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Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2013 Article ID 425369 16 pageshttpdxdoiorg1011552013425369

Review ArticlePhytochemical and Pharmacological Review of Da ChuanxiongFormula A Famous Herb Pair Composed of ChuanxiongRhizoma and Gastrodiae Rhizoma for Headache

Lu Wang1 Jinming Zhang1 Yanlong Hong2 Yi Feng2 Meiwan Chen1 and Yitao Wang1

1 State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macau2 Engineering Research Center of Modern Preparation Technology of TCM of Ministry of Education Shanghai University ofTraditional Chinese Medicine Shanghai 201203 China

Correspondence should be addressed to Yi Feng fyivipsinacom and Meiwan Chen mwchenumacmo

Received 1 April 2013 Revised 4 June 2013 Accepted 24 June 2013

Academic Editor Mee-Ra Rhyu

Copyright copy 2013 Lu Wang et alThis is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Chronic headache such as migraine and nervous headache has become one of the most common locations of pain and one ofthe most difficult diseases to recover due to its numerous causes and inconvenience to keep acesodyne administration for a longtime However there are a series of treatment theories and herbal formulas for this disease in traditional Chinese medicine (TCM)in which Da Chuanxiong formula (DCXF) a herb pair composed of Chuanxiong Rhizoma (CR) Chuanxiong in Chinese andGastrodiae Rhizoma (GR) called as Tianma in China is a greatly classic representativeThis formula has been used for headaches viadispelling wind pathogen and dissipating blood stasis for many years in TCM In recent years the efficiency and representativenessof DCXF have garnered many researchersrsquo attention To reveal the compatibility mechanism and develop innovative Chinese herbherein ethnopharmacological relevance chemical characters and pharmacological actions of DCXF are detailed It is expected togive a comprehensive interpretation of DCXF namely Chuanxiong Tianma herb pair (CTHP) to inherit the essence of herb pairand innovate drug delivery system of this prescription

1 Introduction

With the long-term survival fight against severe environmentearly humans in China acquired the knowledge to treatdisease even death by applying natural material [1 2] Intraditional Chinese medicine Classics such as famous ShengNongrsquos Herbal Classic in Han Dynasty and Compendiumof Materia Medica in Ming Dynasty there are amounts ofrecords about disease treatment experience using naturalplants animals and minerals which were completely calledas traditional Chinese medicine (TCM) [3] Through manyyears of vigilant observations experience and trial and errorexperiments TCM has formed the basis of sophisticatedtraditional medical systems as the health security for Chinesepeople since the dawn of time Additionally with the growingresearch attention from worldwide TCM has developed anincreasingly importantmedical system for not only China butalso rest of the world and continued to provide humankind

with dawn of new remedies for modern critical disease [4ndash6]

In the early stage medical practices single herb was usedas predominant remedy for diseases With the accumula-tion of further therapeutic experience TCM practitionersgradually realized the complexity of pathogenesis and foundsome interesting compatibility art among herbs developingits cosmologic principle of Chinese philosophy includingholism differentiation yinyang and the five elementsUntil now multiherb therapy as an essential component oftraditional medicine systems still has been utilized Herbpair the unique combinations of two relatively fixed herbsin clinic is the most fundamental and the simplest form ofmultiherb therapy to achieve a specific efficacy by a uniquemethodology [7] Many herb pairs were recorded in theTreatise on Febrile and Miscellaneous Diseases and in theSynopsis of the Golden Chamber Though there are severalmethods of herbs compatibility with different aims which

2 Evidence-Based Complementary and Alternative Medicine

are called as ldquoseven relations of Chinese Medicinerdquo such assingular application mutual promotion mutual assistancemutual restraint mutual detoxication mutual inhibition andmutual intoxication [8] herb pairs for mutual potentiationoccupy mostly according to Chinese records and the classicbooks about herbs in China Mutual potentiation also calledas mutual promotion showed significantly better pharmaco-logical efficacy than when the herbs were used individuallybeing applied in many famous herb pairs such as DangguiBuxue Decoction (Astragali Radix and Angelicae sinensisRadix) [9 10] and Dan Qi Fang (Salviae miltiorrhizae andPanax notoginseng) [11]

Da Chuanxiong Formula (DCXF) is not only a famousChinese medicinal prescription but also a classic herb pairfor mutual potentiation composed of two herbs namelyChuanxiong (Ligusticum chuanxiong Hort) and Tianma(Gastrodiae elata Bl) with a crude weight ratio of 4 1 usedfor headache caused by blood stasis andwind-heat syndromeThis herb pair first recorded in ldquoXuan Ming Lun Fangrdquo in JinDynasty has been widely used to promote blood circulationbalance the liver and extinguish wind eliminate pathogensand dredge the collaterals to stop pain with thousands ofyearsrsquo clinical experience In modern medicine its antimi-graine effect has been definitely confirmed [12ndash15] Nowvarious dosage forms of this herb pair on the market suchas capsules pellets oral decoctions and granules are mainlyindicated for a blood stasis type of headache Howeverthe synergism mechanisms of the formulae have not beenelucidated and research progress of this combination hasrarely been summarized

Herein the research status of Chuangxiong-Tianma herbpair (CTHP) namely DCXF is discussed in terms of itsethnopharmacological relevance material basis and phar-macological actions bymeans of modern analysis methods Itis expected to give a comprehensive interpretation ofDXCF inorder to inherit the essence of herb pair and innovative drugdelivery system of this prescription

2 Ethnopharmacological Relevance

21 Traditional Background of Herbs Chuanxiong Rhizoma(CR) Chuan xiong in Chinese is the dried rhizome of Ligus-ticum chuanxiong Hort which belongs to the Umbelliferaefamily and its optimal harvest time is in the period fromApril to May which has been indicated as the best time forthe accumulation of active constituents such as volatile oilsferulic acid and alkaloids [25ndash27] The resources of bothwide and cultivated CR are wide distributed in PengzhouXindu Chongzhou and Dujiangyan in Sichuan provinceof China [28 29] Zhu et al compared the contents oftetramethylpyrazine and ferulic acid which are two mainactive constituents of CR in different CR samples fromdifferent seasons as well as different producing areas usingHPLC finding that the contents of teramethylpyraine andferulic acid were significantly different [27] It has beenused for thousands of years in traditional Chinese Japaneseand Korean folk medicine [30] According to traditionalChinese medicinal theory CR could promote blood and

Qi circulation and dispel wind and relieve pain in TCM[31] For its reputation of facilitating blood circulation anddispersing blood stasis [32] CR is not only used formedicinalpurpose like treating atherosclerosis [33] ischemic stroke[34] vasodilation [35] and thrombus formation [36] but alsofor food preparation and health care products such asmuttonsoup [37] tobacco flavor additive and natural preservative[38]

Gastrodiae Rhizoma (GR) Tianma in Chinese is thedried rhizome of Gastrodiae Elata BI which belongs tothe Orchidaceae family and is widely used as a traditionalmedicine in China Japan and Korea Known as a kind ofcommonly used and expensive traditional Chinese medicineGR is mainly produced in Sichuan Yunnan Guizhou andShanxi province in China [39 40] In humid environmentGR could make a good breeding and it commonly harvestedin early winter or spring for it lies dormant during these spe-cific times to maintain its active substances [40 41] By usingHPLC-DAD and HPLC technique the chromatographicfingerprint of GR was developed to compare the effectivecontents of GR from different habitats and founds have goodsimilarity of fingerprints with 14 different producing areasof China except for the GR in Lueyang Shaanxi province[42] In Chinese medicine GR is one of the most importantherbs used for balancing the liver and extinguishing wind forthe efficacies of moistening viscera calming and protectinghuman body calming liver and suppressing liver-yang andcalming the wind and activating collaterals [20] In ShengNongrsquos herbal classic a famous TCM classic GR is consideredas one of the top grade drugs for it has rejuvenating effectsand nontoxic property which can be used without harm for along time For thousands of years in China GRhas been usedto treat diseases such as headache dizziness paralysis andconvulsion and enhance health by using alone or combiningwith other Chinese herbs [18]

22 Clinical Use of DXCF In TCM it is generally believedthat humanheads inclined to be attacked by pathogenicwindleading to headache In Song Dynast traditional Chinesemedicinal masters thought that expedite blood circulationcould dispel pathogenic wind in body Thus it has been oneof the most important principles to treat headache in TCMsuch as acupuncture moxibustion and herbs Due to thedramatic effect on Qi promotion in blood of CR and thesignificant effect on internal wind elimination of GR like theprevious description DCXF has the undoubted therapeuticeffect for headache caused by blood stasis and wind-heatsyndrome [22] Nowadays DCXF has been used in treatingdifferent types of headaches such as migraine angioneuroticheadache and the headache caused by endogenous of liverfire and stagnation of the liver-Qi [16 17 19 21 23 24 43 44]Interestingly DCXF could effectively control the headacheand relieve the patientrsquos suffering without obvious side effectsBased on pharmacological investigation DCXF could effec-tively enhance the cerebrovascular elasticity change cerebralblood supply and adjust the instability of cerebrovascularpromotion which had advanced functions for improvingclinical symptoms [45]

Evidence-Based Complementary and Alternative Medicine 3

Table 1 Main chemical constituents and relative detection methods of CR

Compound type Compound name Extract Detection method References

Phthalide compounds(Figure 1)

Z-681015840731015840-Diligustilide

Ethanol 1H-NMR13C-NMR [16]Diethyl ether 13C-NMR [17]

Ethanol 1H-NMR13C-NMR [16]60 ethanol LC-ESI-MS [18]95 ethanol TOF-MSNMR [19]Diethyl ether 13C-NMR [17]

Z10158401015840-38-Dihydro-661015840731015840120572-diligustilide Diethyl ether 13C-NMR [17]

4-Hydroxy-3-butylphthalide80 methano HPLC [20]Acetic ether MS [21]95 ethanol TOF-MSNMR [19]

Ligustilide

Acetic ether GC-MS [22]80 methanol HPLC [20]60 ethanol LC-ESI-MS [18]Ethanol 1H-NMR13C-NMR [16]

Senkyunolide F Acetic ether MS [21]

Senkyunolide I 95 ethanol TOF-MSNMR [19]Acetic ether MS [21]

Senkyunolide P 60 ethanol LC-ESI-MS [18]45-Dihydro-3-butylphthalide Diethyl ether 13C-NMR [17]

Chuanxiongol 80 methanol HPLC [20]67-di-Hydroxyligustilide 80 methanol HPLC [20]

3-n-Butylphthalide 60 ethanol LC-ESI-MS [18]Acetic ether GC-MS [22]

Organic acids(Figure 2)

Feulic acid

Ethanol 1H-NMR [23]95 ethanol NMR [19]Ethanol IR1H-NMR [24]

80 methanol HPLC [20]60 ethanol LC-ESI-MS [18]

Caffeic acid95 ethanol NMR [19]Ethanol IR1H-NMR [24]

80 methanol HPLC [20]Succinic acid 95 ethanol NMR [19]Sadanic acid Ethanol IR1H-NMR [24]Sinapic acid Ethanol 1H-NMR [23]

Protocatechuic acid 80 methanol HPLC [20]Augustic acid Acetic ether MS [21]

Phenols(Figure 3)

Chrysophanol Ethanol IR1H-NMR [24]

Pregnenlone

Ethanol 1H-NMR [23]95 ethanol NMR [19]Acetic ether MS [21]95 ethanol NMR [19]

Water EI-MSFAB-MS [21]


Table 1 Continued


Essential oil(Figure 4)

Xiongterpene Acetic ether MS [21]95 ethanol NMR [19]

(4S)-p-menth-1-ene-47-diol Acetic ether MS [21]Water EI-MSFAB-MS [21]

3(R) 8(S) 9(Z)-Falcarindiol Acetic ether MS [21]Water EI-MSFAB-MS [21]

177-Trimethyl-bicyclo[221]hept-2-yl Acetic ether GC-MS [22]b-Phellandrene Acetic ether GC-MS [22]120574-Terpinene Acetic ether GC-MS [22]

(R)-(minus)-p-menth-1-en-4-ol Acetic ether GC-MS [22]p-Mentha-14(8)-diene Acetic ether GC-MS [22]

Monopalmitin 95 ethanol NMR [19](minus)-Spathulenol Acetic ether GC-MS [22]

2-Chloro-1-(24-dimethylphenyl)-2-methyl-1-propanone Acetic ether GC-MS [22]

Alkaloid(Figure 5)

Tetramethylpyrazine 80 methanol HPLC [20]Choline 80 methanol HPLC [20]

In addition DCXF also has many other positive curativeeffects for curing cervical spondylosis [46] cerebral arte-riosclerosis [47 48] ischemic vertigo symptoms [49] andhypertension [50]

3 Chemical Properties

All these bioactivities are attributed to the chemical con-stituents of DCXF Thus to understand the material basesof herb pairs is necessary for annotating the compatibilitytheory and developing it in TCM In order to get thecomprehensive phytochemical information the chemicalconstituents of CR and GR will be introduced briefly at firstfollowed by compatibility behavior of DCXF

31 Chemical Constituents inChuanxiongRhizoma Chuanx-iong Rhizoma (CR) was proven to have many active ingredi-ents such as phthalide compounds phenolic acid essentialoil and alkaloid (Table 1) To date it has been analyzed thatnine volatile oil compounds 12 kinds of alkaloids 16 kinds ofphenolic acid derivatives and 33 kinds of lactone componentsare isolated from CR which contains four main effectivecomponents ligustilide tetramethylpyrazine ferulic acidand senkyunolide A [30 51] Meanwhile polysaccharideceramides and a variety of other small molecule compoundsof lipids are also found as the active compounds in CR

32 Chemical Constituents in Gastrodiae Rhizoma Gas-trodiae Rhizoma (GR) has some main active ingredientsphenols polysaccharides microelement organic acids andso forth (Table 2) It is known that GR has been intensivelyisolated and identified to have 20 phenolic compounds andrelated glycosides 9 organic acids and related esters 3sterols and sterolines and multiple small organic molecular

compounds of furan aldehydes and fatty acids Evidenced bythe recent to relevant reports gastrodin is considered to bethe most effective compound in GR [52ndash55]

33 Chemical Constituents in the DCXF As earlier discussedsynergistic effects of herb pair would not be produced bysimple combination of compounds from two herbs Basedon constituents in single herb currently several studies onDCXF have been investigated on its bioactive materialsResearchers have confirmed that ferulic acid ligustilidegastrodin and other components are the active componentsof treating migraine in Dachuanxiong Decoction (Figure 11)[56] By using the HPLC-DAD-MS119899 coupling technique3 compounds of CR (ferulic acid senkyunolide I andsenkyunolide H) and 8 kinds of compounds of GE (gas-trodin s-(4-hydroxybenzyl)-glutathion parishin parishin Bparishin C p-hydroxybenzaldehyde etc) were identifiedwith a fingerprint of Dachuanxiong Decoction [57] Addi-tionally 17 different kinds of structure of DachuanxiongDecoction (gastrodin senkyunnolide I senkyunnolide H E-ligustilide Z-Ligustilide butylphthalide riligustilide tokino-lide B and levistolide A) were reported by the use of the LC-QTOFMS technique in another research of DachuanxiongDecoction [58] Analyzing the statistics of DachuanxiongDecoction in vivo scientists demonstrated that there were10 more different kinds of compounds including 6 originalsubstances of CR and 4 original substances of GR [59]Additionally gastrodin and parishin are definitely detectedby serum pharmacochemistry in rat plasma after the gavageof Dachuanxiong Decoction and those data help us establisha unified and advanced method to study DCXF [60]

Currently some researchers have made some beneficialattempts to investigate the active ingredients behavior in vivobefore and after the compatibility of the DCXF Compared


O

O

H

H

H

O

O

H

Z-68998400 73998400-Diligustilide

OO

O

OH3C

CH3

Z998400998400-38-Dihydro-669984007 3998400120572-diligustilide

O

OH

O

CH3

4-Hydroxy-3-butylphthalide

O

O

OH

H3C

Chuanxiongol

O

O

H3CCH3

Z-Ligustilide

O

O

CH3

45-Dihydro-3-butylphthalide

O O

H

HO

OH3C

CH3

Senkyunolide P

O

O

3-n-Butylphthalide

O

O

Senkyunolide F

OH

O

O

Senkyunolide I

OH

HO

CH3

O

O

67-di-Hydroxyligustilide

OH

HO

Figure 1 The chemical structures of phthalide compounds of CR

H

HO

H H

O

Pregnenolone

O

O

OHOH

Chrysophanol

CH3

Figure 2 The chemical structures of organic acids of CR

with the pharmacokinetic behaviors of rats in vivo before andafter CR combined with GR the area of GR in the brain tissueof rat drug concentration curve of CR-GR group was 166times larger thanGRonly used group and themean residencetime of was CR-GR group was longer and the clearanceis 6458 of GR only used group which will significantlyillustrate that DCXF could increase the bioavailability andslow down the elimination rate of GR [61] Another recentstudy stated that the hydrolytic metabolites of ligustilidehad been found in Dachuanxiong Decoction administration

group while there was no signal in the ligustilide administra-tion group It is suspected that the discovery of new relatedmetabolite may be related to the interaction of the effectivesubstance in the DCXF [50]

4 Pharmacological Effects

In recent years the preparations based on DCXF have beenused widely for angioneurotic headache and is notable on


HOFerulic acid

CH=CHCOOHH3CO

HO

HO

COOH

Protocatechuic acid

COOH

O

Sedanonic acid

HOOH

O

OSuccinic acid

OH

O

4

5

Sinapic acid

Figure 3 The chemical structures of phenols of CR

S

HO

Pr-i

OH

(4S)-p-menth-1-ene-4 7-diol

OHH

H

(minus)-spathulenol p-mentha-1 4(8)-diene

OO

177-trimethyl-bicyclo[221]hept-2-yl ester

HO

(R)-(minus)-p-menth-1-en-4-ol 120574-Terpinene

O

O3-n-Butylphthalide

CH3

Cl

O

2-Chloro-1-(24-dimethylphenyl)-2-methyl-1-propanone

CH3

CH3

CH3H3C

HO

HO

H

H OH

O

Augustic acid

CHO C C C

OH

3(R) 8(S) 9(Z)-Falcarindiol

H3C CH2

O

OH

O

HO

O

Xiongterpene

H3C

H3C

CH3

CH3CH3

CH3

CH3

O

OH

HO

O

Monopalmitin

Figure 4 The chemical structures of essential oil compounds of CR


N

N

Tetramethylpyrazine

H3C

H3C

CH3

CH3

Choline

N+H3C

CH3

CH3

CH2CH2OH

Figure 5 The chemical structures of alkaloid compounds of CR

Table 2 Main chemical constituents and relative detection methods of GR


Phenols(Figure 6)

Gastrodin Water 1H-NMR13C-NMR [35]Ethanol HPLC [36]

p-Hydroxybenzyl alcohol 70 ethanol EI-MS1HNMR13CNMR [37]Water 1H-NMR13C-NMR [35]

p-Hydroxybenzyl ethyl ether 70 ethanol EI-MS1HNMR13CNMR [37]Water 1H-NMR13C-NMR [35]

p-Hydroxybenzoic acid Water 1H-NMR13C-NMR [35]4-Hydroxy-3-methoxybenzyl ethyl ether Water 1H-NMR13C-NMR [35]

p-Hydroxy-benzyl-methyl ether 70 ethanol EI-MS1HNMR13CNMR [37]Water 1H-NMR13C-NMR [35]

p-Hydroxybenzaldehyde Water 1H-NMR13C-NMR [35]70 ethanol EI-MS1HNMR13CNMR [37]

L-Phenyllactic acid Water 1H-NMR13C-NMR [35]Hibicutaiwanin Water 1H-NMR13C-NMR [35]

441015840-Methylenebis Water 1H-NMR13C-NMR [35]2-Methoxyphenol Water 1H-NMR13C-NMR [35]

Parishin Water 1H-NMR13C-NMR [35]Parishin B Water 1H-NMR13C-NMR [35]Parishin C Water 1H-NMR13C-NMR [35]120573-Sitosterol 70 ethanol EI-MS1HNMR13CNMR [37]

221015840-Methylenebis (6-tert-butyl-4-methylphenl) 70 ethanol EI-MS1HNMR13CNMR [37]Dimethyll phthalate 70 ethanol EI-MS1HNMR13CNMR [37]

Polysaccharides(Figure 7)

Adenosine 70 ethanol EI-MS1HNMR13CNMR [37]Arabinose 70 ethanol EI-MS1HNMR13CNMR [37]Mannose 70 ethanol EI-MS1HNMR13CNMR [37]Xylose 70 ethanol EI-MS1HNMR13CNMR [37]Sucrose 70 Ethanol EI-MS1HNMR13CNMR [37]

Microelement(Figure 8)

Aspartic acid Dry powder Automatic Amino-acid Analyzer [38]Alanine Dry powder Automatic Amino-acid Analyzer [38]

Glutamic acid Dry powder Automatic Amino-acid Analyzer [38]Proline Dry powder Automatic Amino-acid Analyzer [38]Valine Dry powder Automatic Amino-acid Analyzer [38]Lysine Dry powder Automatic Amino-acid Analyzer [38]Leucine Dry powder Automatic Amino-acid Analyzer [38]


Vanillic aldehyde Ethanol HPLC [36]Citronellol Ethanol HPLC [36]

Other(Figure 10)

p-Methylphenyl-1-O-120573-D-glucopyranoside Water 1H-NMR13C-NMR [35]70 ethanol 1H-NMR13C-NMR [37]

Methyl-O-120573-D-glucopyranoside Water 1H-NMR13C-NMR [35]Diosgenin Water 1H-NMR13C-NMR [35]


OH

O

HO

L-Phenyllactic acid

OH

HO

O

p-Hydroxybenzoic acid

OH

O

p-Hydroxybenzyl ethyl ether

OHO

p-Hydroxybenzaldehyde

OH

OH

p-Hydroxybenzyl alcoho

O

HO2-Methoxyphenol

O

O

O

O

Dimethyl phthalateCH3

CH3

O

HO

OH

OCH3

CH3

44998400-Methylenebis(2-methoxyphenol)

OH

CHO

HO

Hibicutaiwanin

O

O

HO

4-Hydroxy-3-methoxybenzyl ethyl ether

O

O

HO


O

HO

O

OH

HO

O

HO

O

O

O

O

O

O

O

O

O

OH

HO

OH

OH

OH

OH

Parishin

H3O

O

OH

HO O

HO

OH

O

HO

HOO

O

O

OH

OH

OH

OHO

OO

Parishin B

Figure 6 Continued


OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH

22998400-Methylenebis(6-tert-butylminus4-methylphenl)

Figure 6 The chemical structures of phenols of GR

O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose

Figure 7 The chemical structures of polysaccharides of GR

both pharmacological action and clinical effect resulting fromblood stasisTherefore the pharmacological actions of DCXFhave been further researched and discussed by scholars

Migraine a multivariate complex disease have a highincidence and could be easily to recur Dachuanxiong Decoc-tion is always the drug of choice for treating migrainesAccording to different pathogenesis types DCXF has beenmainly studied for four aspects as follows

41 Vascular Actions At the onset of migraine it has beendemonstrated that some disturbances occur in the intra- andextracranial vascular contraction-dilation functions Alka-loids could affect the contents of nitric oxide nervous system

(NOS) superoxidase dismutase and methylene dioxyam-phetamine of rats with focal cerebral ischemia [62] Tetram-ethylpyrazine an active ingredient of CR had been assessedas it could protect endothelial cells injured by ox-LDL Theratio of intimal ormedial thickness and the number ofmono-cytes in intimal could be significantly reduced by tetram-ethylpyrazine Meanwhile the MCP-1 and ICAM-1 levels inplasma and inhibited LOX-1 expression in the rabbit aortaswere decreased after the treatment of tetramethylpyrazineIn vitro study revealed that monocyte adhesion to rat aorticendothelial cells was suppressed rat aortic endothelial cellmigration was inhibited and MCP-1 and ICAM-1 expressionin ox-LDL-injured RAECs were downregulated by treatingwith tetramethylpyrazine which produced a certain degree


OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus

Figure 8 The chemical structures of microelement of GR

O

HO

H

OVanillic aldehyde

OH HO

Citronellol

(+)-citronellol (minus)-citronellolCH3CH3CH3CH3

CH3 CH3

Figure 9 The chemical structures of organic acids of GR

of protection in atherosclerosis and endothelial cells [63]For ischemic stroke tetramethylpyrazine was also reportedto have a global inhibitory effect on intracerebral cellu-lar inflammatory response in a rat model of permanentcerebral ischemia [64] Furthermore the effects of tetram-ethylpyrazine on the fever could increase the plasma levelsof tumor necrosis factor-120572 and the hypothalamic levels ofglutamate hydroxyl radicals and prostaglandin-E2 inducedby lipopolysaccharide Reports also demonstrated that byintravenous or intracerebroventricular tetramethylpyrazine1 h after lipopolysaccharide injection tetramethylpyrazinecould attenuate lipopolysaccharide-induced fever [65] Earlyresearch showed that DCXF had a better relaxing effect than aChinese herbal monomer tetramethylpyraine So it was obvi-ous that the mutual promotion of DCXF was verified [66]With the development of research Dachuanxiong Decoctionwas demonstrated to be able to significantly decrease thevasodilatation of artery and vein vascular of dura mater inmigraine model rats and to have obvious therapeutic actionsof preventive effect of learning and memory impairment inthe vascular dementia field [67 68] By using Dachuanxiongsoft capsule the whole blood plasma viscosity and fibrino-gen of rats were reduced prothrombin time was prolongedand aggregation and adhesion of platelet were decreased[69] Moreover DCXF also had protective effects on the rats

with focal cerebral ischemia and reperfusion compared withthe control group intragastrically perfused with saline andthe probable mechanism was that DCXF could upgrade theexpression of vascular epithelial growth factor [70ndash72]

42 Trigeminal Vascular Actions Angiogenic substancescould activate transmitters to stimulate the trigeminal ner-vous system (NOS) such as nitric oxide synthase andcalcitonin gene-related peptide (CGRP) [68 73] It wasdemonstrated that phthalide compounds could obviouslyimprove the behavior disorder of middle cerebral arteryocclusion rats by reducing cerebral ischemia and inhibitplatelet aggregation [74] Ligustilide an active componentsin CR has anti-inflammatory activites on experimentalovariectomized osteopenic rats and its anti-inflammatorypotential was showed up in the regulation of nuclear fac-tor kappa B maleic dialdehyde polymorphonuclear cellsinterleukin-1120573 inducible nitric oxide synthase and tumornecrosis factor-120572 adhesion molecule and cyclooxygenase-2[75] Also tetramethylpyrazine exhibited a neuroprotectiveeffect against ischemic deficits by reduction of behavioraldisturbance brain infarction and edema which mightactively mediate neuroprotection against cerebral ischemiain both the endogenous defense capacity promotion and


O

AcO

AcOOAc

OAc

CH3

p-Methylphenyl-1-O-120573-D-glucopyranoside

O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C

Figure 10 The chemical structures of other compounds of GR

the attenuation of the extent and composition percentage ofthe major cellular inflammatory responses by targeting ofmacrophages ormicroglia by elevatingNrf2HO-1 expression[64] By using nitroglycerin (NO) model DachuanxiongDecoction was shown to decrease migraine symptoms forit could release the pain neurotransmitters by regulating andcontrolling the trigeminal nervous system [76]

43 Cortical Spreading Depression Actions The activationsof receptors in dural vascular such as substance P (SP)NOS and CGRP were significantly inhibited after hav-ing Dachuanxiong Decoction such that the migraine wasreleased [68] It was reported that phenols in GR had antianx-iety effects on mice [77] Gastrodin an effective constituentof phenols in GR could significantly reduce CGRP-ir (+)neuron CGRP-mRNA and pERK12 expression level in ratsand these actions were similar to the effective concentra-tion of sumatriptan succinate [78] Tetramethylpyrazine hadbeen suggested could protect neural system by inhibit theexpression of chemokine receptor 4(CXCR4) Thus it isreasonable to create a new insights into therapeutic potentialof tetramethylpyrazine in the treatment of migraine [79]Ferulic acid an active compound of phthalide in CR wasreported to have some effect on curing peripheral nerveinjury for it could lead to a remarkable CGRP staining of thelamina I-II regions in the dorsal horn ipsilateral to the injuryrecruit a significantly diminished number of macrophagesand shorten a significantly latency and an acceleration of thenerve conductive velocity of the evokedmuscle action poten-tials [80] Recently it was proven that DCXF could reducethe abnormal increased content of CGRP and endothelin inthe plasma of migraine patients during the attack stage andcould also inhibit plasmatic extravasation cerebrovascularabnormal expansion and neurogenic inflammation causedby platelet activation [81] Furthermore the sedation andanalgesia of DCXF was one of the mechanisms of relievingthe headache and treating migraine [82]

44 Stimulating Cerebral Neuron Actions In cerebral neurontheory NO has participated in many cellular signaling trans-ductions Scientists investigated that tetramethylpyrazinehad some effect on neuropathic pain-associated behaviorsand neuronal apoptosis in the spinal dorsal horn and theresults suggested that tetramethylpyrazine-induced analgesia

inhibit the neuronal apoptosis via the modulation of Bcl-2 and caspase-3 proteins in the rat spinal dorsal horn[83] Also tetramethylpyrazine exhibited a neuroprotectiveeffect against ischemic deficits by reduction of behavioraldisturbance brain infarction and edema which mightactively mediate neuroprotection against cerebral ischemiain both the endogenous defense capacity promotion [64]Ligustilide had been reported to possess some neuroprotec-tive effects on transient forebrain ischemia and permanentfocal ischemia After the investigation of the protective effectsof ligustilide on parietal cortex and hippocampus of ratsin chronic cerebral hypoperfusion mode ligustilide showedobvious neuroprotective potential for treating chronic cere-bral hypoperfusion injury which might be attributed to itsantiapoptosis of neuron and antiproliferation of astrocyteboth in cortex and in hippocampus of the rats suggesting thatligustilidemightmake some contribution to the prevention ofmigraine [84] By evaluating the analgesic and antimigraineactivities of senkyunolide I from CR researchers suggeststhat senkyunolide I may be an active component of treatingmigraine It was further explained that the mechanism ofthe relieve of pain in migraine model rats may causedby the adjustment of their turnover rates and the levelsof monoamine neurotransmitters as well as the decreaseof nitric oxide (NO) levels in blood and brain [85] Byobserving NO concentration in glial cells DachuanxiongDecoction is investigated to give rise to the variation of5 hydroxytryptamine (5-HT) in glial cells by changing theconcentration of NO in different doses Additionally it couldincrease and irritate 5-HT1D receptors in glial cells [86 87]expand arterioles and excite neurons [88] By nourishingnerve cells and preventing calcium ions moving into nervecells at the same time DCXF could improve the viability andactivities of nerve cells decrease the intracellular free calciumconcentration and resist neuronal apoptosis [15 89 90]

45 Other Working Elements in Dachuanxiong DecoctionBy exploring the dose-effect relationship of ferulic acid onameliorating pain-depression dyad scientists had demon-strated a clinical pain-depression dyad therapy of ferulic acidand suggested that ferulic acid can reverse pain-depressiondyad which could influence oxidative stress andmonoaminelevel [91] The present study was carried out to elucidate acentrally acting muscle relaxant effect of chloroform solublefraction and its component namely ligustilide cnidilide and


GastrodinGastrodioside

P-Hydroxybenzyl alcoholP-Hydroxy-benzyl methyl ether

P-HydroxybenzlaldehydeP-Hydroxybenzaldehyde

Parishin (B)(C)ArabinoseMannose

Aspartic acid

Glutamica acidVanillic aldehyde

LigustilideLigustrazineFerulic acid

N-ButylphthalideButylidene phthalide

Feulic acidCaffeic acid

ChrysophanolPregnenloneXiongterpene

3(R) 8(S) 9(Z)-FalcarindiolSenkyunolide P(F)(I)

Trimethylamine

Sadanic acid

Palmitic acidAdenosine

Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine

Current index components

N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene

middot middot middot middot middot middot

Chuanxiong RhizomaGastrodiae Rhizoma


HPLC automatic amino-acid analyzer

1H-NMR13C-NMR TOF-MSNMR

GC-MS LC-ESI-MS EI-MS 1H-NMR 13C-NMR

Figure 11 Chemical structures of current index components in Dachuanxiong Decoction

senkyunolide obtained from the rhizome of CR As a curare-like action was not observed a muscle relaxation inducedby these phthalide compounds is considered to be due tocentral origin [92] Thus it is possible that ferulic acid mighthelp release the pain of migraine by influencing oxidativestress and monoamine level while ligustilide cnidilide andsenkyunolide also contribute to the treatment of migraine bymuscle relaxation

Since ancient times doctors of TCM have protected thedose as a secret part of treatment that should not be given tothe public Although the same herbal drug is used in differentdose proportions there are different efficacies with its dosecombinations From the historical evolution of drug usescholars usually adjust the ratio of Chinese herb prescriptionson the basis of individual conditions Consequently theoptimumproportion ofDCXFhas been investigated in recent


years By investigating its different proportions the resultsconfirmed that the ratio of CR-GR (CR GR = 1 4) was thebest compatibility [93] After observing the effects of thecortex neuron cytoplasm of rats with different compatibilityratios scientists demonstrated that the optimum proportioncould notably lower the content of cytoplasm (Ca2+) ofneuron in both normal oxygen supply and anoxic conditions[93] Dachuanxiong Decoction is proved to have effects onacute blood-stasis and the influence for the blood velocityof rabbits common carotid in different ratios of CR and GRwhich have no effects on the condition of only using GR [94]

Furthermore researchers discovered that there are dif-ferent effect pathways of CR and GR in DCXF For CR itoccurred on vessel while for GR it was on a nerve Ultimatelyit stimulated synergistic effects and enforced efficiency bothby simultaneous use [94]

All these pharmacological effects are responsible for itssignificant therapeutic effects on migraine vertigo pains inrheumatoid arthritis numb limbs neck stiffness attentiondeficit and memory problems

5 Prospects and Discussion

In summary as per the review presented herein DCXF theabbreviation of Da Chuanxiong Formula is an importanttraditional medicinal pair as well as formula in traditionalChinese medicinal systems for a long time Organic acidsphthalides phenols polysaccharides ceramides cerebro-sides and microelements are believed to be the main bioac-tive constituents of DCXF The herb pair exhibits significantclinical effects on antimigraine neuron protection and heartand cerebral functions improvement with an abundant TCMconnotation to balance the liver extinguish wind promoteblood and dispel wind

According to the basic theory of TCM prescription thepurpose of pair TCM herbs is to produce synergistic effectsto enhance therapeutic efficacy andor to minimize toxicityand adverse effects For DCXF to increase pharmacologicaleffects might be a main reason using CR and GR togetherIn spite of TCM theory illustration on its compatibilityeffects in which CR and GR would be responsible foractivating blood circulation and repressing liver yang itscompatibility mechanism is still rare to reveal right nowDespite the uncovery of increasing chemical compoundsin CR and GR some compounds such as ferulic acid andgastrodin are considered to be active constituents for thereason of high contents in herbs and absorption compoundsin blood [59] However these supposed active compoundscould not represent DCXF The herbal decoction generallyhas multiple components acting on multiple targets So farthe real active compounds for each effective target have notbeen revealed as well as the change of compounds contentsin herbal decoction and pharmacokinetical behaviour in vivoafter their compatibility To investigate the interaction amongcompounds fromCR andGR in terms of quality and quantitybetween single herb and formula would be the key to explaintheir synergistic effects

In addition in spite of hundreds of years applicationhistory safety studies of DCXF also should be scientificallyperformed owing to high risk of cerebrovascular disease It isof utmost urgency thatmore extensive clinical research espe-cially using randomized double-blind placebo-controlledcrossover studies should be carried out Furthermore moreinvestigation is also needed to research on the effectivecomponents types the differences and interaction in DCXFthe differences in terms of quality and quantity between CRGR and DCXF the amount and the behavior of absorptiondistribution metabolism excretion in vivo

This review gives a brief summarization of recent researchadvances of DCXF in the hope to provide some significantreferences for the study of DCXF even for the compatibilityof herb pair in TCM Such an analysis will also help toidentify the research gaps for generating novel drug deliverysystem Thus the data and studies presented in this reviewwill be helpful for new product planning RampD investmentevaluation and RampD productivity measurements

Conflict of Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contribution

LuWang and JinmingZhang contributed equally to thiswork

Acknowledgments

This study was supported by theMacao Science and Technol-ogy Development Fund (0772011A3 0742012A3) and theResearch Fund of the University ofMacau (SRG025-ICMS13-CMW MYRG 208 (Y3-L4)-ICMS11-WYT)

References

[1] C M Wang and L D Wu History of Chinese Medicine WorldScientific 1932

[2] G Maciocia The Foundations of Chinese Medicine ElsevierChurchill Livingstone 2005

[3] J Xu and Y Yang ldquoTraditional Chinesemedicine in the Chinesehealth care systemrdquo Health Policy vol 90 no 2-3 pp 133ndash1392009

[4] R Yuan and Y Lin ldquoTraditional Chinese medicinean approachto scientific proof and clinical validationrdquo Pharmacology andTherapeutics vol 86 no 2 pp 191ndash198 2000

[5] W Y Jiang ldquoTherapeutic wisdom in traditional Chinesemedicine a perspective from modern sciencerdquo DiscoveryMedicine vol 5 no 29 pp 455ndash461 2009

[6] R Xue Z Fang M Zhang et al ldquoTcmid traditional Chinesemedicine integrative database for herb molecular mechanismanalysisrdquo Nucleic Acids Research vol 41 no D1 pp D1089ndashD1095 2013

[7] S Wang Y Hu W Tan et al ldquoCompatibility art of traditionalChinese medicine from the perspective of herb pairsrdquo Journalof Ethnopharmacology vol 143 no 2 pp 412ndash423 2012


[8] D Xu ldquoMutual understanding between traditional Chinesemedicine and systems biology gaps challenges and oppor-tunitiesrdquo International Journal of Functional Informatics andPersonalised Medicine vol 2 no 3 pp 248ndash260 2009

[9] X D Wen L W Qi J Chen et al ldquoAnalysis of interactionproperty of bioactive components in Danggui BuxueDecoctionwith protein by microdialysis coupled with HPLC-DAD-MSrdquoJournal of Chromatography B vol 852 no 1-2 pp 598ndash6042007

[10] Q T Gao J K H Cheung J Li et al ldquoA Chinese herbal decoc-tion Danggui Buxue Tang prepared from Radix Astragali andRadix Angelicae Sinensis stimulates the immune responsesrdquoPlanta Medica Natural Products and Medicinal Plant Researchvol 72 no 13 pp 1227ndash1231 2006

[11] Y J Wei P Li B Shu et al ldquoAnalysis of chemical and met-abolic components in traditional Chinese medicinal combinedprescription containing Radix Salvia miltiorrhiza and RadixPanax notoginseng by LC-ESI-MS methodsrdquo Biomedical Chro-matography vol 21 no 8 pp 797ndash809 2007

[12] W Xiao W H Cai and Q Xiao ldquoEffects of dachuan xiongfangon concentration of substance p in blood and ganglion oftrigeminal nerve of rats with migrainerdquo Acta Chinese Medicineand Pharmacology vol 2 no 38 pp 32ndash34 2010

[13] MM Zhou K Yang and Y TWang ldquoEffects of da chuanxiongfang on dural vessels and nos sp and cgrp receptors in thetrigeminal nucleus of nitroglycerin-induced migrainous ratrdquoPharmacology and Clinics of Chinese Materia Medica vol 25no 2 pp 9ndash10 2009

[14] MM Zhou K Yang andY TWang ldquoAssessment of synergisticeffect of gastrodia elata and rhizoma chuanxiong in dachuanx-iong pills on treating migraine by hemorheology and bloodvelocityrdquo Pharmacology and Clinics of Chinese Materia Medicavol 24 no 1 pp 6ndash8 2008

[15] G Yao C Peng D Zhou et al ldquoExperimental study ofdachuanxiong decoction on injury induced by ischemia innerve cellsrdquo China Traditional Chinese Medicine vol 26 no 4pp 314ndash318 2004

[16] X D Li ldquoThe efficacy observation of treatment of angioneu-rotic headache by tianma chuanxiong capsulesrdquo Anthology ofMedicine vol 1 no 3 pp 339ndash340 2004

[17] H Y Liu G Q Yang and G H Pu ldquo300 treatment cases ofmigraine by tianma chuanxiong decoctionrdquoTraditional ChineseMedicinal Research vol 1 no 1 pp 51ndash52 2001

[18] X H Tang B Li L Y Hu et al ldquoThe compatibility applicationsof tianmardquo Journal of Shanxi Collee of Traditional ChineseMedicine vol 13 no 3 pp 75ndash76 2012

[19] G Z Feng ldquo32 cases of migraine treated by Chinese medicinerdquoChinese Journal of ConvalescenMedicine vol 2 no 10 p 3 2001

[20] Q Miao ldquoNew advance in identification of Chinese medicinetianmardquo China Medical Herald vol 8 no 20 pp 20ndash25 2011

[21] L Kezhong ldquo35 treatment cases of wind-fire type of livermeridian by tianma chuanxiong decoctionrdquo Henan TraditionalChinese Medicine no 12 pp 48ndash49 2008

[22] M L Zhang ldquo43 treatment cases of wind-fire type of livermeridian by chuanxiong tianma decoctionrdquo Shaanxi Journal ofTraditional Chinese Medicine vol 30 no 10 pp 3ndash5 2009

[23] H F Liu ldquo43 treatment cases ofmigraine by tianma chuanxiongdecoctionrdquo Modern Journal of Integrated Chinese Traditionaland Western Medicine vol 2 no 5 p 2 2005

[24] K Z Li ldquo35 treatment cases of wind-fire type of liver meridianby tianma chuanxiong decoctionrdquo Henan Traditional ChineseMedicine vol 1 no 12 pp 48ndash49 2008

[25] X F Chen D R Ding S R Liu W X Huang and S X LiuldquoStudies on biologlcal characteristics or Ligusticum chuanxionghortrdquoChina Journal of ChineseMateriaMedica vol 19 no 8 pp463ndash510 1994

[26] G H Jiang M R Jia Y Y Ma et al ldquoAppropriate collectingtime and different productive processing method of ligusticumchuanxiongrdquoWest China Journal of Pharmaceutcal Sciences vol23 no 3 pp 312ndash314 2008

[27] C F Zhu Q X Shi Y P Yan et al ldquoDetermination andfingerprint analysis of tetramethylpyrazine and ferulic acid inLigusticum chuanxiongrdquo Zhong Yao Cai vol 31 no 8 pp 1113ndash1115 2008

[28] X J Shi L Chen and C Peng ldquoComparative study of chem-ical composition in different specifications of the chuanxionggoodsrdquo Journal of Sichuan of Traditional Medicine vol 29 no4 pp 58ndash61 2011

[29] W D Chen P H Peng L H Wang and S Guo ldquoStudies onenvironmental geochemistry in district road areas of ligusticumchuanxiongrdquoChinese Journal of Soil Science vol 40 no 4 2009

[30] W Li Y Tang Y Chen and J A Duan ldquoAdvances in thechemical analysis and biological activities of chuanxiongrdquoMolecules vol 17 no 9 pp 10614ndash10651 2012

[31] J Yang F Cai Y Tan et al ldquoAnalysis of regularity of clinicalmedication for migraine with text mining approachrdquo ChineseJournal of Information on Traditional Chinese Medicine vol 20no 2 pp 30ndash32 2013

[32] Y Jin T Liang Q Fu et al ldquoFingerprint analysis of Ligusticumchuanxiong using hydrophilic interaction chromatography andreversed-phase liquid chromatographyrdquo Journal of Chromatog-raphy A vol 1216 no 11 pp 2136ndash2141 2009

[33] L Zhang Y R Jiang C Y Guo C F Wu K J Chen andH J Yin ldquoEffects of active components of Red Paeonia andRhizoma chuanxiong on angiogenesis in atherosclerosis plaquein rabbitsrdquo Chinese Journal of Integrative Medicine vol 15 no 5pp 359ndash364 2009

[34] X Yang X Zeng and T Wu ldquoChuanxiong preparations forpreventing strokerdquo Cochrane Database Systematic Reviews vol20 no 1 2010

[35] M J Liang L C He and G D Yang ldquoScreening analysis andin vitro vasodilatation of effective components fromLigusticumChuanxiongrdquo Life Sciences vol 78 no 2 pp 128ndash133 2005

[36] M Li S Handa Y Ikeda and S Goto ldquoSpecific inhibit-ing characteristics of tetramethylpyrazine one of the activeingredients of the Chinese herbal medicine lsquoChuanxiongrsquo onplatelet thrombus formation under high shear ratesrdquoThrombo-sis Research vol 104 no 1 pp 15ndash28 2001

[37] J F Yuan Z Q Zhang Z C Fan and J X Yang ldquoAntioxidanteffects and cytotoxicity of three purified polysaccharides fromLigusticum chuanxiong Hortrdquo Carbohydrate Polymers vol 74no 4 pp 822ndash827 2008

[38] J G Wu Y J Wei X Ran H Zhang H Nian and L P QinldquoInhibitory effects of essential oil from rhizomes of Ligusticumchuanxiong on hypertrophic scarring in the rabbit ear modelrdquoPharmaceutical Biology vol 49 no 7 pp 764ndash769 2011

[39] G Wu M J Qin J C Kang and X Ji ldquoDetermination ofgastrodins and polysaccharides in rhizoma gastrodiardquo Researchand Practice on Chinese Medicine vol 21 no 1 pp 40ndash43 2007

[40] S H Liu M Duan F Tao and S Wang ldquoQuality evaluationof the gastrodia elata in eight originsrdquo Journal of LiaoningUniversity of Traditional Chinese Medicine vol 14 no 10 pp89ndash90 2010


[41] H J Zhang J J Zhou and X S Li ldquoStudy advance of gastrodiaelata b1rdquo Amino Acids and Biotic Resources vol 25 no 1 pp17ndash20 2003

[42] W Zhang Y X Sheng J L Zhang J T Xu and S Q SunldquoEvaluation of the quality of Gastrodia elata Bl by HPLC-DADMSrdquo Yao Xue Xue Bao vol 42 no 4 pp 418ndash423 2007

[43] Q F Su ldquoThe curative effect observations of 300 treatment casesofmigraine by tianma chuanxiong decoctionrdquoChinaHealthcareInnovation vol 1 no 16 pp 34ndash35 2008

[44] G Q Yang ldquo300 treatment cases of migraine by tianmachuanxiong decoctionrdquo Chinese General Practice vol 4 no 11pp 9ndash11 2001

[45] Y M Li ldquo30 treatment cases of vascular headache by chuanx-iong tianma decoction coodinated with flunarizine hydrochlo-ride capsulesrdquo Journal of Emergency in Traditional ChineseMedicine vol 20 no 5 pp 833ndash834 2011

[46] H Q Wang ldquoThe clinical observation of 345 treatment cases ofcervical spondylosis by gegen chuanxiong tianma decoctionrdquoJournal of Sichuan of Traditional Medicine vol 1 no 12 pp 97ndash98 2009

[47] Y Zhou ldquo35 treatment cases of cerebral arteriosclerosis bychuanxiong tianma decoctionrdquo Henan Traditional ChineseMedicine vol 1 no 4 pp 22ndash23 2003

[48] Y F Wang J S Zhang J T Zhang et al ldquo88 treatmentcases of vertebrobasilar atherosclerosis by tianma danggui andchuanxiongrdquoWest China Medical Journal vol 1 no 1 pp 183ndash184 2010

[49] B Q Xu Z X Shen and J A Yao ldquoThe efficacy observation of68 treatment cases by tianma chuanxiong decoctionrdquo Journalof Anhui Traditional Chinese Medical College vol 2 no 3 p 51994

[50] S M Ni D W Qian and J A Duan ldquoMetablites of ligustilideand gastrodin from dachuanxiong decoction in rabbit plasmardquoChinese Traditional Patent Medicine vol 32 no 7 p 6 2010

[51] X Ran L Ma C Peng H Zhang and L P Qin ldquoLigusticumchuanxiong Hort a review of chemistry and pharmacologyrdquoPharmaceutical Biology vol 49 no 11 pp 1180ndash1189 2011

[52] Y Q Xiao L Li and X L You ldquoStudies on chemicalconstituents of effective part of Gastrodia elatardquo ZhongguoZhongyao Zazhi vol 27 no 1 pp 35ndash36 2002

[53] P Guan J M Shi and Y Q Gao ldquoStudy on the volatilecomponents of gastrodia elatardquo Journal of Sichuan NormalUniversity (Natural Science Edition) vol 1 no 5 pp 615ndash6182008

[54] D Wang G Yang B Li Z Li and Y Chen ldquoInvestigation ofthe chemico-physical characteristics of the active componentsin the Chinese herb Gastrodia elata B1 by capillary zoneelectrophoresisrdquo Analytical Sciences vol 18 no 4 pp 409ndash4122002

[55] B Yan H Zhang N Pang X Chen Z Yu and K BildquoSimultaneous determination of four components in Gastrodiaelata by RP-HPLCrdquo China Journal of Chinese Materia Medicavol 34 no 22 pp 2903ndash2906 2009

[56] J Guo J A Duan E X Shang Y Tang and D Qian ldquoDeter-mination of ligustilide in rat brain after nasal administration ofessential oil from Rhizoma Chuanxiongrdquo Fitoterapia vol 80no 3 pp 168ndash172 2009

[57] L Shen X Lin S Liang et al ldquoCharacterization on centralingredients of active components in dachuanxiong fang basedon hplc-dad-mssimnrdquo Chinese Experimental Formulas of ChineseMedicine Magazine vol 18 no 7 pp 128ndash134 2012

[58] S M Ni D W Qian E X Shang et al ldquoAnalysis of chemicalcomposition of dachuanxiong fang by ultra performance liquidchromatography-electrospray ionization-quadrupole time offlightmass spectrometryrdquo Chinese Experimental Formulas ofChinese Medicine Magazine vol 1 no 16 pp 39ndash45 2010

[59] Y Wei X Lin N Zhang and Y Feng ldquoUPLC-MS analysis ofconstituents of Dachuanxiong Fang active parts absorbed intobloodrdquo China Journal of Chinese Materia Medica vol 36 no 9pp 1245ndash1248 2011

[60] X Lin Y Yuan Y Hong D Xu L Shen and Y Feng ldquoIn vivotransmigration of active ingredients from Gastrodia elata inDachuanxiong FangrdquoChina Journal of Chinese MateriaMedicavol 36 no 9 pp 1175ndash1178 2011

[61] Q Zhen J Y Liu S L Fu Y Liu J Qian and M YangldquoEffects of chuanxiong rhizoma on brain pharmacokinetics ofgastrodigenin in ratsrdquoChinese Journal of NewDrugs andClinicalRemedies vol 31 no 5 pp 263ndash266 2012

[62] Y F Ji and H X Liu ldquoAlkaloids of chuanxiong affects thecontents of no nos sod and mda in focal cerebral ischemiamodel ratsrdquo Chinese Medicine Modern Distance Education ofChina vol 9 no 2 pp 212ndash213 2011

[63] G F Wang C G Shi M Z Sun et al ldquoTetramethylpyrazineattenuates atherosclerosis development and protects endothe-lial cells from ox-ldlrdquo Cardiovascular Drugs and Therapy vol27 no 3 pp 199ndash210 2013

[64] T K Kao C Y Chang Y C Ou et al ldquoTetramethylpyrazinereduces cellular inflammatory response following permanentfocal cerebral ischemia in ratsrdquo Experimental Neurology vol247C pp 188ndash201 2013

[65] C H Chang W T Huang C H Kao S H Chen and C HLin ldquoTetramethylpyrazine decreases hypothalamic glutamatehydroxyl radicals and prostaglandin-e2 and has antipyreticeffectsrdquo Inflammation Research vol 62 no 5 pp 527ndash535 2013

[66] J L Tang F J Yang and Z R Wang ldquoThe influence ofdachuanxiongfang extracts on tension of cerebral vesselsrdquoSichuan Journal of Hysiological Sciences vol 25 no 6 pp 12ndash13 2004

[67] Y Zhao W Wang Y Zu et al ldquoEffect of big chuanxiongprescription extraction on preventing learning and memorydysfunction of vascular dementia ratrdquo Information on Tradi-tional Chinese Medicine vol 25 no 1 pp 67ndash69 2008

[68] MM Zhou K Yang and Y TWang ldquoThe infulence of trigem-inal nucleus nos sp and cgrp of nitroglycerin caused migrainemodel rats with da chuanxiong formulardquo Pharmacology andClinics of Chinese Materia Medica vol 25 no 6 pp 2ndash4 2009

[69] S J Xiang G L Du X H Li et al ldquoStudy on efficacy ofdachuanxiong soft capsulerdquo Chinese Journal of Information onTraditional Chinese Medicine vol 8 no 19 pp 22ndash24 2004

[70] L He and Z J Zhang ldquoThe protective effect of Dachuanxiong-wan on the rats with focal cerebral ischemia and reperfusionrdquoJournal of Sichuan University (Medical Science Edition) vol 35no 6 pp 821ndash823 2004

[71] Z J Zhang S Y Kong D Zhou and L He ldquoEffect ofDachuanxiongwan on the expression of vascular epithelialgrowth factor in rats with cerebral ischemiardquo Journal of SichuanUniversity (Medical Science Edition) vol 37 no 2 pp 246ndash2492006

[72] M K Zhou L He and B Wu ldquoEffect of da chuanxiong pill onthe secretion level of vascular endothelial growth factor in bloodvesselrdquo Chinese Journal of Clinical Rehabilitation vol 8 no 19pp 3842ndash3843 2004


[73] M M Zhou K Yang and Y T Wang ldquoThe influence of dachuanxiong fang on the behavior and dural inflammation ofexperimental rat migraine modelrdquo Pharmacology and Clinics ofChinese Materia Medica vol 24 no 4 pp 3ndash5 2008

[74] JW Tian F H Fu andW L Jiang ldquoThe protection and relativemechanism of phthalide to prevent the cerebaral ischemia ofratrdquo China Journal of Chinese Materia Medica vol 30 no 6 pp466ndash468 2005

[75] Z Ma and L Bai ldquoThe anti-inflammatory effect of z-ligustilidein experimental ovariectomized osteopenic ratsrdquo Inflammationvol 35 no 6 pp 1793ndash1797 2012

[76] W Xiao W H Cai and Q Xiao ldquoEffects of dachuan xiongfangon concentration of substance p in blood and ganglion oftrigeminal nerve of rats with migrainerdquo Chinese Medicine andPharmacology vol 38 no 2 pp 3ndash6 2010

[77] S L Li ldquoAnti-anxiety effect of gastrodia elata and its phenoliccompounds in micerdquoWorld Phytomedicines vol 22 no 1 p 352007

[78] G G Luo W J Fan X Y Yuan et al ldquoThe pharmacologicalmechanism of gastrodin on calcitonin gene-related peptide ofcultured rat trigeminal ganglionrdquo Yao Xue Xue Bao vol 46 no12 pp 1451ndash1456 2011

[79] Z Chen X Pan A G Georgakilas et al ldquoTetramethylpyrazine(tmp) protects cerebral neurocytes and inhibits glioma bydown regulating chemokine receptor cxcr4 expressionrdquo CancerLetters 2013

[80] S C Lee C C Tsai C H Yao Y Chen and M Wu ldquoFerulicacid enhances peripheral nerve regeneration across long gapsrdquoEvidence-Based Complementary and Alternative Medicine vol2013 Article ID 876327 8 pages 2013

[81] Z Q Chen J L Hong C Sun et al ldquoThe clinical significanceof the relative peptide level detection of plasma endothelin andcalcitonin of migrainerdquo Clinical Medicine vol 6 no 1 pp 3ndash62005

[82] Q Zhen S F Wei and Z F Wu ldquoThe influence of the palsmacgrp and et of migraine modle rat by using da chuanxiongformulardquo Pharmacology and Clinics of Chinese Materia Medicavol 27 no 4 pp 3ndash5 2011

[83] Y F Leng X M Gao S X Wang and Y Xing ldquoEffects oftetramethylpyrazine on neuronal apoptosis in the superficialdorsal horn in a rat model of neuropathic painrdquoThe AmericanJournal of Chinese Medicine vol 40 no 6 pp 1229ndash1239 2012

[84] Z Feng Y Lu X Wu et al ldquoLigustilide alleviates brain damageand improves cognitive function in rats of chronic cerebralhypoperfusionrdquo Journal of Ethnopharmacology vol 144 no 2pp 313ndash321 2012

[85] Y H Wang S Liang D S Xu et al ldquoEffect and mechanism ofsenkyunolide i as an anti-migraine compound from Ligusticumchuanxiongrdquo Journal of Pharmacy and Pharmacology vol 63no 2 pp 261ndash266 2011

[86] L HWan Z P Fang and Z RWang ldquoEffects of da chuanxiongfang extract on intracellular nitri oxide of neurogilardquo WestChina Journal of Pharmaceutcal Sciences vol 4 no 5 pp 255ndash257 2003

[87] H J Yang G Li and B L Bian ldquoNitric oxide supersensitivityinduced by hyposerotonin and the pharmacological effect ofdachuanxiong pillrdquo Chinese Journal of Experimental TraditionalMedical Formulae vol 11 no 1 pp 22ndash24 2005

[88] L H Wan Z P Fang and Z R Wang ldquoThe effect of dachuanxiong fang extract on 5-ht1d receptor expression ofneurogilardquo Medical Journal of West China vol 1 no 1 pp 1ndash22003

[89] G Yao C Peng and D Zhou ldquoResearches of the influences ofnerve cells apoptosis of migraine rats by using dachuanxiongdecoctionrdquo Chinese Traditional Patent Medicine vol 25 no 12pp 994ndash996 2004

[90] G Yao C Peng D Zhou and YWang ldquoEffect of dachuanxiongprescription on nerve cell injury of migraine ratrdquo ChineseTraditional Patent Medicine vol 25 no 12 p 3 2003

[91] L Zhang Q D Wang H M Shi and J C Pan ldquoInfluence offerulic acid on the pain-depression dyad induced by reserpinerdquoYao Xue Xue Bao vol 48 no 1 pp 32ndash37 2013

[92] Y Ozaki S Sekita and M Harada ldquoCentrally acting mus-cle relaxant effect of phthalides (Ligustilide Cnidilide andSenkyunolide) obtained from Cnidium officinale MakinordquoYakugaku Zasshi vol 109 no 6 pp 402ndash406 1989

[93] S J Liao and D Zhou ldquoEffect of szechwan lovge rhizome andtall gastrodia tuber in different proportion on [Ca2+]i of thecultured cortex neurons under normal situation and hypoxiardquoWest China Journal of Pharmaceutcal Sciences vol 3 no 2 pp165ndash169 2003

[94] M M Zhou K Yang and Y T Wang ldquoThe synergistic effectsresearh of da chuanxiong fang in treating migraine that evalu-ated by hemorheology and blood flow velocityrdquo Pharmacologyand Clinics of Chinese Materia Medica vol 3 no 4 pp 6ndash82008

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


are called as ldquoseven relations of Chinese Medicinerdquo such assingular application mutual promotion mutual assistancemutual restraint mutual detoxication mutual inhibition andmutual intoxication [8] herb pairs for mutual potentiationoccupy mostly according to Chinese records and the classicbooks about herbs in China Mutual potentiation also calledas mutual promotion showed significantly better pharmaco-logical efficacy than when the herbs were used individuallybeing applied in many famous herb pairs such as DangguiBuxue Decoction (Astragali Radix and Angelicae sinensisRadix) [9 10] and Dan Qi Fang (Salviae miltiorrhizae andPanax notoginseng) [11]

Da Chuanxiong Formula (DCXF) is not only a famousChinese medicinal prescription but also a classic herb pairfor mutual potentiation composed of two herbs namelyChuanxiong (Ligusticum chuanxiong Hort) and Tianma(Gastrodiae elata Bl) with a crude weight ratio of 4 1 usedfor headache caused by blood stasis andwind-heat syndromeThis herb pair first recorded in ldquoXuan Ming Lun Fangrdquo in JinDynasty has been widely used to promote blood circulationbalance the liver and extinguish wind eliminate pathogensand dredge the collaterals to stop pain with thousands ofyearsrsquo clinical experience In modern medicine its antimi-graine effect has been definitely confirmed [12ndash15] Nowvarious dosage forms of this herb pair on the market suchas capsules pellets oral decoctions and granules are mainlyindicated for a blood stasis type of headache Howeverthe synergism mechanisms of the formulae have not beenelucidated and research progress of this combination hasrarely been summarized

Herein the research status of Chuangxiong-Tianma herbpair (CTHP) namely DCXF is discussed in terms of itsethnopharmacological relevance material basis and phar-macological actions bymeans of modern analysis methods Itis expected to give a comprehensive interpretation ofDXCF inorder to inherit the essence of herb pair and innovative drugdelivery system of this prescription

2 Ethnopharmacological Relevance

21 Traditional Background of Herbs Chuanxiong Rhizoma(CR) Chuan xiong in Chinese is the dried rhizome of Ligus-ticum chuanxiong Hort which belongs to the Umbelliferaefamily and its optimal harvest time is in the period fromApril to May which has been indicated as the best time forthe accumulation of active constituents such as volatile oilsferulic acid and alkaloids [25ndash27] The resources of bothwide and cultivated CR are wide distributed in PengzhouXindu Chongzhou and Dujiangyan in Sichuan provinceof China [28 29] Zhu et al compared the contents oftetramethylpyrazine and ferulic acid which are two mainactive constituents of CR in different CR samples fromdifferent seasons as well as different producing areas usingHPLC finding that the contents of teramethylpyraine andferulic acid were significantly different [27] It has beenused for thousands of years in traditional Chinese Japaneseand Korean folk medicine [30] According to traditionalChinese medicinal theory CR could promote blood and

Qi circulation and dispel wind and relieve pain in TCM[31] For its reputation of facilitating blood circulation anddispersing blood stasis [32] CR is not only used formedicinalpurpose like treating atherosclerosis [33] ischemic stroke[34] vasodilation [35] and thrombus formation [36] but alsofor food preparation and health care products such asmuttonsoup [37] tobacco flavor additive and natural preservative[38]

Gastrodiae Rhizoma (GR) Tianma in Chinese is thedried rhizome of Gastrodiae Elata BI which belongs tothe Orchidaceae family and is widely used as a traditionalmedicine in China Japan and Korea Known as a kind ofcommonly used and expensive traditional Chinese medicineGR is mainly produced in Sichuan Yunnan Guizhou andShanxi province in China [39 40] In humid environmentGR could make a good breeding and it commonly harvestedin early winter or spring for it lies dormant during these spe-cific times to maintain its active substances [40 41] By usingHPLC-DAD and HPLC technique the chromatographicfingerprint of GR was developed to compare the effectivecontents of GR from different habitats and founds have goodsimilarity of fingerprints with 14 different producing areasof China except for the GR in Lueyang Shaanxi province[42] In Chinese medicine GR is one of the most importantherbs used for balancing the liver and extinguishing wind forthe efficacies of moistening viscera calming and protectinghuman body calming liver and suppressing liver-yang andcalming the wind and activating collaterals [20] In ShengNongrsquos herbal classic a famous TCM classic GR is consideredas one of the top grade drugs for it has rejuvenating effectsand nontoxic property which can be used without harm for along time For thousands of years in China GRhas been usedto treat diseases such as headache dizziness paralysis andconvulsion and enhance health by using alone or combiningwith other Chinese herbs [18]

22 Clinical Use of DXCF In TCM it is generally believedthat humanheads inclined to be attacked by pathogenicwindleading to headache In Song Dynast traditional Chinesemedicinal masters thought that expedite blood circulationcould dispel pathogenic wind in body Thus it has been oneof the most important principles to treat headache in TCMsuch as acupuncture moxibustion and herbs Due to thedramatic effect on Qi promotion in blood of CR and thesignificant effect on internal wind elimination of GR like theprevious description DCXF has the undoubted therapeuticeffect for headache caused by blood stasis and wind-heatsyndrome [22] Nowadays DCXF has been used in treatingdifferent types of headaches such as migraine angioneuroticheadache and the headache caused by endogenous of liverfire and stagnation of the liver-Qi [16 17 19 21 23 24 43 44]Interestingly DCXF could effectively control the headacheand relieve the patientrsquos suffering without obvious side effectsBased on pharmacological investigation DCXF could effec-tively enhance the cerebrovascular elasticity change cerebralblood supply and adjust the instability of cerebrovascularpromotion which had advanced functions for improvingclinical symptoms [45]










Ligustilide








Feulic acid






Phenols(Figure 3)


Pregnenlone




Table 1 Continued










Alkaloid(Figure 5)











O

O

H

H

H

O

O

H


OO

O

OH3C

CH3


O

OH

O

CH3


O

O

OH

H3C

Chuanxiongol

O

O

H3CCH3

Z-Ligustilide

O

O

CH3


O O

H

HO

OH3C

CH3

Senkyunolide P

O

O

3-n-Butylphthalide

O

O

Senkyunolide F

OH

O

O

Senkyunolide I

OH

HO

CH3

O

O


OH

HO


H

HO

H H

O

Pregnenolone

O

O

OHOH

Chrysophanol

CH3







HOFerulic acid

CH=CHCOOHH3CO

HO

HO

COOH

Protocatechuic acid

COOH

O

Sedanonic acid

HOOH

O

OSuccinic acid

OH

O

4

5

Sinapic acid


S

HO

Pr-i

OH


OHH

H


OO


HO


O

O3-n-Butylphthalide

CH3

Cl

O


CH3

CH3

CH3H3C

HO

HO

H

H OH

O

Augustic acid

CHO C C C

OH


H3C CH2

O

OH

O

HO

O

Xiongterpene

H3C

H3C

CH3

CH3CH3

CH3

CH3

O

OH

HO

O

Monopalmitin



N

N

Tetramethylpyrazine

H3C

H3C

CH3

CH3

Choline

N+H3C

CH3

CH3

CH2CH2OH




Phenols(Figure 6)


















Other(Figure 10)




OH

O

HO

L-Phenyllactic acid

OH

HO

O


OH

O


OHO


OH

OH


O

HO2-Methoxyphenol

O

O

O

O


CH3

O

HO

OH

OCH3

CH3


OH

CHO

HO

Hibicutaiwanin

O

O

HO


O

O

HO


O

HO

O

OH

HO

O

HO

O

O

O

O

O

O

O

O

O

OH

HO

OH

OH

OH

OH

Parishin

H3O

O

OH

HO O

HO

OH

O

HO

HOO

O

O

OH

OH

OH

OHO

OO

Parishin B

Figure 6 Continued


OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH



O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose







OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























Ligustilide








Feulic acid






Phenols(Figure 3)


Pregnenlone




Table 1 Continued










Alkaloid(Figure 5)











O

O

H

H

H

O

O

H


OO

O

OH3C

CH3


O

OH

O

CH3


O

O

OH

H3C

Chuanxiongol

O

O

H3CCH3

Z-Ligustilide

O

O

CH3


O O

H

HO

OH3C

CH3

Senkyunolide P

O

O

3-n-Butylphthalide

O

O

Senkyunolide F

OH

O

O

Senkyunolide I

OH

HO

CH3

O

O


OH

HO


H

HO

H H

O

Pregnenolone

O

O

OHOH

Chrysophanol

CH3







HOFerulic acid

CH=CHCOOHH3CO

HO

HO

COOH

Protocatechuic acid

COOH

O

Sedanonic acid

HOOH

O

OSuccinic acid

OH

O

4

5

Sinapic acid


S

HO

Pr-i

OH


OHH

H


OO


HO


O

O3-n-Butylphthalide

CH3

Cl

O


CH3

CH3

CH3H3C

HO

HO

H

H OH

O

Augustic acid

CHO C C C

OH


H3C CH2

O

OH

O

HO

O

Xiongterpene

H3C

H3C

CH3

CH3CH3

CH3

CH3

O

OH

HO

O

Monopalmitin



N

N

Tetramethylpyrazine

H3C

H3C

CH3

CH3

Choline

N+H3C

CH3

CH3

CH2CH2OH




Phenols(Figure 6)


















Other(Figure 10)




OH

O

HO

L-Phenyllactic acid

OH

HO

O


OH

O


OHO


OH

OH


O

HO2-Methoxyphenol

O

O

O

O


CH3

O

HO

OH

OCH3

CH3


OH

CHO

HO

Hibicutaiwanin

O

O

HO


O

O

HO


O

HO

O

OH

HO

O

HO

O

O

O

O

O

O

O

O

O

OH

HO

OH

OH

OH

OH

Parishin

H3O

O

OH

HO O

HO

OH

O

HO

HOO

O

O

OH

OH

OH

OHO

OO

Parishin B

Figure 6 Continued


OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH



O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose







OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 1 Continued










Alkaloid(Figure 5)











O

O

H

H

H

O

O

H


OO

O

OH3C

CH3


O

OH

O

CH3


O

O

OH

H3C

Chuanxiongol

O

O

H3CCH3

Z-Ligustilide

O

O

CH3


O O

H

HO

OH3C

CH3

Senkyunolide P

O

O

3-n-Butylphthalide

O

O

Senkyunolide F

OH

O

O

Senkyunolide I

OH

HO

CH3

O

O


OH

HO


H

HO

H H

O

Pregnenolone

O

O

OHOH

Chrysophanol

CH3







HOFerulic acid

CH=CHCOOHH3CO

HO

HO

COOH

Protocatechuic acid

COOH

O

Sedanonic acid

HOOH

O

OSuccinic acid

OH

O

4

5

Sinapic acid


S

HO

Pr-i

OH


OHH

H


OO


HO


O

O3-n-Butylphthalide

CH3

Cl

O


CH3

CH3

CH3H3C

HO

HO

H

H OH

O

Augustic acid

CHO C C C

OH


H3C CH2

O

OH

O

HO

O

Xiongterpene

H3C

H3C

CH3

CH3CH3

CH3

CH3

O

OH

HO

O

Monopalmitin



N

N

Tetramethylpyrazine

H3C

H3C

CH3

CH3

Choline

N+H3C

CH3

CH3

CH2CH2OH




Phenols(Figure 6)


















Other(Figure 10)




OH

O

HO

L-Phenyllactic acid

OH

HO

O


OH

O


OHO


OH

OH


O

HO2-Methoxyphenol

O

O

O

O


CH3

O

HO

OH

OCH3

CH3


OH

CHO

HO

Hibicutaiwanin

O

O

HO


O

O

HO


O

HO

O

OH

HO

O

HO

O

O

O

O

O

O

O

O

O

OH

HO

OH

OH

OH

OH

Parishin

H3O

O

OH

HO O

HO

OH

O

HO

HOO

O

O

OH

OH

OH

OHO

OO

Parishin B

Figure 6 Continued


OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH



O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose







OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

O

H

H

H

O

O

H


OO

O

OH3C

CH3


O

OH

O

CH3


O

O

OH

H3C

Chuanxiongol

O

O

H3CCH3

Z-Ligustilide

O

O

CH3


O O

H

HO

OH3C

CH3

Senkyunolide P

O

O

3-n-Butylphthalide

O

O

Senkyunolide F

OH

O

O

Senkyunolide I

OH

HO

CH3

O

O


OH

HO


H

HO

H H

O

Pregnenolone

O

O

OHOH

Chrysophanol

CH3







HOFerulic acid

CH=CHCOOHH3CO

HO

HO

COOH

Protocatechuic acid

COOH

O

Sedanonic acid

HOOH

O

OSuccinic acid

OH

O

4

5

Sinapic acid


S

HO

Pr-i

OH


OHH

H


OO


HO


O

O3-n-Butylphthalide

CH3

Cl

O


CH3

CH3

CH3H3C

HO

HO

H

H OH

O

Augustic acid

CHO C C C

OH


H3C CH2

O

OH

O

HO

O

Xiongterpene

H3C

H3C

CH3

CH3CH3

CH3

CH3

O

OH

HO

O

Monopalmitin



N

N

Tetramethylpyrazine

H3C

H3C

CH3

CH3

Choline

N+H3C

CH3

CH3

CH2CH2OH




Phenols(Figure 6)


















Other(Figure 10)




OH

O

HO

L-Phenyllactic acid

OH

HO

O


OH

O


OHO


OH

OH


O

HO2-Methoxyphenol

O

O

O

O


CH3

O

HO

OH

OCH3

CH3


OH

CHO

HO

Hibicutaiwanin

O

O

HO


O

O

HO


O

HO

O

OH

HO

O

HO

O

O

O

O

O

O

O

O

O

OH

HO

OH

OH

OH

OH

Parishin

H3O

O

OH

HO O

HO

OH

O

HO

HOO

O

O

OH

OH

OH

OHO

OO

Parishin B

Figure 6 Continued


OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH



O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose







OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















HOFerulic acid

CH=CHCOOHH3CO

HO

HO

COOH

Protocatechuic acid

COOH

O

Sedanonic acid

HOOH

O

OSuccinic acid

OH

O

4

5

Sinapic acid


S

HO

Pr-i

OH


OHH

H


OO


HO


O

O3-n-Butylphthalide

CH3

Cl

O


CH3

CH3

CH3H3C

HO

HO

H

H OH

O

Augustic acid

CHO C C C

OH


H3C CH2

O

OH

O

HO

O

Xiongterpene

H3C

H3C

CH3

CH3CH3

CH3

CH3

O

OH

HO

O

Monopalmitin



N

N

Tetramethylpyrazine

H3C

H3C

CH3

CH3

Choline

N+H3C

CH3

CH3

CH2CH2OH




Phenols(Figure 6)


















Other(Figure 10)




OH

O

HO

L-Phenyllactic acid

OH

HO

O


OH

O


OHO


OH

OH


O

HO2-Methoxyphenol

O

O

O

O


CH3

O

HO

OH

OCH3

CH3


OH

CHO

HO

Hibicutaiwanin

O

O

HO


O

O

HO


O

HO

O

OH

HO

O

HO

O

O

O

O

O

O

O

O

O

OH

HO

OH

OH

OH

OH

Parishin

H3O

O

OH

HO O

HO

OH

O

HO

HOO

O

O

OH

OH

OH

OHO

OO

Parishin B

Figure 6 Continued


OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH



O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose







OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N

N

Tetramethylpyrazine

H3C

H3C

CH3

CH3

Choline

N+H3C

CH3

CH3

CH2CH2OH




Phenols(Figure 6)


















Other(Figure 10)




OH

O

HO

L-Phenyllactic acid

OH

HO

O


OH

O


OHO


OH

OH


O

HO2-Methoxyphenol

O

O

O

O


CH3

O

HO

OH

OCH3

CH3


OH

CHO

HO

Hibicutaiwanin

O

O

HO


O

O

HO


O

HO

O

OH

HO

O

HO

O

O

O

O

O

O

O

O

O

OH

HO

OH

OH

OH

OH

Parishin

H3O

O

OH

HO O

HO

OH

O

HO

HOO

O

O

OH

OH

OH

OHO

OO

Parishin B

Figure 6 Continued


OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH



O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose







OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















OH

O

HO

L-Phenyllactic acid

OH

HO

O


OH

O


OHO


OH

OH


O

HO2-Methoxyphenol

O

O

O

O


CH3

O

HO

OH

OCH3

CH3


OH

CHO

HO

Hibicutaiwanin

O

O

HO


O

O

HO


O

HO

O

OH

HO

O

HO

O

O

O

O

O

O

O

O

O

OH

HO

OH

OH

OH

OH

Parishin

H3O

O

OH

HO O

HO

OH

O

HO

HOO

O

O

OH

OH

OH

OHO

OO

Parishin B

Figure 6 Continued


OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH



O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose







OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















OHO HO

HO O

HO

HO

OOH

OH

O

O

O

HOOH

HOO

O

O

Parishin C

H

HO

H

HH

120573-Sitosterol

O

OH

HOHO

HOO

OHGastrodin

OH OH



O N

N

N

N

OHOH

HO

Adenosine

NH2

H

HHO

OHH

OHH

O

D-ArabinoseCH2OH

H

OHH

HHO

HHO

O

L-ArabinoseCH2OH

O OH

HO OH

OHXylose

O

OH

OH

OHO

O

OH

Sucrose

HO

CH2OHCH2OH

CH2OH

O OH

OH

OH

HO

HO

Mannose







OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















OHO

O

OHAspartic acid

NH2

OH

O

AlanineNH2

H3C HO OH

O O

Glutamic acid

NH2 NH

OH

O

ProlineOH

O

Valine

NH2

H3CCH3

OH

OLeucine

NH2

H3C

CH3OH

O

Lysine

NH+3

H3N+

minus


O

HO

H

OVanillic aldehyde

OH HO

Citronellol


CH3 CH3






O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

AcO

AcOOAc

OAc

CH3


O

O

O

H

H HH

Diosgenin

CH3

CH3CH3

H3C












Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















Aspartic acid







Trimethylamine

Sadanic acid


Detection methods

O

O

HO

HO

Ferulic acid

O

O

Ligustilide

N

N

Tetramethylpyraine


N

N

Ligustrazine

OO

Senkyunolide A

O

Glu

Gastrodin

120573-Sitosterol

HOH2C

H3C

H3C

CH3

CH3

120574-Terpinene























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























Acknowledgments


References







































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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