several bioactivecompounds have been isolated from the root of the plantnamely baicalein baicalin wogonin and oroxylinA Baicalinpossesses anti-HIV antitumor antioxidant and free radicalscavenging effects Wogonin has antirespiratory syncytialvirus antihepatitis B virus antitumor antioxidant and freeradical scavenging effects while oroxylin A has antirespira-tory syncytial virus activity [45] Baicalin had been used intreatment of bronchitis asthma and skin allergy [25] Studieshave shown that baicalin inhibited thrombin-catalyzed fibrinpolymerization and platelet functions prolonged aPTT andPT significantly and inhibited the activities and productionof thrombin and FXa

Further study done on baicalin showed that it sugges-tively inhibited thrombin- (3Uml) and collagen- (1 120583gml)

induced mouse platelet aggregation in a concentration-dependent manner with IC

50of baicalin in PRP being 456

and 411 120583M respectively [25] A study also demonstrated thatbaicalin enhanced the phenylephrine-induced contractionthrough inhibiting the production orand release of endothe-lial nitric oxide in the isolated rat mesenteric artery rings[46] A treatment with active metabolite wogonin namedflavonoid wogonoside (WGN) has been shown to inhibitthrombin-catalyzed fibrin polymerization and thrombin-induced platelet aggregation The inhibition is concentrationdependent and at 30 120583M of WGN it is about 50 inhibitionwith final concentration of thrombin at 3Uml WGN wasalso shown to elicit anticoagulant effects in mice [26]Further studies on the root extract of Scutellaria baicalensisGeorgi have shown a significant inhibition activity of plateletaggregation ratio of rabbits induced by ADP (5 120583M) withaverage inhibition rate of 4552 at 4023mgml of extractand that of aspirin group was 5496 [27]

310 Gardenia jasminoides Ellis This plant had been knownas Zhi Zi in Chinese herb directory It has been traditionallyused as an analgesic for several medical conditions such aspain due to liver problem dysentery and trauma for externalapplication [47]

Gardenia jasminoides Ellis with its bioactive compoundsiridoid glycosides (IG) has been studied IGs have beenshown to have antithrombotic properties through the inhi-bition of platelet aggregation with a little effect on thecoagulation time of peripheral blood A study showed thatIGs may significantly and dose-dependently reduce arterialthrombus load in a model of carotid artery thrombosisand inhibit collagen-induced platelet aggregation in rats at1 120583gml Pretreatment with IGs for 3 days with dose of100mgkg gave 13 platelet aggregation ratio comparableto aspirin (18) at 40mgkg [28] Another compound ofGardenia jasminoides Ellis called genipin (GE) with differ-ent concentrations has shown significant inhibition on thecollagen-induced platelet aggregation in vitro but only a littleeffect on that induced by ADP and AA [29] In anotherin vivo thrombosis model it has also been confirmed thatGardenia jasminoides Ellis extract can reduce the weight orlength of thrombus Itsmechanism of antiplatelet aggregationand inhibition on thromboembolism was probably related tothe activation via inhibiting endothelin-1 (ET-1) expressionas a potent vasoconstrictive peptide GE was found to bevery effective in reducing the nuclear factor kappa B (NF-120581B) by disturbing the I120581B degradation NF-120581B is an inducerof cyclooxygenase-2 (COX-2) expression By reducingNF-120581Bactivity the production of COX-2 and inducible nitric oxidesynthase (iNOS) is downregulated [30 48]

4 Conclusion

This review focused on the availability ofmedicinal herbs thatpossess antiplatelet properties Most studies are still at thepreliminary stage asmany steps are required so that the herbscan be used as a substitution or can be combinedwith currentantiplatelet agents such as aspirin and clopidogrel

6 Thrombosis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work is supported by Exploratory Research GrantScheme Ministry of Education Malaysia (5527163) Theauthors also acknowledge the Faculty ofMedicine andHealthSciences Universiti Putra Malaysia for providing libraryresource facilities and support

References

[1] World Health Organization WHO Traditional Medicine Strat-egy 2002ndash2005 WHO 2002

[2] Antithrombotic Trialistsrsquo Collaboration ldquoCollaborative meta-analysis of randomised trials of antiplatelet therapy for preven-tion of death myocardial infarction and stroke in high riskpatientsrdquo British Medical Journal vol 324 no 7329 pp 71ndash862002

[3] K L K Koo A J Ammit V H Tran C C Duke andB D Roufogalis ldquoGingerols and related analogues inhibitarachidonic acid-induced human platelet serotonin release andaggregationrdquo Thrombosis Research vol 103 no 5 pp 387ndash3972001

[4] J W Eikelboom J Hirsh J I Weitz M Johnston Q Yi andS Yusuf ldquoAspirin-resistant thromboxane biosynthesis and therisk of myocardial infarction stroke or cardiovascular death inpatients at high risk for cardiovascular eventsrdquo Circulation vol105 no 14 pp 1650ndash1655 2002

[5] Y Liu H-J Yin D-Z Shi and K-J Chen ldquoChinese herb andformulas for promoting blood circulation and removing bloodstasis and antiplatelet therapiesrdquo Evidence-Based Complemen-tary and Alternative Medicine vol 2012 Article ID 184503 8pages 2012

[6] P Prakash A Misra W R Surin et al ldquoAnti-platelet effects ofCurcuma oil in experimental models of myocardial ischemia-reperfusion and thrombosisrdquoThrombosis Research vol 127 no2 pp 111ndash118 2011

[7] H S Lee ldquoAntiplatelet property of Curcuma longa L rhizome-derived ar-turmeronerdquo Bioresource Technology vol 97 no 12pp 1372ndash1376 2006

[8] K C Srivastava A Bordia and S K Verma ldquoCurcumina major component of food spice turmeric (Curcuma longa)inhibits aggregation and alters eicosanoid metabolism inhuman blood plateletsrdquo Prostaglandins Leukotrienes and Essen-tial Fatty Acids vol 52 no 4 pp 223ndash227 1995

[9] B Samuelsson G Folco E Granstrom H Kindahl and CMalmsten ldquoProstaglandins and thromboxanes biochemicaland physiological considerationsrdquo Advances in ProstaglandinandThromboxane Research vol 4 pp 1ndash25 1978

[10] Z Fatehi-HassanabadM Jafarzadeh A Tarhini andM FatehildquoThe antihypertensive and vasodilator effects of aqueous extractfrom Berberis vulgaris fruit on hypertensive ratsrdquo PhytotherapyResearch vol 19 no 3 pp 222ndash225 2005

[11] G Motalleb P Hanachi O Fauziah and R Asmah ldquoEffectof Berberis vulgaris fruit extract on alpha-fetoprotein geneexpression and chemical carcinogen metabolizing enzymes

activities in hepatocarcinogenesis ratsrdquo Iranian Journal of Can-cer Prevention vol 1 no 1 pp 33ndash42 2012

[12] C G Huang Z L Chu S JWei H Jiang and B H Jiao ldquoEffectof berberine on arachidonic acid metabolism in rabbit plateletsand endothelial cellsrdquoThrombosis Research vol 106 no 4-5 pp223ndash227 2002

[13] M El Sayed D Ghareeb E Sarhan and A Khalil ldquoTherapeuticbio-screening of the bioactive ingredients of Berberis vulgarisrdquoFunctional Plant Science and Biotechnology vol 5 no 1 pp 63ndash68 2011

[14] W Tang J Cao X Zhang and Y Zhao ldquoOsmanthus fragransseeds a source of secoiridoid glucosides and its antioxidizingand novel platelet-aggregation inhibiting functionrdquo Journal ofFunctional Foods vol 14 no 3 pp 337ndash344 2015

[15] C-M Teng C-C Chen F-N Ko et al ldquoTwo antiplatelet agentsfrom Magnolia officinalisrdquo Thrombosis Research vol 50 no 6pp 757ndash765 1988

[16] H Yoo S-K Ku W Lee et al ldquoAntiplatelet anticoagulant andprofibrinolytic activities of cudratricusxanthone Ardquo Archives ofPharmacal Research vol 37 no 8 pp 1069ndash1078 2014

[17] L Zhang J-R Du J Wang et al ldquoZ-ligustilide extracted fromRadix angelica sinensis decreased platelet aggregation inducedby ADP ex vivo and arterio-venous shunt thrombosis in vivo inratsrdquo Yakugaku Zasshi vol 129 no 7 pp 855ndash859 2009

[18] N-Y Yang G-S Zhou Y-P Tang et al ldquoTwo new 120572-pinenederivatives from Angelica sinensis and their anticoagulativeactivitiesrdquo Fitoterapia vol 82 no 4 pp 692ndash695 2011

[19] K C Srivastava ldquoEffects of aqueous extracts of onion garlic andginger on platelet aggregation and metabolism of arachidonicacid in the blood vascular system in vitro studyrdquoProstaglandinsLeukotrienes and Medicine vol 13 no 2 pp 227ndash235 1984

[20] J-H Guh F-N Ko T-T Jong and C-M Teng ldquoAntiplateleteffect of gingerol isolated from Zingiber officinalerdquo Journal ofPharmacy and Pharmacology vol 47 no 4 pp 329ndash332 1995

[21] K C Srivastava ldquoIsolation and effects of some ginger com-ponents on platelet aggregation and eicosanoid biosynthesisrdquoProstaglandins Leukotrienes and Medicine vol 25 no 2-3 pp187ndash198 1986

[22] E Nurtjahja-Tjendraputra A J Ammit B D Roufogalis VH Tran and C C Duke ldquoEffective anti-platelet and COX-1 enzyme inhibitors from pungent constituents of gingerrdquoThrombosis Research vol 111 no 4-5 pp 259ndash265 2003

[23] X H Wang and Y Di ldquoMechanism of cooked blanched garlicleaves against platelet aggregationrdquo Journal of ExperimentalHematology vol 22 no 3 pp 753ndash757 2014

[24] R Apitz-Castro S Cabrera M R Cruz E Ledezma and MK Jain ldquoEffects of garlic extract and of three pure componentsisolated from it on human platelet aggregation arachido-nate metabolism release reaction and platelet ultrastructurerdquoThrombosis Research vol 32 no 2 pp 155ndash169 1983

[25] W Lee S-K Ku and J-S Bae ldquoAntiplatelet anticoagulantand profibrinolytic activities of baicalinrdquo Archives of PharmacalResearch vol 38 no 5 pp 893ndash903 2015

[26] S-K Ku and J-S Bae ldquoAntithrombotic activities of wogoninandwogonoside via inhibiting platelet aggregationrdquo Fitoterapiavol 98 pp 27ndash35 2014

[27] Y Zhang X Wang X Wang et al ldquoProtective effect offlavonoids from Scutellaria baicalensis Georgi on cerebralischemia injuryrdquo Journal of Ethnopharmacology vol 108 no 3pp 355ndash360 2006

Thrombosis 7

[28] P Wang Q Wang C Luo C Tan and X Yuan ldquoIridoidglycosides extracted from Zhizi (Fructus Gardeniae) decreasecollagen-induced platelet aggregation and reduce carotid arterythrombosis in an in vivo rat modelrdquo Journal of TraditionalChinese Medicine vol 33 no 4 pp 531ndash534 2013

[29] Y Suzuki K Kondo Y Ikeda and K Umemura ldquoAntithrom-botic effect of geniposide and genipin in the mouse thrombosismodelrdquo Planta Medica vol 67 no 9 pp 807ndash810 2001

[30] H Liu Y-F Chen F Li and H-Y Zhang ldquoFructus Gardenia(Gardenia jasminoides J Ellis) phytochemistry pharmacologyof cardiovascular and safety with the perspective of new drugsdevelopmentrdquo Journal of Asian Natural Products Research vol15 no 1 pp 94ndash110 2013

[31] C-Y Hung Y-C Tsai and K-Y Li ldquoPhenolic antioxidantsisolated from the flowers ofOsmanthus fragransrdquoMolecules vol17 no 9 pp 10724ndash10737 2012

[32] A-N Li S Li H-B Li D-P Xu X-R Xu and F Chen ldquoTotalphenolic contents and antioxidant capacities of 51 edible andwild flowersrdquo Journal of Functional Foods vol 6 no 1 pp 319ndash330 2014

[33] S Fujita and J Taira ldquoBiphenyl compounds are hydroxyl radicalscavengers their effective inhibition for UV-induced mutationin Salmonella typhimurium TA102rdquo Free Radical Biology andMedicine vol 17 no 3 pp 273ndash277 1994

[34] H Liu C Zang A Emde et al ldquoAnti-tumor effect of honokiolalone and in combination with other anti-cancer agents inbreast cancerrdquo European Journal of Pharmacology vol 591 no1ndash3 pp 43ndash51 2008

[35] Y-J Lee Y M Lee C-K Lee J K Jung S B Han and J THong ldquoTherapeutic applications of compounds in theMagnoliafamilyrdquo Pharmacology amp Therapeutics vol 130 no 2 pp 157ndash176 2011

[36] B Jawan S Goto T-L Pan et al ldquoThe protective mechanismof magnolol a Chinese herb drug against warm ischemia-reperfusion injury of rat liverrdquo Journal of Surgical Research vol110 no 2 pp 378ndash382 2003

[37] C-M Teng F-N Ko J-P Wang et al ldquoAntihaemostatic andantithrombotic effect of some antiplatelet agents isolated formChinese herbsrdquo Journal of Pharmacy and Pharmacology vol 43no 9 pp 667ndash669 1991

[38] B W Lee J H Lee S-T Lee et al ldquoAntioxidant and cytotoxicactivities of xanthones from Cudrania tricuspidatardquo Bioorganicamp Medicinal Chemistry Letters vol 15 no 24 pp 5548ndash55522005

[39] G-S Jeong D-S Lee and Y-C Kim ldquoCudratricusxanthoneA from Cudrania tricuspidata suppresses pro-inflammatorymediators through expression of anti-inflammatory hemeoxygenase-1 in RAW2647 macrophagesrdquo InternationalImmunopharmacology vol 9 no 2 pp 241ndash246 2009

[40] R-B An D-H Sohn and Y-C Kim ldquoHepatoprotective com-pounds of the roots ofCudrania tricuspidata on tacrine-inducedcytotoxicity in Hep G2 cellsrdquo Biological and PharmaceuticalBulletin vol 29 no 4 pp 838ndash840 2006

[41] M Yang G C F Chan R Deng et al ldquoAn herbal decoc-tion of Radix astragali and Radix angelicae sinensis promoteshematopoiesis and thrombopoiesisrdquo Journal of Ethnopharma-cology vol 124 no 1 pp 87ndash97 2009

[42] H Wu D Ye Y Bai and Y Zhao ldquoEffect of dry ginger androasted ginger on experimental gastric ulcers in ratsrdquo ChinaJournal of Chinese Materia Medica vol 15 no 5 pp 278ndash3181990

[43] S Malu G Obochi E Tawo and B Nyong ldquoAntibacterialactivity andmedicinal properties of ginger (Zingiber officinale)rdquoGlobal Journal of Pure and Applied Sciences vol 15 no 3-4 pp365ndash368 2009

[44] S-T Huang C-Y Wang R-C Yang C-J Chu H-T Wu andJ-H S Pang ldquoWogonin an active compound in Scutellariabaicalensis induces apoptosis and reduces telomerase activityin the HL-60 leukemia cellsrdquo Phytomedicine vol 17 no 1 pp47ndash54 2010

[45] H-B Li and F Chen ldquoIsolation and purification of baicaleinwogonin and oroxylin A from the medicinal plant Scutellariabaicalensis by high-speed counter-current chromatographyrdquoJournal of Chromatography A vol 1074 no 1-2 pp 107ndash1102005

[46] J Sun B Kh Tan S-H Huang M Whiteman and Y-Z ZhuldquoEffects of natural products on ischemic heart diseases andcardiovascular systemrdquo Acta Pharmacologica Sinica vol 23 no12 pp 1142ndash1151 2002

[47] S-C Wang T-Y Tseng C-M Huang and T-H Tsai ldquoGar-denia herbal active constituents applicable separation proce-duresrdquo Journal of Chromatography B vol 812 no 1-2 pp 193ndash202 2004

[48] Y-J Surh K-S ChunH-H Cha et al ldquoMolecularmechanismsunderlying chemopreventive activities of anti-inflammatoryphytochemicals down-regulation of COX-2 and iNOS throughsuppression of NF-120581B activationrdquo Mutation ResearchmdashFundamental and Molecular Mechanisms of Mutagenesis vol480-481 pp 243ndash268 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 Thrombosis

activity Thus inability to benefit from regular aspirin dosageleads to the failure of aspirin as an antiplatelet therapy [4]

Medicinal plants serve as a greater resource for newmedication and their potential currently became a topic ofinterest to the researchers all over the world The WorldHealth Organisation (WHO) has recommended medicinalplants to be used more effectively in healthcare system [1]Recently there is a trend of studies on the development ofnatural compound present in traditional medicinal herbsdemonstrating antiplatelet properties The currently knownmechanisms of action that can be used to interfere with theprimary haemostatic system that regulates receptors suchas catecholamine collagen thrombin prostacyclin ADPPGD2 PGE

2 and serotonin TXA

2 cAMP cGMP and

calcium have been identified to be the effective target ofantiplatelet therapy [5] In order to have a wider variety oftreatments screening of medicinal herbs that is postulated tohave high potential of antiplatelet properties was performed

2 Methods

The information about medicinal plants that are traditionallyused in the management of coronary atherothrombotic dis-ease was obtained from published papers and texts on eth-nobotanical studies as well as those investigating the effects ofplant(s) used with anticoagulation effect A literature searchon electronic databases such as Google Scholar PubMedand Scopus up to 2015 was carried out using ldquoantiplateletrdquoand ldquoherbalrdquo as the keywords for primary search and thenldquoplant name ndash accepted or synonymsrdquo ldquoconstituentsrdquo andorldquomechanismrdquo for the secondary search

In order to highlight the medicinal plants traditionallyused in CADs management with the potential of integrationin the healthcare system not all identified plants wereincluded in this paperTherefore this review was not exhaus-tive of all plants used traditionally for treating CADs

3 Results and Discussions

CADcan be prevented or treated by interferingwith itsmech-anism of thrombosis The primary goal of antithrombotictherapy is to inhibit platelet activation (primary haemostasis)and fibrin formation via cascade (secondary haemostasis)from happening There are four steps in platelet activa-tion pathways which are adhesion aggregation secretionand procoagulation which lead to secondary haemostasisHowever this review focuses on primary haemostasis andthe main method used in these various studies was lightimpedance aggregometry either in vivo or in vitro Thereare a lot of plants that exhibit antiplatelet properties Tenplants from various families and regions are discussed asthey possibly contain the compound responsible for thoseproperties as listed in Table 1

31 Curcuma longa (Turmeric) Turmeric is derived from therhizomes of Curcuma longa and has been used in SoutheastAsia for a long time as an Indian spice and treatmentfor several conditions such as stomachache wounds and

joint problems in Ayurvedic medicine [6] Turmeric itselfhas been extensively used for its antioxidant antimicrobialanti-inflammatory and antiproliferative propertiesThemostlipophilic component of Curcuma longa extracted calledCurcuma oil (C oil) has been utilized as antimicrobialantifungal antiviral and anti-inflammatory agent and alsoused for wound healing activity

A fraction of C oil namely ar-turmerone has beenshown to inhibit collagen- (10 120583gml) adenosine-51015840-diphosphate- (ADP- (10 120583M)) and thrombin- (064Uml)induced platelet aggregation The effect of C oil on plateletaggregation (in vivo) in rats significantly reduced collagen-(28) ADP- (31) and thrombin- (34) induced plateletaggregation in comparison to aspirin (50 to 75)While thesethree agonists had significantly inhibitory effect calciumionophore PAF and arachidonic acid were not affectedat all [6] This study is supported by another study doneon ar-turmerone that showed that ar-turmerone inhibitedplatelet activation induced by collagen (2 120583gml) gave 100inhibition at concentration of 100 120583gml and 80 and60 inhibition at concentration of 10 120583gml and 5 120583gmlrespectively [7] In a study that used curcumin (500120583M)a major ingredient of Curcuma longa showed effectiveinhibition against AA-induced platelet aggregation (10mM)A further study has noted that an increase in lipoxygenase-(LOX-) derived products was observed in curcumin-treatedplatelets [8] These could be due to the redirection of AA toLOX pathway orand potentiation of the enzyme AA is amembrane-derived fatty acid metabolized by cyclooxygenaseto prostaglandin (PG) endoperoxide intermediates such asPGH2 In platelets endoperoxides are further metabolized

to thromboxane A2and PGs [9] This suggests that the

antiplatelet effect of C oil possibly affects the cyclooxygenase(COX) pathway in platelet at membranereceptor level

32 Berberis vulgaris Scientifically named as Berberis vul-garis the herb known as ldquobarberryrdquo is a native herb in Europeand Asia and is wildly grown in Canada to Pennsylvania Intraditional Chinese medicine barberry was mentioned morethan 3000 years ago to have diverse medicinal propertiesincluding antimicrobial antiemetic antipyretic and antipru-ritic properties Scientifically barberry may offer healthcarebenefits as an antihypertensive and vasodilator agent [10]and play a prominent role in apoptosis in the treatment ofhepatocarcinogenic rats [11]

A study has been done to investigate the antiplateleteffects of Berberis vulgaris on alkaloid component namedberberine (BR) towards rabbits as in vivo model In thestudy platelet aggregation induced by adenosine diphosphate(ADP) collagen AA and calcium ionophore A23187 wasdifferentially inhibited in which collagen-induced platelet ag-gregationwasmost potently inhibited and calcium ionophoreA23187-induced platelet aggregation was least inhibited Theinhibition of platelet aggregation is dose dependent from10 to 30mgkg giving the maximum inhibition of 525[12] There is also another report of inhibitory effects on AAmetabolism and calcium influx partial agonist activity onplatelet 1205722-adrenoceptors using Berberis vulgaris extract [13]

Thrombosis 3

Table1Summaryof

inhibitio

nof

platele

tactivationby

medicinalherbs

Reference

Plants

Com

poun

dDoseo

fplantsrsquoextract

Agonistanddo

sage

Postu

latedantip

latelet

prop

ertie

sIn

vivo

orin

vitro

[6ndash8]

Turm

eric(Curcumalonga)

Ar-turm

eron

ecurcum

in100120583

gml500120583


ADP(10120583

M)and

thrombin(064U

ml)

Adhesio

nIn

vivo

[1213]

Barberry

(Berberis

vulga

ris)

Berberine

30mgkg

Collagen

Adhesio

nIn

vivo

[14]

Osm

anthus

fragran

s28m

gml


Adhesio

nsecretion

Invitro

[15]

Magno

lia(M

agnolia

officin

alis)

Magno

lolho

nokiol


Adhesio

nIn

vitro

[16]


reau

Cudratric

usxantho

neA

10120583M

Thrombin(3Um

l)Aggregatio

nIn

vitro

[1718]

Don

gqu

ai(Angelica

sinensis)

Z-Ligustilid

e40

mgkg

ADP(5120583M)

Secretion

Invivo

[19ndash22]

Ginger(Zingiberoffi

cinale)

Gingerolparado

l25120583M

AA(20m

M)a

ndAA(2120583M)

Secretion

Invitro

[2324]

Garlic

(Allium

sativ

um)

Methano

lextract

48ndash9

5gkg

ADP(10120583



thrombin(01Um

l)AA

(11mM)andPA

F(10120583

M)

Adhesio

nsecretion

and

aggregation

Invitro

invivo

[25ndash27]

Scutellariabaica

lensis

Georgi

Baicalinw

ogon

oside

456120583M30120583

MTh

rombin(3Um


and

ADP(5120583M)

Adhesio

nsecretion

Invitro

[28ndash30]

Fructusgardenia


100m

gk


Adhesio

nvasoconstrictio

nIn

vivo

4 Thrombosis












Thrombosis 5


50values of 4 120583M[22]











4 Conclusion


6 Thrombosis



Acknowledgments


References





























Thrombosis 7



























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Thrombosis 3

Table1Summaryof

inhibitio

nof

platele

tactivationby

medicinalherbs

Reference

Plants

Com

poun

dDoseo

fplantsrsquoextract

Agonistanddo

sage

Postu

latedantip

latelet

prop

ertie

sIn

vivo

orin

vitro

[6ndash8]

Turm

eric(Curcumalonga)

Ar-turm

eron

ecurcum

in100120583

gml500120583


ADP(10120583

M)and

thrombin(064U

ml)

Adhesio

nIn

vivo

[1213]

Barberry

(Berberis

vulga

ris)

Berberine

30mgkg

Collagen

Adhesio

nIn

vivo

[14]

Osm

anthus

fragran

s28m

gml


Adhesio

nsecretion

Invitro

[15]

Magno

lia(M

agnolia

officin

alis)

Magno

lolho

nokiol


Adhesio

nIn

vitro

[16]


reau

Cudratric

usxantho

neA

10120583M

Thrombin(3Um

l)Aggregatio

nIn

vitro

[1718]

Don

gqu

ai(Angelica

sinensis)

Z-Ligustilid

e40

mgkg

ADP(5120583M)

Secretion

Invivo

[19ndash22]

Ginger(Zingiberoffi

cinale)

Gingerolparado

l25120583M

AA(20m

M)a

ndAA(2120583M)

Secretion

Invitro

[2324]

Garlic

(Allium

sativ

um)

Methano

lextract

48ndash9

5gkg

ADP(10120583



thrombin(01Um

l)AA

(11mM)andPA

F(10120583

M)

Adhesio

nsecretion

and

aggregation

Invitro

invivo

[25ndash27]

Scutellariabaica

lensis

Georgi

Baicalinw

ogon

oside

456120583M30120583

MTh

rombin(3Um


and

ADP(5120583M)

Adhesio

nsecretion

Invitro

[28ndash30]

Fructusgardenia


100m

gk


Adhesio

nvasoconstrictio

nIn

vivo

4 Thrombosis












Thrombosis 5


50values of 4 120583M[22]











4 Conclusion


6 Thrombosis



Acknowledgments


References





























Thrombosis 7



























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















4 Thrombosis












Thrombosis 5


50values of 4 120583M[22]











4 Conclusion


6 Thrombosis



Acknowledgments


References





























Thrombosis 7



























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Thrombosis 5


50values of 4 120583M[22]











4 Conclusion


6 Thrombosis



Acknowledgments


References





























Thrombosis 7



























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















6 Thrombosis



Acknowledgments


References





























Thrombosis 7



























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Thrombosis 7



























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Medicinal Herbals with Antiplatelet ...

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Transcript of Review Article Medicinal Herbals with Antiplatelet ...