review article neuropharmacological potential of gastrodia elata...

Review ArticleNeuropharmacological Potential of Gastrodia elataBlume and Its Components

Jung-Hee Jang12 Yeonghoon Son1 Seong Soo Kang1 Chun-Sik Bae1

Jong-Choon Kim1 Sung-Ho Kim1 Taekyun Shin3 and Changjong Moon1

1College of Veterinary Medicine and Animal Medical Institute Chonnam National University Gwangju 500-757 Republic of Korea2Cheongju Hamsoa Oriental Clinic Cheongju 361-814 Republic of Korea3College of Veterinary Medicine Jeju National University Jeju 690-756 Republic of Korea

Correspondence should be addressed to Taekyun Shin shintjejunuackr and Changjong Moon mooncchonnamackr

Received 21 April 2015 Revised 6 September 2015 Accepted 15 September 2015

Academic Editor Thierry Hennebelle

Copyright copy 2015 Jung-Hee Jang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Research has been conducted in various fields in an attempt to develop new therapeutic agents for incurable neurodegenerativediseases Gastrodia elata Blume (GE) a traditional herbal medicine has been used in neurological disorders as an anticonvulsantanalgesic and sedative medication Several neurodegenerative models are characterized by oxidative stress and inflammationin the brain which lead to cell death via multiple extracellular and intracellular signaling pathways The blockade of certainsignaling cascadesmay represent a compensatory therapy for injured brain tissue Antioxidative and anti-inflammatory compoundsisolated from natural resources have been investigated as have various synthetic chemicals Specifically GE rhizome extract andits components have been shown to protect neuronal cells and recover brain function in various preclinical brain injury modelsby inhibiting oxidative stress and inflammatory responses The present review discusses the neuroprotective potential of GE andits components and the related mechanisms we also provide possible preventive and therapeutic strategies for neurodegenerativedisorders using herbal resources

1 Introduction

Incurable neurodegenerative disorders result in aplasticimpairment of brain function Many previous studies haveidentified the underlying etiology and pathogenesis ofneurodegenerative disorders however current therapeuticstrategies provide limited symptom relief or suppression ofdisease progression for incurable neurodegenerative disor-ders including Alzheimerrsquos disease (AD) Parkinsonrsquos disease(PD) stroke and seizure For example AD is clinicallytreated using cholinesterase inhibitors glutamatemodulators[1] and antiamyloid 120573 (A120573) peptide agents to mitigate thesymptoms and neurodegeneration [2] Clinical therapies forthe treatment of PD include L-34-dihydroxyphenylalanine(L-DOPA) for dopaminergic neuron degeneration andnondopaminergic drugs to alleviate nonmotor symptoms[3] Thrombolytic agents have restricted use against acuteischemic stroke [4] The development of new therapeutic

agents that effectively treat and promote recovery in neu-rodegenerative diseases is urgently needed Here traditionalherbal medicine is suggested to be a potential therapeuticapproach as an alternative medicine for incurable neurode-generative diseases

A combination of several herbs is typically used clinicallyin traditional herbal medicine the interactions among herbsfollowing decoction of several medical herbs have synergisticeffects that increase their efficacy and reduce possible adversereactions by decreasing toxicity [5] Because the pathogenesisof certain diseases involves multiple targets associated withdifferent pathways a complex prescription such as decoctionthat includes multiple herbs is an extremely beneficial thera-peutic approach [6] Thus the discovery of new properties oftraditional herbal medicines such as herb-herb interactionsand multiple targets may provide a solution to the treatmentof incurable neurodegenerative disorders However thereare various limitations to the investigation of such complex

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2015 Article ID 309261 14 pageshttpdxdoiorg1011552015309261

2 Evidence-Based Complementary and Alternative Medicine

prescriptions For example it is difficult to accurately evaluatethe inherent efficacy of each herb in such complexes andto identify the target component involved in the diseasemechanism and thus the treatment effectTherefore we mustfirst study each individual component of traditional herbalmedicines to determine the pharmacological mechanismsinvolved

Gastrodia elata Blume (GE) which belongs to the Orchi-daceae family is a saprophyte that grows in the woods ofEast Asia The dried rhizome (tuber) of this plant (tianma)is used as a traditional herbal medicine to treat neurologicaldisorders such as vertigo general paralysis epilepsy andtetanusTheGE rhizomehas been used clinically as a complexprescription rather than as a single herb For example BanxiaBaishu Tianma Tang which is a decoction composed ofGE rhizome and other herbs such as Pinellia ternata andAtractylodes is prescribed to treat hypertension in East Asia[7 8] The effects of a complex prescription mixed togetherwith GE rhizome and other herbs have been demonstratedin patients with Tourettersquos syndrome [9] Ningdong granule(ie GE rhizomeCodonopsis pilosulaOphiopogon japonicuswhite peony root Rhinocerotidae oyster earthworm andlicorice root) attenuated symptoms of Tourettersquos syndromein children and returned abnormal levels of interleukin-(IL-) 12 and tumor necrosis factor- (TNF-) alpha in theserum to normal In addition many previous studies haveattempted to elucidate the pharmacological effects ofmultipleherb decoctions that include GE rhizome to provide newtherapeutic opportunities for neurodegenerative diseases [610 11] Additionally previous studies have investigated thepharmacokinetics of GE components While higher relativebioavailability of gastrodin and parishin was obtained inrats after oral administration of GE rhizome powder at lowdoses higher bioavailability was shown after administrationof high doses of the GE rhizome aqueous extract [12]Moreover a detection technique was developed to determinethe pharmacokinetics of gastrodin in rat blood brain andbile and this technique might be a useful method for thedetermination of the metabolism of gastrodin [13] Howeverfurther studies are necessary to elucidate the pharmacologicaland pharmacokinetic properties of GE and its components inthe context of brain tissue injury

Most of the previous studies have attempted to identifythe biologically active components of the GE rhizomeand a variety of compounds have been isolated from theaqueous or methanol extracts of GE rhizome Methanolextracts of GE rhizome reportedly exert neuroprotectiveand antioxidant effects [14] One study isolated andidentified 14 GE compounds using silica gel columnchromatography and fractionated 8 phenolic components[15] 4-hydroxybenzaldehyde (4-HBAL) 4-hydroxybenzylalcohol (4-HBA) benzyl alcohol bis-(4-hydroxyphenyl)methane 4-(41015840-hydroxybenzyloxy)benzyl methylether4-hydroxy-3-methoxybenzyl alcohol (vanillyl alcohol) 4-hydroxy-3-methoxybenzaldehyde (vanillin) and 4-hydroxy-3-methoxybenzoic acid (vanillic acid) (Figure 1) Amongthem several GE compounds including 4-HBAL 4-HBAbenzyl alcohol vanillyl alcohol vanillin and vanillic acid arelisted on the Everything Added to Food in the United States

(EAFUS) database as Food andDrugAdministration- (FDA-)approved food additives (httpwwwaccessdatafdagovscriptsfcnfcnnavigationcfmrpt=eafuslistingampdisplayAll=true) Several new compounds were recently isolated byvarious chromatography techniques in total 64 compoundswere identified from GE rhizome including parishinJ and parishin K [16] A previous study reported themetabolic profile of parishin in rat plasma and urine afteradministration of parishin to investigate the pharmacologicaleffects [17] However among these components of GEgastrodin 4-HBAL 4-HBA vanillin and vanillyl alcoholare the major active components in terms of their neu-ropharmacological properties [18] Gastrodin the mainbioactive component of GE has since been obtainedvia ethanol and aqueous extraction and is the phenolicglucoside of 4-HBA [19] (Figure 1) Another main bioactivecomponent vanillin which can be isolated from methanolextracts is an aromatic aldehyde that contains a hydroxylgroup para to aldehyde (Figure 1) Vanillin may be effectiveas a new antiepileptic drug as vanillin reportedly haseffects on human epilepsy patients 184 patients treated withvanillin monotherapy for 3 months showed improvementin a previous study [20] In addition vanillin is a potentanti-inflammatory agent that inhibits the generation ofreactive oxygen species (ROS) [21] Benzyl alcohol 4-HBALand 4-HBA have anti-inflammatory effects via the inhibitionof the activities of cyclooxygenase- (COX-) 1 and COX-2 andvanillyl alcohol significantly increases the radical-scavengingactivity of DPPH [21] In vivo and in vitro experiments havedemonstrated that GE and its components have variouspharmacological actions that result in antioxidant anti-inflammatory and anticonvulsant effects [14 20] Herewe report on the potential therapeutic potential of GE forthe treatment of neurodegenerative disorders includingepilepsy ischemia AD and PD

In this review we provide an overview of the efficacy ofGE and its components in a variety of neurodegenerativemodels We also discuss the possible mechanisms involvedin ameliorating a broad range of brain disorders that lead toneuronal death

2 Protective Effects of GE and Its Componentsin Neurodegenerative Disease Models

Several studies have revealed the effects of GE and itscomponents on various in vivo and in vitro models ofneurodegenerative disorders such as epilepsy ischemia ADand PD (Table 1)

21 Induced Seizure Model Previous studies have demon-strated the anticonvulsant properties of GE in rodent mod-els of seizure Kainic acid (KA) is an excitatory agonistthat induces limbic seizures and excitotoxicity in the hip-pocampus [22] The anticonvulsant effect of GE rhizomeextract has been documented in rodent KA models oftemporal epilepsy [23ndash26] The ether fraction of GE rhizomemethanol extracts has anticonvulsant effects on this modeland histopathological findings have shown that treatment

Evidence-Based Complementary and Alternative Medicine 3

HO

O

OH

HO

OO

O

HO

O

O

OHO

HO

O

O

OH

OH

OH

OH

O

HO

HO

HO

OH

OH

HO

4-Hydroxybenzaldehyde (4-HBAL)4-Hydroxybenzyl alcohol (4-HBA)

Benzyl alcohol Bis-(4-Hydroxyphenyl) methane

4-(4-Hydroxy-3-methoxybenzyl)alcohol (vanillyl alcohol)

4-Hydroxy-3-methoxybenzaldehyde(vanillin) 4-Hydroxy-3-methoxybenzoic acid

(vanillic acid)

Gastrodin

H3C

H3C

H3C

H3C

4-(4998400-Hydroxybenzyloxy)benzyl methylether

Figure 1 Chemical structure of representative Gastrodia elata Blume compounds

with ether fraction of GE rhizome extract attenuates KA-induced neuronal cell death in the hippocampal cornusammonis (CA) 1 and 3 regions [25] In addition oral admin-istration of GE rhizome ethanol extract significantly delayedthe onset time of neurobehavioral change and reduced thenumber of seizure-like behaviors such aswet dog shakes pawtremor and facial myoclonia consistent with the reducedlevel of lipid peroxides in the rat brain [24] Moreover aprevious study also demonstrated that GE rhizome aqueousextract reduced the epileptic attack durations by measuringbehavioral observations including wet dog shakes pawtremor and facial myoclonia [26] Cocaine also reportedly

induces seizures by inhibiting gamma aminobutyric acid(GABA)A currents and enhancing dopamine and gluta-mate transmission [27 28] Treatment with GE rhizomemethanol extract following cocaine administration delaysthe onset of neurobehavioral changes and shortens seizureduration [29] Animals fed 4-HBAL from the ether frac-tion of GE rhizome methanol extracts exhibit less con-vulsant activities than rats who receive pentylenetetrazole(PTZ) treatment alone [30] Based on previous studiesKA- cocaine- and PTZ-induced seizures may be suitablemodels for identifying the antiepileptic effects of GE and itscomponents


Table1Pathologicalmod

elsu

sedto

identifythee

ffectso

fGastro

diaela

ta(G

E)andits

compo

nentso

nneurod

egeneratived

isorders

Mod

elIndu

cer

Extracts

compo

nents

Doserouteregimen

Animalor

cell

Major

finding

Reference

Seizure

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Seizureo

nsettim

euarrSeizured

urationdarr

[29]

KAEF

MEof

GE

200or

500m

gkgpo14

days

before

and4days

after

KAinjection

ICRmice

Onsettim

eofn

eurobehavioral

changeuarr

Severityof

convulsio

nsdarr

Hippo

campaln

euronald

amagedarr

[25]

KAGErhizom

emdashethano

lextract

05or

10gkgpo30

min

before

KAinjection

SDrats

Seizureo

nsettim

euarrSeizure-lik

ebehaviordarr

[24]

KAGErhizom

emdashaqueou

sextract

05or

10gkgpo1w

eekbefore

or2

weeks

after

KAinjection

SDrats

Threetypes

ofseizure(wetdo

gshakespaw

tremorand

facial

myoclo

nia)darr

[26]

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Seizurer

ecoverytim

edarrSeizures

everitydarr

[30]

Ischem

ia

Hypoxia

Gastro

din

25ndash100120583gmL

Ratcortic

alneuron

sNeuronalsurvivaluarr

[42]

MCA

OGastro

din

50mgkgip10min

before

MCA

OSD

rats

Infarctvolum

edarrCerebralinjurydarr

Aminoacidsuarr

[41]

MCA

OGastro

din

50or

100m

gkgipattheo

nsetof

MCA

OSD

rats

Infarctvolum

edarrEd

emav

olum

edarr[40]

Transie

ntglob

alisc

hemia

EFMEof

GErhizom

e200or

500m

gkgpo14

days

before

brainisc

hemia

Mon

goliangerbils

Neuronald

amagein

hipp

ocam

palC

A1darr

[39]

Transie

ntglob

alisc

hemia

Vanillin

4-HBA

Land4-HBA

40mgkgip30

min

before

andaft

erisc

hemia

Mon

goliangerbils

Neuronalsurvivalin

hipp

ocam

palC

A1uarr

[38]

Alzh

eimerrsquosdisease

A120573(1ndash

42)

GErhizom

emdashchloroform

extract

20120583gmLfor2

4hPC

12andprim

aryneuron

alcells

Neuronalcellprotectionuarr

[45]

A120573(1ndash

42)

GErhizom

emdashmethano

lextractgastrodin

and4-HBA

10120583gmLfor4

8hBV

2mou

semicroglialcell

Cellviabilityuarr

[48]

A120573(25ndash35)

GErhizom

epow

der

500or

1000

mgkgpofor5

2days

Wistar

rats

Amyloiddepo

sitsdarr

Spatialm

emoryuarr

Cholinea

cetyltransfe

raseuarr

[47]

Parkinsonrsquos

disease

MPP+

Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Cellviabilityuarr

Oxidativ

estre

ssdarr

[54]

MPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

Cellviabilityuarr

Cytotoxicitydarr

[53]

MPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

Cellviabilityuarr

Cytotoxicitydarr

[55]

MPT

PMPP+

Gastro

din

1030and60

mgkgpofor15days

15and25120583M4

hpriortoMPP+

expo

sure

C57B

L6m

ice

SH-SY5

Ycells

Bradykinesiadarr

Motor

impairm

entdarr

Cellviabilityuarr

[52]

4-HBA

4-hydroxybenzylalcoho

l4-HBA

L4-hydroxybenzaldehyde6-OHDA6-hydroxydo

pamineEF

ME

etherfractionof

methano

lextractG

EGastro

diaela

taICR

Instituteo

fCancerR

esearch

KAkainic

acidL-D

OPA

L-34-dihydroxyph

enylalanineMCA

Om

iddlec

erebralarteryo

cclusio

nMPP+1-m

ethyl-4

-phenylpyridiniumM

PTP1-m

ethyl-4

-phenyl-1236-te

trahydropyrid

inePC

pheochrom

ocytom

aPT

ZpentylenetetrazoleSDSprague

Daw

ley


Days 0 1 2 3

Seizure scoring

minus1

TMT (26 mgkg ip)

Vanillin (100 mgkg ip daily)

(a)

Days after treatment

Seiz

ure s

core

0

1

2

3

4

5

Seizure score(i) Aggression

(ii) Weak tremor

(iii) Systemic tremor

(iv) Tremor and spasmodic gait

(v) Death

lowast

lowast

lowast

1 2 3

TMT + vanillin (n = 18)TMT (n = 18)

(b)

Figure 2 (a) Experimental scheme used to evaluate the effect ofvanillin in a trimethyltin- (TMT-) induced seizure model Micereceived a single injection of TMT (26mgkg intraperitoneal (ip))and vanillin (100mgkg ip) once daily for 3 days at minus1 day 0 daysand 1 day relative to TMT injection Behavioral changes used tomeasure seizure activity were observed and scored 1 2 and 3 daysafter TMT injection (b)The anticonvulsant effect of vanillin againstTMT-induced clinical seizure symptoms in C57BL6 mice Data arepresented asmeans plusmn standard errors of themean (SEM) lowast119875 lt 005lowastlowast

119875 lt 001 versus TMT-treated group

The organotin compound trimethyltin (TMT) is a potentneurotoxicant whose effects are characterized by selectiveneuronal death in the limbic system including the hippocam-pus [31] In addition we have performed experiments toidentify the antiepileptic effects of vanillin a GE componentin a TMT-induced seizure model The vanillin used inthis study was purchased from Sigma-Aldrich (Cat numberV1104) and was dissolved in 2 ethanol within phosphate-buffered saline (pH 74) As shown in Figure 2(a) mice

received a single injection of TMT (26mgkg intraperitoneal(ip)) and a daily injection of vanillin (100mgkg ip) for 3consecutive days Seizure behaviors were examined 1ndash3 daysafter treatment consistent with previous studies [32ndash35] Forstatistical analysis the data are reported as mean plusmn SEM andwere analyzed by one-way analysis of variance (ANOVA)followed by the Student-Newman-Keuls post hoc test formultiple comparisons In all analyses 119875 lt 005 was takento indicate statistical significance Vanillin treatment signif-icantly reduced seizure behaviors induced by TMT treatment(Figure 2(b)) In addition during histological examinationwe determined the amount of nuclear pyknosis in thegranular cell layer (GCL) of the hippocampal dentate gyrusand observed a marked decrease in neuronal cell death asin a previous study [33] Semiquantitative analysis of nuclearpyknosis revealed that vanillin treatment significantly attenu-ated neuronal damage induced by TMT treatment (Figure 3)Thus GE and its components may be potential therapeuticcandidates for the treatment of epileptic seizures Furtherstudy is necessary to identify the mechanisms of the anticon-vulsant action by GE and a variety of its components and todetect components that are effective against human epilepsy

22 Ischemia Model Cerebral ischemia-induced neurolog-ical dysfunction is caused by secondary injury processesincluding excitotoxicity ionic imbalance and ROS gener-ation [36] which lead to neuronal cell death by induc-ing tissue infarction [37] Thus brain ischemia may sharecommonmechanismswith neurodegenerative disordersTheneuroprotective properties of the GE or its componentshave been demonstrated in ischemic animal models Studieshave shown that vanillin 4-HBAL and 4-HBA significantlyreduce neuronal cell death in the hippocampal CA1 regionof Mongolian gerbils with transient global ischemia [38]Further the ether fraction ofGE rhizome remarkably protectsagainst hippocampal neuron damage in this model [39]The phenolic glucoside gastrodin significantly decreasedinfarction volume and edema volume in the brain improvedneurological scores and ameliorated cerebral injury in arat ischemic model with middle cerebral artery occlusion(MCAO) [40] In a previous study involving the sameischemic model gastrodin treatment before MCAO oper-ation decreased the volume of cerebral infarction and therelease of cerebral amino acids [41] In addition a previousin vitro study demonstrated that gastrodin pretreatmentsignificantly increases neuronal survival in hypoxia-exposedrat cortical neurons [42] These findings support the conceptthat GE or its components have protective effects againstneuronal damage due to ischemia in in vivo and in vitroexperiments suggesting that GE and its components may actas potential preventive or therapeutic agents in human stroke

23 AD and PD Models AD is an important neurode-generative disorder characterized by progressive cognitiveimpairment A major pathological hallmark of AD is theaccumulation of senile plaques composed of A120573 protein[43 44] Many previous studies have reported on the poten-tial therapeutic properties of traditional herbs against AD


Hilus

GCL

TMT

GCL

Hilus

0

20

40

60

80

100

120

140

160

Num

ber o

f con

dens

ed n

ucle

iTMT

TMT + vanillin

TMT + vanillin

P lt 001 (n = 10)

Figure 3 Inhibitory effect of vanillin on neuronal cell death in the granular cell layer after TMT injection Mice received a single injection ofTMT (26mgkg intraperitoneal (ip)) and vanillin (100mgkg ip) once daily for 3 days atminus1 day 0 days and 1 day relative to TMT injectionMice were sacrificed 3 days after TMT injection Photomicrographs (left panels 410158406-diamidino-2-phenylindole (DAPI) staining) show thatthe increased amount of nuclear pyknosis induced by TMT treatment was significantly reduced by vanillin treatment Semiquantitativeanalysis of neuronal cell death performed by counting nuclear pyknosis showed that vanillin suppressed neuronal cell death (119899 = 10micegroup) Data are presented as means plusmn SEMs Scale bars indicate 40120583m

Among the compounds tested GE is reportedly a promisingcandidate for use in protecting neuronal cells against ADpathogenesis [45 46] In rats injected with A120573

25ndash35 to modelAD chronic administration of powdered GE rhizome dis-solved in water markedly reduced amyloid plaque depositionin the hippocampus and significantly improved impaired spa-tialmemory in theMorriswatermaze test these changeswereconsistent with the increased expression of choline acetyl-transferase in the medial septum and hippocampus [47] Aprevious study demonstrated the neuroprotective effect of GErhizome chloroform extract in vitro using rat pheochromo-cytoma (PC12) cells incubated with A120573

1ndash42 [45] In additionmethanol extract of GE rhizome and its pure componentsgastrodin and 4-HBA have been shown to have protectiveeffects against A120573-induced cell death in BV2 microglial cellspossibly through upregulation of glucose-regulated protein78 (Grp78) an antiapoptotic endoplasmic reticulum (ER)stress protein related to protein-folding machinery [48]

Similar to AD PD is one of the most common neu-rodegenerative disorders It is characterized by a loss ofdopaminergic neurons in the substantia nigra pars compactawhich leads to symptoms of rigidity resting tremor andbradykinesia [49]Theneurotoxin 1-methyl-4-phenyl-1236-tetrahydropyridine (MPTP) which can be metabolized into1-methyl-4-phenylpyridinium (MPP+) induces neuronal celldeath and is widely used in animal models of PD [50 51]In a previous study that used the MPTP-induced PD mousemodel gastrodin had a neuroprotective effect as demon-strated by reduced bradykinesia and motor impairment inthe pole and rotarod tests respectively [52] In additiongastrodin treatment significantly decreased the neuronal cellviability induced by MPP+ [52] The protective effects of

ethanol extract of GE rhizome or gastrodin against MPP+-induced neurotoxicity have also been demonstrated in SH-SY5Y cells by inhibiting oxidative and apoptotic signaling[53] and in dopaminergic cells by inducing heme oxygenase-1 (HO-1) expression [54] In MN9D dopaminergic cellsvanillyl alcohol inhibits the cytotoxicity induced by MPP+[55] L-DOPA is a dopaminergic drug used to treat PD butlong-term L-DOPA treatment results in L-DOPA-induceddyskinesia (LID) [56] Therefore GE or its components haveneuroprotective effects on in vivo and in vitro AD and PDmodels andmay be potential preventive or therapeutic agentsfor human AD and PD

3 Pharmacological Mechanisms ofGE and Its Components

Several studies have attempted to clarify the pharmacologicalmechanisms of GE and its components in neurologicaldisorders (Table 2)

31 Effects of GE and Its Components on NeurotransmissionGABA is themajor inhibitory neurotransmitter in the centralnervous system (CNS) and malfunction of its transmis-sion may result in pathological conditions such as seizureischemia and learning impairment Previous studies haveshown that GE and its components may confer neuropro-tection by inhibiting the degradation of GABA and thusenhance GABA levels [30 57 67] In rats the decreased brainGABA content induced by PTZ treatment can be reversedby treatment with the ether fraction of the methanol extractof GE rhizome suggesting that GE may have anticonvulsant


Table2Ph

armacologicaleffectsof

GEandits

compo

nentso

nneurod

egeneration

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells

Histologicalandbiochemicalevaluatio

nRe

ferences

Neurotransm

ission

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Recovery

ofbrainGABA

contents

[30]

Neurotransm

ission

Stroking

ofthe

back

Gastro

din

60mgkgpofor1

week

Mon

goliangerbils

Decreased

GABA

-Tim

mun

oreactivity

Decreased

SSADHSSA

Rim

mun

oreactivity

[57]

Neurotransm

ission

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Attenu

ationof

cocaine-indu

cedseizurev

iaGABA

Abut

notG

ABA

Breceptor

activ

ation

[29]

Neurotransm

ission

Pentob

arbital

GErhizom

emdashethano

lextract

2550and100m

gkgpo1h

before

pentob

arbitalinjectio

nICRmiceprim

arycultu

reof

cerebellarg

ranu

lecells

Prolon

gedtotalsleep

time

Redu

cedsle

eplatency

IncreasedGADandGABA

Areceptor

subtype

expressio

n[58]

Neurotransm

ission

andantio

xidatio

nTransie

ntglob

alisc

hemia

Vanillin

4-HBA

Land

4-HBA

40mgkgsc30m

inbefore

and

30min369and

24haft

erisc

hemia

0016008042and

10120583Mfor

2h

Mon

goliangerbilsP

C12

cells

Dow

nregulated

8-OHdG

immun

oreactivity

IncreasedGABA

-Tin

thee

arlysta

geaft

erisc

hemia

Antioxidant

activ

ityon

lipid

peroxidatio

n[38]

Antioxidatio

nGlutamate

Gastro

din

011and10120583M

PC12

cells

InhibitedRO

Sprod

uctio

nInhibitedMDAM

MPandSO

Dlevels

Blockedglutam

ate-indu

ced[Ca2+]Iinflu

xBlockedCa

MKI

IASK

-1and

phosph

orylation

ofMAPK

[59]

Antioxidatio

nMPP

+Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Decreased

ROSprod

uctio

nIndu

cedHO-1expressio

nthroug

hp38

MAPK

Nrf2

signalin

gpathway

[54]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[53]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[55]

Antioxidatio

nA120573(25ndash35)

GErhizom

emdashaqueou

sextract

20120583Mfor

48h

PC12

cells

Decreased

ROSprod

uctio

nUpregulated

enzymaticactiv

ities

ofcatalase

SODand

glutathion

eperoxidase

[60]

Antioxidatio

nMCA

OGErhizom

emdashaqueou

sextract

4-HBA

500m

gkgip

25mgkgip3days

priortoMCA

OSD

rats

Increasedlevelsof

genesrela

tedto

antio

xidant

syste

m(protein

disulfide

isomerasea

nd1-C

ysperoxiredo

xin)

[61]

Anti-infl

ammation

CUS

Gastro

din

50100and

200m

gkgipfor14days

51020and50120583gmL

SDrats

Prim

aryhipp

ocam

palcells

Upregulated

neuralste

mcellproliferatio

nRe

ducedNF-120581BandIL-1120573

[62]

Anti-infl

ammation

LPS

Gastro

din

3040and60120583M1hpriortoLP

Sexpo

sure

BV-2

cells

Decreased

levelsof

proinfl

ammatoryenzymes

(iNOSCO

X-2)

andproinfl

ammatory

cytokines(TN

F-120572IL-1120573)

Redu

cedph

osph

orylationof

ERK1

2JNK

p38

MAPK

and

CREB

[63]

Anti-infl

ammation

Roteno

neGastro

din

02g

kgpo

Wistar

rats

Supp

ressed

microglialactivation

Redu

cedIL-1120573expressio

n[64]

Anti-infl

ammation

KAGErhizom

emdashethano

lextract

051gkgpo30m

inpriortoKA

injection

SDrats

Decreased

microglialactivation(ED1)

Redu

cednN

OSactiv

ation

[65]


Table2Con

tinued

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

02505and

1120583gmLfor2

4hRA

W2647cells

InhibitedNOprod

uctio

nRe

ducediN

OSandCO

X-2expressio

n[66]

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

4-HBA

110and

100120583

gmL

50100and

200n

MBV

-2cells

InhibitedJN

KandNF-120581Bsig

nalin

gpathways

InhibitedNOandiN

OS

[18]

4-HBA


l4-HBA

L4-hydroxybenzaldehyde8-OHdG

8-hydroxy-21015840-deoxyguanosineASK

-1apo

ptosissig

nal-regulatingk

inase-1Ca

MKI

ICa2+calmod

ulin-dependent

kinaseIIC

OX-

2cyclo

oxygenase-2CU

Schronicun

predictablestr

essEF

ME

etherfractionof

methano

lextractE

RKextracellu

lars

ignal-regulated

kinaseG

ABA

-Tgam

maam

inob

utyricacid

transaminaseGADglutamate

decarboxylase

GE

Gastro

diaela

taG

REE

Gastro

diaela

tarhizom

eethano

lextractiNOS

indu

ciblenitric

oxidesynthaseJNK

c-junN-te

rminal

kinasesKA

kainicacidL

PSlipop

olysaccharide

MAPK

mito

gen-activ

ated

proteinkinaseM

CAOm

iddlecerebralartery

occlu

sion

MDAm

alon

dialdehydeM

MP

mito

chon

drialm

embranepo

tentialnN

OS

neuron

alnitricoxidesynthaseN

On

itricoxidePT

ZpentylenetetrazoleR

OSreactiv

eoxygenspeciesSO

Dsup

eroxided

ismutaseSSADHsuccinics

emialdehyded

ehydrogenaseSSA

Rsuccinicsemialdehyder

eductase


activity [30] In Mongolian gerbils seizure severity can beattenuated by gastrodin treatment via inhibition of GABA-degrading enzymes including GABA transaminase (GABA-T) succinic semialdehyde dehydrogenase (SSADH) andsuccinic semialdehyde reductase (SSAR) in the hippocampalregions [57] Moreover gastrodin has been found to regulateGABA neurotransmitter levels by inhibiting SSADH [68]However another study reported opposite findings regardingGABA-T levels after treatment with various GE componentsin a transient global ischemia model 4-HBA treatmentincreasedGABA-T levels in the early stage of ischemia whichmight have contributed to cell survival through the energysupply generated by rapid GABA degradation in neuronalcells [38] This discrepancy among results regarding GABA-T levels may be related to differences in the pathogenesis ofseizure and ischemia

Methanol extract of GE rhizome delays seizure onset andshortens seizure duration in cocaine-induced convulsion byactivating the GABAA receptor [29] A previous in vivo studyshowed that GE rhizome ethanol extract increased the totalsleep time and reduced sleep latency in pentobarbital-treatedmice and an in vitro study also demonstrated an increasedlevel of GABAA receptors following treatment with GErhizome ethanol extract [58] In another study the anxiolyticeffects of 4-HBA and 4-HBALwere inhibited byWAY 100635a serotonin (5-HT

1A) receptor antagonist and flumazenil aGABAA receptor antagonist respectively [69] These resultsindicate that GE extract and its components may be involvedin the regulation of GABAA receptor in neurological disor-ders However further studies are required to clarify the pre-cise mechanisms underlying the effects of GE and its compo-nents on GABA-degradative enzymes and GABA receptors

32 Effects of GE and Its Components on Oxidative ResponseThe level of ROS production is an important factordetermining the severity of neurodegenerative disease andenhancing antioxidant activity may be a possible mechanisminvolved in the neuroprotective effects of GE [70 71] In atransient global ischemiamodel 4-HBA treatment decreased8-hydroxy-21015840-deoxyguanosine (8-OHdG) immunoreactivitywhich is one of the major products of DNA oxidation [38]In AD and PD in vivo and in vitro models GE rhizomeaqueous and ethanol extract ameliorated neurodegenerationby reducing oxidative stress respectively [53 60] A previousstudy also demonstrated that the protective effect of GErhizome aqueous extract in an AD model may be relatedto inhibition of apoptosis and upregulation of antioxidativeenzymes including catalase superoxide dismutase (SOD)and glutathione peroxidase [60] In addition GE rhizomeethanol extract had a neuroprotective effect as demonstratedby reductions in ROS production BaxBcl-2 ratio cleavedcaspase-3 and PARP proteolysis induced by MPTP ina PD in vitro model with SH-SY5Y or MN9D cellsrespectively [53 55] Gastrodin and vanillyl alcohol reduceROS production in MPP+-induced neurotoxicity [54 55]Gastrodin may confer neuroprotection by enhancing theexpression of antioxidant enzyme HO-1 via activation of thep38 mitogen-activated kinase (MAPK)Nrf-2 pathway

in human dopaminergic cells [54] This compoundhas also been found to have antioxidative effects in aglutamate-induced injury model by measuring the levels ofmalondialdehyde mitochondrial membrane potential andsuperoxide dismutase [59] In that study gastrodin preventedglutamate-induced oxidative stress in PC12 cells by blocking[Ca2+]I influx and inhibiting calmodulin-dependent kinaseII (CaMKII) activation apoptosis signal-regulating kinase 1(ASK1) and p38 MAPK phosphorylation [59] In a transientfocal ischemia rat model water extract of GE rhizome and4-HBA treatment induced antioxidant gene transcriptionin the brain [61] These studies have revealed parts of themechanisms involved in the neuroprotective effects of GEand its components Further studies of the mechanisms ofaction of other GE components are necessary

33 Effects of GE and Its Components on NeuroinflammationThe role of the inflammatory response has been investi-gated in neurodegenerative disorders including AD PDand epilepsy [72 73] Many studies have demonstrated thatamelioration of inflammatory responses might be anotherpossible mechanism by which GE and its componentsexert neuroprotective effects In rat models of KA-inducedepilepsy treatment of GE rhizome ethanol extract reducesthe number of activated microglial cells with a concomi-tant decrease in neuronal nitric oxide synthase- (NOS-)stained cells [65] In a rotenone-induced rat PD modelgastrodin inhibits microglial activation and inflammatorycytokines [64] Depression-like behaviors can be reversedfollowing gastrodin administration possibly due to theinhibition of IL-1120573 expression a proinflammatory cytokine[62] In RAW2647 macrophages treatment of GE rhizomeethanol extract inhibits NO production and the expressionof iNOS and COX-2 induced by lipopolysaccharide (LPS)[66] In microglial BV-2 cells activated by LPS GE rhizomeethanol extract inhibits inflammatory cytokines such asTNF-120572 and IL-1120573 and downregulates the c-Jun N-terminalkinase (JNK) and nuclear factor kappa-light-chain-enhancerof activated B cells (NF-120581B) signaling pathways [18] Fur-thermore gastrodin significantly reduces the protein andmRNA expression levels of iNOS COX-2 TNF-120572 IL-1120573and NF-120581B which may be related to the inhibition of theNF-120581B signaling pathway and phosphorylation of MAPKs[63]

Resident microglia transform into a phagocytic pheno-type under stimuli such as cell death accumulated debrisexcess aberrant protein or the presence of viral or bacterialpathogens Furthermore microglia serve important func-tions associated with inflammatory responses cytotoxicityrepair remodeling and immunosuppression in brain injuryand neurodegeneration [74] We examined microglial acti-vation and performed a biochemical analysis to determinewhether vanillin has anti-inflammatory effects (Figure 4)The expression level of Iba1 immunoreactivity was mea-sured by Western blotting to semiquantitatively analyze theanti-inflammation effects of vanillin as in previous studies[32 34] The expression level of Iba1 in the hippocam-pus after TMT administration was significantly increased


Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +

Vanillin TMT TMT + vanillin

P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)

Figure 4 Inhibitory effect of vanillin on microglial activation in the mouse hippocampus after TMT treatment Mice received a singleinjection of TMT (26mgkg intraperitoneal (ip)) and vanillin (100mgkg ip) once daily for 3 days at minus1 day 0 days and 1 day relativeto TMT injection Mice were sacrificed 3 days after TMT injection (a) Representative immunoblots show Iba1 (a marker of microglia) and120573-actin expression in themouse hippocampus Bar graphs show that the increased Iba1 expression in themouse hippocampus following TMTtreatmentwas significantly ameliorated by vanillin treatmentData are presented asmeansplusmn SEMs (b) Photomicrographs show representativeimages of Iba1 expression in the dentate gyrus (DG) CA1 andCA3The number of activatedmicroglia a hypertrophied form following TMTtreatment markedly decreased following vanillin treatment Scale bars indicate 300120583m in the left panels and 100 120583m in other panels

but the level was attenuated in the vanillin-treated group(Figure 4(a)) Iba1 immunoreactivitywas assessed 3 days afterTMT administration using immunohistochemical stainingto investigate the histological and morphological changes inmicroglia in the hippocampus as in previous studies [3234] In the vehicle- and vanillin-treated controls microgliashowed few cell bodies within the GCL In the TMT-treatedgroup activated microglia displaying a hypertrophied form

with long thickened branching processes were prominentthroughout the GCL (Figure 4(b)) However in the TMT +vanillin-treated group the density of activated microglia wasreduced throughout the GCL CA1 and CA3 (Figure 4(b))Thus our results confirmed that TMT-induced microglialactivation was ameliorated by vanillin treatment in themouse hippocampus after TMT treatment Similar to GErhizome ethanol extract and gastrodin [62 65] vanillin a GE


SSADH

Neurotransmitter imbalance Oxidative stress Neuroinflammation

GABA

Glutamate

SSA GABA-TGABA

vesicle

Succinic acidCell membrane

nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron

Neuropharmacological effects of GE

neurotransmitter oxidative stressDownregulation of proinflammatory

MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial

processing Upregulation of inhibitory

Synaptic

NF-120581B

Figure 5 Schematic representation of the neuropharmacological effects of Gastrodia elata (GE) Multiple disease mechanisms such asneurotransmitter imbalance oxidative damage and neuroinflammation reportedly induce a variety of neurodegenerative disorders GE hasthe potential to positively restore the neuronal cell damage in neurodegenerative diseases via the upregulation of inhibitory neurotransmittersand downregulation of oxidative stress and neuroinflammation ASK-1 apoptosis signal-regulating kinase-1 CaMKII Ca2+calmodulin-dependent kinase II COX-2 cyclooxygenase-2 GABA-T gamma aminobutyric acid transaminase GAD glutamate decarboxylase GEGastrodia elata iNOS inducible nitric oxide synthase JNK c-jun N-terminal kinases MAPK mitogen-activated protein kinase NO nitricoxide SOD superoxide dismutase SSADH succinic semialdehyde dehydrogenase

componentmay have anti-inflammatory effects by inhibitingmicroglial activation

4 Conclusion

Many patients suffer from incurable neurodegenerative dis-orders but there are few therapeutic drugs for treating thesediseases The pathological mechanisms involved in neu-rodegenerative diseases are mediated by neurotransmitterimbalance oxidative stress and neuroinflammation how-ever treatment efficacy is not satisfactory Herbal decoctionsincluding GE rhizome have been used in oriental medicinein East Asia to treat a variety of diseases To reveal theactive components within such herbal decoctions numerousstudies have investigated cellular and molecular mechanismsusing GE and its components In this review we summarizedthe protective effects of GE against neurodegenerative disor-ders and proposed the underlying mechanisms of the neu-ropharmacological potential ofGE and its componentsThesemechanisms may be related to the correction of neurotrans-mitter imbalance and inhibition of oxidative response andneuroinflammation (Figure 5) In addition we confirmedthat administration of vanillin an active component of GEameliorates TMT-induced seizures which may be relatedto the reduced neuronal death and microglial activationTherefore this review encourages the identification of specificGE components for use in possible preventive or therapeuticstrategies for various neurodegenerative disorders and mayalso be helpful for the development of new treatments forincurable disorders

Conflict of Interests

The authors declare that there is no conflict of interests

Authorsrsquo Contribution

Jung-Hee Jang and Yeonghoon Son contributed equally tothis study

Acknowledgments

Due to space limitations the authors may have omittedsome of the relevant literatures in this review The animalexperiment in this study was supported by the AnimalMedical Institute of Chonnam National University Thiswork was supported by a grant from the Next-GenerationBioGreen 21 Program (no PJ01135201) Rural DevelopmentAdministration Republic of Korea

References

[1] D S Knopman ldquoCurrent treatment of mild cognitive impair-ment and Alzheimerrsquos diseaserdquo Current Neurology and Neuro-science Reports vol 6 no 5 pp 365ndash371 2006

[2] K Yamada and T Nabeshima ldquoAnimal models of Alzheimerrsquosdisease and evaluation of anti-dementia drugsrdquo PharmacologyampTherapeutics vol 88 no 2 pp 93ndash113 2000

[3] A H V Schapira E Bezard J Brotchie et al ldquoNovel pharmaco-logical targets for the treatment of Parkinsonrsquos diseaserdquo NatureReviews Drug Discovery vol 5 no 10 pp 845ndash854 2006


[4] S Davis K Lees and G Donnan ldquoTreating the acute strokepatient as an emergency current practices and future opportu-nitiesrdquo International Journal of Clinical Practice vol 60 no 4pp 399ndash407 2006

[5] L Shi X Tang X Dang et al ldquoInvestigating herb-herbinteractions the potential attenuated toxicity mechanism of thecombined use of Glycyrrhizae radix et rhizoma (Gancao) andSophorae flavescentis radix (Kushen)rdquo Journal of Ethnopharma-cology vol 165 pp 243ndash250 2015

[6] S C C Chik T C T Or D Luo C L H Yang and A SY Lau ldquoPharmacological effects of active compounds on neu-rodegenerative disease with gastrodia and uncaria decoctiona commonly used poststroke decoctionrdquo The Scientific WorldJournal vol 2013 Article ID 896873 22 pages 2013

[7] X Xiong X Yang Y Liu Y Zhang P Wang and J WangldquoChinese herbal formulas for treating hypertension in tra-ditional Chinese medicine perspective of modern sciencerdquoHypertension Research vol 36 no 7 pp 570ndash579 2013

[8] J Y Jiang X Z Wang and S S Luo ldquoEffect of banxiabaizhu tianma decoction on the left ventricular hypertrophy ofhypertrophiedmyocardium in spontaneously hypertensive ratrdquoZhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi JieheZazhi vol 30 no 10 pp 1061ndash1066 2010

[9] H-X Tang A-Y Li J-J Li G-S Hou and F Zhang ldquoEffectof Ningdong Granule on the levels of IL-12 and TNF-alpha inchildren patients with Tourettersquos syndromerdquo Zhongguo ZhongXi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi vol 34 no4 pp 435ndash438 2014

[10] P-J Chen and L-Y Sheen ldquoGastrodiae rhizoma (tian ma) areview of biological activity and antidepressant mechanismsrdquoJournal of Traditional and Complementary Medicine vol 1 no1 pp 31ndash40 2011

[11] J Liu and A Mori ldquoAntioxidant and free radical scavengingactivities of Gastrodia elata Bl and Uncaria rhynchophylla(Miq) JacksrdquoNeuropharmacology vol 31 no 12 pp 1287ndash12981992

[12] Y Zhao X-J Gong X Zhou and Z-J Kang ldquoRelative bioavail-ability of gastrodin and parishin from extract and powderof Gastrodiae rhizoma in ratrdquo Journal of Pharmaceutical andBiomedical Analysis vol 100 pp 309ndash315 2014

[13] L-C Lin Y-F ChenW-C Lee Y-TWu and T-H Tsai ldquoPhar-macokinetics of gastrodin and its metabolite p-hydroxybenzylalcohol in rat blood brain and bile by microdialysis coupledto LC-MSMSrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 48 no 3 pp 909ndash917 2008

[14] T-Y Jung S-I Suh H Lee et al ldquoProtective effects of severalcomponents of Gastrodia elata on lipid peroxidation in gerbilbrain homogenatesrdquo Phytotherapy Research vol 21 no 10 pp960ndash964 2007

[15] X-HDuan Z-L Li D-S Yang F-L ZhangQ Lin andRDaildquoStudy on the chemical constituents of Gastrodia elatardquo ZhongYao Cai vol 36 no 10 pp 1608ndash1611 2013

[16] Z Li Y Wang H Ouyang et al ldquoA novel dereplication strategyfor the identification of two new trace compounds in the extractof Gastrodia elata using UHPLCQ-TOF-MSMSrdquo Journal ofChromatography B Analytical Technologies in the Biomedicaland Life Sciences vol 988 pp 45ndash52 2015

[17] C Tang LWang J Li X LiuM Cheng andH Xiao ldquoAnalysisof the metabolic profile of parishin by ultra-performance liquidchromatographyquadrupole-time of flightmass spectrometryrdquoBiomedical Chromatography 2015

[18] B-W Kim S Koppula J-W Kim et al ldquoModulation of LPS-stimulated neuroinflammation in BV-2 microglia by Gastrodiaelata 4-hydroxybenzyl alcohol is the bioactive candidaterdquoJournal of Ethnopharmacology vol 139 no 2 pp 549ndash557 2012

[19] H-B Li and F Chen ldquoPreparative isolation and purificationof gastrodin from the Chinese medicinal plant Gastrodia elataby high-speed counter-current chromatographyrdquo Journal ofChromatography A vol 1052 no 1-2 pp 229ndash232 2004

[20] L M Ojemann W L Nelson D S Shin A O Rowe and RA Buchanan ldquoTian ma an ancient Chinese herb offers newoptions for the treatment of epilepsy and other conditionsrdquoEpilepsy amp Behavior vol 8 no 2 pp 376ndash383 2006

[21] J Y Lee Y W Jang H S Kang H Moon S S Sim and C JKim ldquoAnti-inflammatory action of phenolic compounds fromGastrodia elata rootrdquo Archives of Pharmacal Research vol 29no 10 pp 849ndash858 2006

[22] A B Young and G E Fagg ldquoExcitatory amino acid receptorsin the brain membrane binding and receptor autoradiographicapproachesrdquo Trends in Pharmacological Sciences vol 11 no 3pp 126ndash133 1990

[23] C-L Hsieh N-Y Tang S-Y Chiang C-T Hsieh and L Jaung-Geng ldquoAnticonvulsive and free radical scavenging actions oftwo herbs Uncaria rhynchophylla (MIQ) Jack and Gastrodiaelata Bl in kainic acid-treated ratsrdquo Life Sciences vol 65 no20 pp 2071ndash2082 1999

[24] C-L Hsieh S-Y Chiang K-S Cheng et al ldquoAnticonvulsiveand free radical scavenging activities of Gastrodia elata Blin kainic acid-treated ratsrdquo The American Journal of ChineseMedicine vol 29 no 2 pp 331ndash341 2001

[25] H-J KimK-DMoon S-YOh S-P Kim and S-R Lee ldquoEtherfraction of methanol extracts of Gastrodia elata a traditionalmedicinal herb protects against kainic acid-induced neuronaldamage in the mouse hippocampusrdquo Neuroscience Letters vol314 no 1-2 pp 65ndash68 2001

[26] C-L Hsieh J-J Lin S-Y Chiang et al ldquoGastrodia elatamodulated activator protein 1 via c-Jun N-terminal kinasesignaling pathway in kainic acid-induced epilepsy in ratsrdquoJournal of Ethnopharmacology vol 109 no 2 pp 241ndash247 2007

[27] I Ushijima T Kobayashi M Suetsugi K Watanabe MYamada and K Yamaguchi ldquoCocaine evidence for NMDA-beta-carboline- and dopaminergic-mediated seizures in micerdquoBrain Research vol 797 no 2 pp 347ndash350 1998

[28] J-H Ye and J Ren ldquoCocaine inhibition of GABAA current roleof dephosphorylationrdquo Critical Reviews in Neurobiology vol 18no 1-2 pp 85ndash94 2006

[29] E-J Shin J-H Bach T-T L Nguyen et al ldquoGastrodia elata Blattenuates cocaine-induced conditioned place preference andconvulsion but not behavioral sensitization in mice impor-tance of GABAA receptorsrdquo Current Neuropharmacology vol9 no 1 pp 26ndash29 2011

[30] J-H Ha D-U Lee J-T Lee et al ldquo4-Hydroxybenzaldehydefrom Gastrodia elata B1 is active in the antioxidation andGABAergic neuromodulation of the rat brainrdquo Journal ofEthnopharmacology vol 73 no 1-2 pp 329ndash333 2000

[31] R Besser G Kramer R Thumler J Bohl L Gutmann andH C Hopf ldquoAcute trimethyltin limbic-cerebellar syndromerdquoNeurology vol 37 no 6 pp 945ndash950 1987

[32] M Yang J Kim T Kim et al ldquoPossible involvement of galectin-3 in microglial activation in the hippocampus with trimethyltintreatmentrdquoNeurochemistry International vol 61 no 7 pp 955ndash962 2012


[33] J Kim M Yang S-H Kim et al ldquoPossible role of the glycogensynthase kinase-3 signaling pathway in trimethyltin-inducedhippocampal neurodegeneration inmicerdquo PLoSONE vol 8 no8 Article ID e70356 2013

[34] J Kim M Yang Y Son et al ldquoGlial activation with concur-rent up-regulation of inflammatory mediators in trimethyltin-induced neurotoxicity in micerdquo Acta Histochemica vol 116 no8 pp 1490ndash1500 2014

[35] S Lee M Yang J Kim et al ldquoNestin expression and glialresponse in the hippocampus of mice after trimethyltin treat-mentrdquo Acta Histochemica vol 116 no 8 pp 1276ndash1288 2014

[36] C Iadecola ldquoBright and dark sides of nitric oxide in ischemicbrain injuryrdquo Trends in Neurosciences vol 20 no 3 pp 132ndash1391997

[37] M Endres D Biniszkiewicz R W Sobol et al ldquoIncreasedpostischemic brain injury in mice deficient in uracil-DNAglycosylaserdquoThe Journal of Clinical Investigation vol 113 no 12pp 1711ndash1721 2004

[38] H J Kim I K Hwang and M H Won ldquoVanillin 4-hydroxybenzyl aldehyde and 4-hydroxybenzyl alcohol preventhippocampal CA1 cell death following global ischemiardquo BrainResearch vol 1181 no 1 pp 130ndash141 2007

[39] H-J Kim S-R Lee and K-D Moon ldquoEther fraction ofmethanol extracts of Gastrodia elata medicinal herb protectsagainst neuronal cell damage after transient global ischemia ingerbilsrdquo Phytotherapy Research vol 17 no 8 pp 909ndash912 2003

[40] X Zeng S Zhang L Zhang K Zhang and X Zheng ldquoA studyof the neuroprotective effect of the phenolic glucoside gastrodinduring cerebral ischemia in vivo and in vitrordquo Planta Medicavol 72 no 15 pp 1359ndash1365 2006

[41] X Bie Y Chen J Han H Dai H Wan and T Zhao ldquoEffectsof gastrodin on amino acids after cerebral ischemia-reperfusioninjury in rat striatumrdquo Asia Pacific Journal of Clinical Nutritionvol 16 no 1 pp 305ndash308 2007

[42] X Xu Y Lu and X Bie ldquoProtective effects of gastrodin onhypoxia-induced toxicity in primary cultures of rat corticalneuronsrdquo Planta Medica vol 73 no 7 pp 650ndash654 2007

[43] M A Findeis ldquoApproaches to discovery and characterization ofinhibitors of amyloid 120573-peptide polymerizationrdquo Biochimica etBiophysica Acta vol 1502 no 1 pp 76ndash84 2000

[44] R B Postuma W He J Nunan et al ldquoSubstrate-bound beta-amyloid peptides inhibit cell adhesion and neurite outgrowthin primary neuronal culturesrdquo Journal of Neurochemistry vol74 no 3 pp 1122ndash1130 2000

[45] D S H L Kim J-Y Kim and Y S Han ldquoAlzheimerrsquos dis-ease drug discovery from herbs neuroprotectivity from beta-amyloid (1-42) insultrdquo Journal of Alternative and Complemen-tary Medicine vol 13 no 3 pp 333ndash340 2007

[46] Y Su Q Wang C Wang K Chan Y Sun and H KuangldquoThe treatment of Alzheimerrsquos disease using Chinese MedicinalPlants from disease models to potential clinical applicationsrdquoJournal of Ethnopharmacology vol 152 no 3 pp 403ndash423 2014

[47] G-BHuang T Zhao S SMuna et al ldquoTherapeutic potential ofGastrodia elata blume for the treatment of alzheimerrsquos diseaserdquoNeural Regeneration Research vol 8 no 12 pp 1061ndash1070 2013

[48] G-H Lee H-R Kim S-Y Han et al ldquoGastrodia elata blumeand its pure compounds protect BV-2 microglial-derived celllines against 120573-amyloid the involvement of GRP78 and CHOPrdquoBiological Research vol 45 no 4 pp 403ndash410 2012

[49] W Dauer and S Przedborski ldquoParkinsonrsquos disease mechanismsand modelsrdquo Neuron vol 39 no 6 pp 889ndash909 2003

[50] B R Bloem I Irwin O J S Buruma et al ldquoThe MPTPmodel versatile contributions to the treatment of idiopathicParkinsonrsquos diseaserdquo Journal of the Neurological Sciences vol 97no 2-3 pp 273ndash293 1990

[51] K F Tipton and T P Singer ldquoAdvances in our understandingof the mechanisms of the neurotoxicity of MPTP and relatedcompoundsrdquo Journal of Neurochemistry vol 61 no 4 pp 1191ndash1206 1993

[52] H Kumar I-S Kim S V More B-W Kim Y-Y Bahk and D-K Choi ldquoGastrodin protects apoptotic dopaminergic neuronsin a toxin-induced Parkinsonrsquos disease modelrdquo Evidence-BasedComplementary and Alternative Medicine vol 2013 Article ID514095 13 pages 2013

[53] H An I S Kim S Koppula et al ldquoProtective effects ofGastrodia elataBlume onMPP+-induced cytotoxicity in humandopaminergic SH-SY5Y cellsrdquo Journal of Ethnopharmacologyvol 130 no 2 pp 290ndash298 2010

[54] G Jiang Y Hu L Liu J Cai C Peng and Q Li ldquoGastrodinprotects against MPP+-induced oxidative stress by up regu-lates heme oxygenase-1 expression through p38 MAPKNrf2pathway in human dopaminergic cellsrdquo Neurochemistry Inter-national vol 75 pp 79ndash88 2014

[55] I S Kim D-K Choi and H J Jung ldquoNeuroprotective effectsof vanillyl alcohol in gastrodia elata blume through suppressionof oxidative stress and anti-apoptotic activity in toxin-induceddopaminergic MN9D cellsrdquo Molecules vol 16 no 7 pp 5349ndash5361 2011

[56] G Fabbrini J M Brotchie F Grandas M Nomoto and C GGoetz ldquoLevodopa-induced dyskinesiasrdquo Movement Disordersvol 22 no 10 pp 1379ndash1389 2007

[57] S-J An S-K Park I K Hwang et al ldquoGastrodin decreasesimmunoreactivities of 120574-aminobutyric acid shunt enzymesin the hippocampus of seizure-sensitive gerbilsrdquo Journal ofNeuroscience Research vol 71 no 4 pp 534ndash543 2003

[58] J J Choi E-H Oh M K Lee Y B Chung J T Hongand K-W Oh ldquoGastrodiae Rhizoma ethanol extract enhancespentobarbital-induced sleeping behaviors and rapid eye move-ment sleep via the activation of GABAA-ergic transmissionin rodentsrdquo Evidence-Based Complementary and AlternativeMedicine vol 2014 Article ID 426843 9 pages 2014

[59] G Jiang H Wu Y Hu J Li and Q Li ldquoGastrodin inhibitsglutamate-induced apoptosis of PC12 cells via inhibition ofCaMKIIASK-1p38 MAPKp53 signaling cascaderdquo Cellularand Molecular Neurobiology vol 34 no 4 pp 591ndash602 2014

[60] C-F Ng C-H Ko C-M Koon et al ldquoThe aqueous extract ofrhizome of Gastrodia elata protected Drosophila and PC12 cellsagainst beta-amyloid-induced neurotoxicityrdquo Evidence-BasedComplementary and Alternative Medicine vol 2013 Article ID516741 12 pages 2013

[61] S J Yu J R Kim C K Lee et al ldquoGastrodia elata blumeand an active component p-hydroxybenzyl alcohol reducefocal ischemic brain injury through antioxidant related geneexpressionsrdquo Biological and Pharmaceutical Bulletin vol 28 no6 pp 1016ndash1020 2005

[62] H Wang R Zhang Y Qiao et al ldquoGastrodin amelioratesdepression-like behaviors and up-regulates proliferation ofhippocampal-derived neural stem cells in rats involvement ofits anti-inflammatory actionrdquo Behavioural Brain Research vol266 pp 153ndash160 2014

[63] J-N Dai Y Zong L-M Zhong et al ldquoGastrodin inhibitsexpression of inducible no synthase cyclooxygenase-2 andproinflammatory cytokines in cultured LPS-stimulated


microglia via MAPK pathwaysrdquo PLoS ONE vol 6 no 7 ArticleID e21891 2011

[64] C Li X Chen N Zhang Y Song and Y Mu ldquoGastrodininhibits neuroinflammation in rotenone-induced Parkinsonrsquosdisease model ratsrdquo Neural Regeneration Research vol 7 no 5pp 325ndash331 2012

[65] C-L Hsieh C-L Chen N-Y Tang et al ldquoGastrodia elata BLmediates the suppression of nNOS and microglia activation toprotect against neuronal damage in kainic acid-treated ratsrdquoTheAmerican Journal of ChineseMedicine vol 33 no 4 pp 599ndash6112005

[66] E-K Ahn H-J Jeon E-J Lim H-J Jung and E-H ParkldquoAnti-inflammatory and anti-angiogenic activities of Gastrodiaelata Blumerdquo Journal of Ethnopharmacology vol 110 no 3 pp476ndash482 2007

[67] J-H Choi andD-U Lee ldquoA new citryl glycoside fromGastrodiaelata and its inhibitory activity on GABA transaminaserdquo Chem-ical amp Pharmaceutical Bulletin vol 54 no 12 pp 1720ndash17212006

[68] N-I Baek S Y Choi J K Park et al ldquoIsolation and iden-tification of succinic semialdehyde dehydrogenase inhibitorycompound from the rhizome ofGastrodia elata blumerdquoArchivesof Pharmacal Research vol 22 no 2 pp 219ndash224 1999

[69] J W Jung B H Yoon H R Oh et al ldquoAnxiolytic-like effects ofGastrodia elata and its phenolic constituents inmicerdquo Biologicaland Pharmaceutical Bulletin vol 29 no 2 pp 261ndash265 2006

[70] H H Szeto ldquoMitochondria-targeted peptide antioxidantsnovel neuroprotective agentsrdquo The AAPS Journal vol 8 no 3pp E521ndashE531 2006

[71] S R Pieczenik and J Neustadt ldquoMitochondrial dysfunction andmolecular pathways of diseaserdquo Experimental and MolecularPathology vol 83 no 1 pp 84ndash92 2007

[72] B Liu and J-S Hong ldquoRole of microglia in inflammation-mediated neurodegenerative diseases mechanisms and strate-gies for therapeutic interventionrdquoThe Journal of Pharmacologyand Experimental Therapeutics vol 304 no 1 pp 1ndash7 2003

[73] A Vezzani and T Granata ldquoBrain inflammation in epilepsyexperimental and clinical evidencerdquo Epilepsia vol 46 no 11 pp1724ndash1743 2005

[74] A Sierra O Abiega A Shahraz and H Neumann ldquoJanus-faced microglia beneficial and detrimental consequences ofmicroglial phagocytosisrdquo Frontiers in Cellular Neuroscience vol7 article 6 2013

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


prescriptions For example it is difficult to accurately evaluatethe inherent efficacy of each herb in such complexes andto identify the target component involved in the diseasemechanism and thus the treatment effectTherefore we mustfirst study each individual component of traditional herbalmedicines to determine the pharmacological mechanismsinvolved

Gastrodia elata Blume (GE) which belongs to the Orchi-daceae family is a saprophyte that grows in the woods ofEast Asia The dried rhizome (tuber) of this plant (tianma)is used as a traditional herbal medicine to treat neurologicaldisorders such as vertigo general paralysis epilepsy andtetanusTheGE rhizomehas been used clinically as a complexprescription rather than as a single herb For example BanxiaBaishu Tianma Tang which is a decoction composed ofGE rhizome and other herbs such as Pinellia ternata andAtractylodes is prescribed to treat hypertension in East Asia[7 8] The effects of a complex prescription mixed togetherwith GE rhizome and other herbs have been demonstratedin patients with Tourettersquos syndrome [9] Ningdong granule(ie GE rhizomeCodonopsis pilosulaOphiopogon japonicuswhite peony root Rhinocerotidae oyster earthworm andlicorice root) attenuated symptoms of Tourettersquos syndromein children and returned abnormal levels of interleukin-(IL-) 12 and tumor necrosis factor- (TNF-) alpha in theserum to normal In addition many previous studies haveattempted to elucidate the pharmacological effects ofmultipleherb decoctions that include GE rhizome to provide newtherapeutic opportunities for neurodegenerative diseases [610 11] Additionally previous studies have investigated thepharmacokinetics of GE components While higher relativebioavailability of gastrodin and parishin was obtained inrats after oral administration of GE rhizome powder at lowdoses higher bioavailability was shown after administrationof high doses of the GE rhizome aqueous extract [12]Moreover a detection technique was developed to determinethe pharmacokinetics of gastrodin in rat blood brain andbile and this technique might be a useful method for thedetermination of the metabolism of gastrodin [13] Howeverfurther studies are necessary to elucidate the pharmacologicaland pharmacokinetic properties of GE and its components inthe context of brain tissue injury

Most of the previous studies have attempted to identifythe biologically active components of the GE rhizomeand a variety of compounds have been isolated from theaqueous or methanol extracts of GE rhizome Methanolextracts of GE rhizome reportedly exert neuroprotectiveand antioxidant effects [14] One study isolated andidentified 14 GE compounds using silica gel columnchromatography and fractionated 8 phenolic components[15] 4-hydroxybenzaldehyde (4-HBAL) 4-hydroxybenzylalcohol (4-HBA) benzyl alcohol bis-(4-hydroxyphenyl)methane 4-(41015840-hydroxybenzyloxy)benzyl methylether4-hydroxy-3-methoxybenzyl alcohol (vanillyl alcohol) 4-hydroxy-3-methoxybenzaldehyde (vanillin) and 4-hydroxy-3-methoxybenzoic acid (vanillic acid) (Figure 1) Amongthem several GE compounds including 4-HBAL 4-HBAbenzyl alcohol vanillyl alcohol vanillin and vanillic acid arelisted on the Everything Added to Food in the United States

(EAFUS) database as Food andDrugAdministration- (FDA-)approved food additives (httpwwwaccessdatafdagovscriptsfcnfcnnavigationcfmrpt=eafuslistingampdisplayAll=true) Several new compounds were recently isolated byvarious chromatography techniques in total 64 compoundswere identified from GE rhizome including parishinJ and parishin K [16] A previous study reported themetabolic profile of parishin in rat plasma and urine afteradministration of parishin to investigate the pharmacologicaleffects [17] However among these components of GEgastrodin 4-HBAL 4-HBA vanillin and vanillyl alcoholare the major active components in terms of their neu-ropharmacological properties [18] Gastrodin the mainbioactive component of GE has since been obtainedvia ethanol and aqueous extraction and is the phenolicglucoside of 4-HBA [19] (Figure 1) Another main bioactivecomponent vanillin which can be isolated from methanolextracts is an aromatic aldehyde that contains a hydroxylgroup para to aldehyde (Figure 1) Vanillin may be effectiveas a new antiepileptic drug as vanillin reportedly haseffects on human epilepsy patients 184 patients treated withvanillin monotherapy for 3 months showed improvementin a previous study [20] In addition vanillin is a potentanti-inflammatory agent that inhibits the generation ofreactive oxygen species (ROS) [21] Benzyl alcohol 4-HBALand 4-HBA have anti-inflammatory effects via the inhibitionof the activities of cyclooxygenase- (COX-) 1 and COX-2 andvanillyl alcohol significantly increases the radical-scavengingactivity of DPPH [21] In vivo and in vitro experiments havedemonstrated that GE and its components have variouspharmacological actions that result in antioxidant anti-inflammatory and anticonvulsant effects [14 20] Herewe report on the potential therapeutic potential of GE forthe treatment of neurodegenerative disorders includingepilepsy ischemia AD and PD

In this review we provide an overview of the efficacy ofGE and its components in a variety of neurodegenerativemodels We also discuss the possible mechanisms involvedin ameliorating a broad range of brain disorders that lead toneuronal death

2 Protective Effects of GE and Its Componentsin Neurodegenerative Disease Models

Several studies have revealed the effects of GE and itscomponents on various in vivo and in vitro models ofneurodegenerative disorders such as epilepsy ischemia ADand PD (Table 1)

21 Induced Seizure Model Previous studies have demon-strated the anticonvulsant properties of GE in rodent mod-els of seizure Kainic acid (KA) is an excitatory agonistthat induces limbic seizures and excitotoxicity in the hip-pocampus [22] The anticonvulsant effect of GE rhizomeextract has been documented in rodent KA models oftemporal epilepsy [23ndash26] The ether fraction of GE rhizomemethanol extracts has anticonvulsant effects on this modeland histopathological findings have shown that treatment


HO

O

OH

HO

OO

O

HO

O

O

OHO

HO

O

O

OH

OH

OH

OH

O

HO

HO

HO

OH

OH

HO





(vanillic acid)

Gastrodin

H3C

H3C

H3C

H3C







elsu

sedto

identifythee

ffectso

fGastro

diaela

ta(G

E)andits

compo

nentso

nneurod

egeneratived

isorders

Mod

elIndu

cer

Extracts

compo

nents

Doserouteregimen

Animalor

cell

Major

finding

Reference

Seizure

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Seizureo

nsettim

euarrSeizured

urationdarr

[29]

KAEF

MEof

GE

200or

500m

gkgpo14

days

before

and4days

after

KAinjection

ICRmice

Onsettim

eofn

eurobehavioral

changeuarr

Severityof

convulsio

nsdarr

Hippo

campaln

euronald

amagedarr

[25]

KAGErhizom

emdashethano

lextract

05or

10gkgpo30

min

before

KAinjection

SDrats

Seizureo

nsettim

euarrSeizure-lik

ebehaviordarr

[24]

KAGErhizom

emdashaqueou

sextract

05or

10gkgpo1w

eekbefore

or2

weeks

after

KAinjection

SDrats

Threetypes

ofseizure(wetdo

gshakespaw

tremorand

facial

myoclo

nia)darr

[26]

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Seizurer

ecoverytim

edarrSeizures

everitydarr

[30]

Ischem

ia

Hypoxia

Gastro

din

25ndash100120583gmL

Ratcortic

alneuron


[42]

MCA

OGastro

din

50mgkgip10min

before

MCA

OSD

rats

Infarctvolum


Aminoacidsuarr

[41]

MCA

OGastro

din

50or

100m

gkgipattheo

nsetof

MCA

OSD

rats

Infarctvolum

edarrEd

emav

olum

edarr[40]

Transie

ntglob

alisc

hemia

EFMEof

GErhizom

e200or

500m

gkgpo14

days

before

brainisc

hemia

Mon

goliangerbils

Neuronald

amagein

hipp

ocam

palC

A1darr

[39]

Transie

ntglob

alisc

hemia

Vanillin

4-HBA

Land4-HBA

40mgkgip30

min

before

andaft

erisc

hemia

Mon

goliangerbils

Neuronalsurvivalin

hipp

ocam

palC

A1uarr

[38]

Alzh

eimerrsquosdisease

A120573(1ndash

42)

GErhizom

emdashchloroform

extract

20120583gmLfor2

4hPC

12andprim

aryneuron

alcells


[45]

A120573(1ndash

42)

GErhizom

emdashmethano

lextractgastrodin

and4-HBA

10120583gmLfor4

8hBV

2mou

semicroglialcell

Cellviabilityuarr

[48]

A120573(25ndash35)

GErhizom

epow

der

500or

1000

mgkgpofor5

2days

Wistar

rats

Amyloiddepo

sitsdarr

Spatialm

emoryuarr

Cholinea

cetyltransfe

raseuarr

[47]

Parkinsonrsquos

disease

MPP+

Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Cellviabilityuarr

Oxidativ

estre

ssdarr

[54]

MPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

Cellviabilityuarr

Cytotoxicitydarr

[53]

MPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

Cellviabilityuarr

Cytotoxicitydarr

[55]

MPT

PMPP+

Gastro

din

1030and60

mgkgpofor15days

15and25120583M4

hpriortoMPP+

expo

sure

C57B

L6m

ice

SH-SY5

Ycells

Bradykinesiadarr

Motor

impairm

entdarr

Cellviabilityuarr

[52]

4-HBA


l4-HBA


pamineEF

ME

etherfractionof

methano

lextractG

EGastro

diaela

taICR

Instituteo

fCancerR

esearch

KAkainic

acidL-D

OPA

L-34-dihydroxyph

enylalanineMCA

Om

iddlec

erebralarteryo

cclusio

nMPP+1-m

ethyl-4

-phenylpyridiniumM

PTP1-m

ethyl-4

-phenyl-1236-te

trahydropyrid

inePC

pheochrom

ocytom

aPT


Daw

ley


Days 0 1 2 3

Seizure scoring

minus1

TMT (26 mgkg ip)


(a)


Seiz

ure s

core

0

1

2

3

4

5


(ii) Weak tremor



(v) Death

lowast

lowast

lowast

1 2 3


(b)








Hilus

GCL

TMT

GCL

Hilus

0

20

40

60

80

100

120

140

160

Num

ber o

f con

dens

ed n

ucle

iTMT

TMT + vanillin

TMT + vanillin

P lt 001 (n = 10)











Table2Ph


GEandits

compo

nentso

nneurod

egeneration

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Neurotransm

ission

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Recovery

ofbrainGABA

contents

[30]

Neurotransm

ission

Stroking

ofthe

back

Gastro

din

60mgkgpofor1

week

Mon

goliangerbils

Decreased

GABA

-Tim

mun

oreactivity

Decreased

SSADHSSA

Rim

mun

oreactivity

[57]

Neurotransm

ission

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Attenu

ationof

cocaine-indu

cedseizurev

iaGABA

Abut

notG

ABA

Breceptor

activ

ation

[29]

Neurotransm

ission

Pentob

arbital

GErhizom

emdashethano

lextract

2550and100m

gkgpo1h

before

pentob

arbitalinjectio

nICRmiceprim

arycultu

reof

cerebellarg

ranu

lecells

Prolon

gedtotalsleep

time

Redu

cedsle

eplatency

IncreasedGADandGABA

Areceptor

subtype

expressio

n[58]

Neurotransm

ission

andantio

xidatio

nTransie

ntglob

alisc

hemia

Vanillin

4-HBA

Land

4-HBA

40mgkgsc30m

inbefore

and

30min369and

24haft

erisc

hemia

0016008042and

10120583Mfor

2h

Mon

goliangerbilsP

C12

cells

Dow

nregulated

8-OHdG

immun

oreactivity

IncreasedGABA

-Tin

thee

arlysta

geaft

erisc

hemia

Antioxidant

activ

ityon

lipid

peroxidatio

n[38]

Antioxidatio

nGlutamate

Gastro

din

011and10120583M

PC12

cells

InhibitedRO

Sprod

uctio

nInhibitedMDAM

MPandSO

Dlevels

Blockedglutam

ate-indu

ced[Ca2+]Iinflu

xBlockedCa

MKI

IASK

-1and

phosph

orylation

ofMAPK

[59]

Antioxidatio

nMPP

+Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Decreased

ROSprod

uctio

nIndu

cedHO-1expressio

nthroug

hp38

MAPK

Nrf2

signalin

gpathway

[54]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[53]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[55]

Antioxidatio

nA120573(25ndash35)

GErhizom

emdashaqueou

sextract

20120583Mfor

48h

PC12

cells

Decreased

ROSprod

uctio

nUpregulated

enzymaticactiv

ities

ofcatalase

SODand

glutathion

eperoxidase

[60]

Antioxidatio

nMCA

OGErhizom

emdashaqueou

sextract

4-HBA

500m

gkgip

25mgkgip3days

priortoMCA

OSD

rats

Increasedlevelsof

genesrela

tedto

antio

xidant

syste

m(protein

disulfide

isomerasea

nd1-C

ysperoxiredo

xin)

[61]

Anti-infl

ammation

CUS

Gastro

din

50100and

200m

gkgipfor14days

51020and50120583gmL

SDrats

Prim

aryhipp

ocam

palcells

Upregulated

neuralste

mcellproliferatio

nRe


[62]

Anti-infl

ammation

LPS

Gastro

din


Sexpo

sure

BV-2

cells

Decreased

levelsof

proinfl

ammatoryenzymes

(iNOSCO

X-2)

andproinfl

ammatory

cytokines(TN

F-120572IL-1120573)

Redu

cedph

osph

orylationof

ERK1

2JNK

p38

MAPK

and

CREB

[63]

Anti-infl

ammation

Roteno

neGastro

din

02g

kgpo

Wistar

rats

Supp

ressed


Redu


n[64]

Anti-infl

ammation

KAGErhizom

emdashethano

lextract

051gkgpo30m

inpriortoKA

injection

SDrats

Decreased


Redu

cednN

OSactiv

ation

[65]


Table2Con

tinued

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

02505and

1120583gmLfor2

4hRA

W2647cells

InhibitedNOprod

uctio

nRe

ducediN

OSandCO

X-2expressio

n[66]

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

4-HBA

110and

100120583

gmL

50100and

200n

MBV

-2cells

InhibitedJN

KandNF-120581Bsig

nalin

gpathways

InhibitedNOandiN

OS

[18]

4-HBA


l4-HBA



-1apo

ptosissig

nal-regulatingk

inase-1Ca

MKI

ICa2+calmod

ulin-dependent

kinaseIIC

OX-

2cyclo

oxygenase-2CU

Schronicun

predictablestr

essEF

ME

etherfractionof

methano

lextractE

RKextracellu

lars

ignal-regulated

kinaseG

ABA

-Tgam

maam

inob

utyricacid


decarboxylase

GE

Gastro

diaela

taG

REE

Gastro

diaela

tarhizom

eethano

lextractiNOS

indu

ciblenitric

oxidesynthaseJNK

c-junN-te

rminal

kinasesKA

kainicacidL

PSlipop

olysaccharide

MAPK

mito

gen-activ

ated

proteinkinaseM

CAOm

iddlecerebralartery

occlu

sion

MDAm

alon

dialdehydeM

MP

mito

chon

drialm

embranepo

tentialnN

OS

neuron


On

itricoxidePT


OSreactiv

eoxygenspeciesSO

Dsup

eroxided


emialdehyded

ehydrogenaseSSA


eductase










Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +


P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)





SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















HO

O

OH

HO

OO

O

HO

O

O

OHO

HO

O

O

OH

OH

OH

OH

O

HO

HO

HO

OH

OH

HO





(vanillic acid)

Gastrodin

H3C

H3C

H3C

H3C







elsu

sedto

identifythee

ffectso

fGastro

diaela

ta(G

E)andits

compo

nentso

nneurod

egeneratived

isorders

Mod

elIndu

cer

Extracts

compo

nents

Doserouteregimen

Animalor

cell

Major

finding

Reference

Seizure

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Seizureo

nsettim

euarrSeizured

urationdarr

[29]

KAEF

MEof

GE

200or

500m

gkgpo14

days

before

and4days

after

KAinjection

ICRmice

Onsettim

eofn

eurobehavioral

changeuarr

Severityof

convulsio

nsdarr

Hippo

campaln

euronald

amagedarr

[25]

KAGErhizom

emdashethano

lextract

05or

10gkgpo30

min

before

KAinjection

SDrats

Seizureo

nsettim

euarrSeizure-lik

ebehaviordarr

[24]

KAGErhizom

emdashaqueou

sextract

05or

10gkgpo1w

eekbefore

or2

weeks

after

KAinjection

SDrats

Threetypes

ofseizure(wetdo

gshakespaw

tremorand

facial

myoclo

nia)darr

[26]

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Seizurer

ecoverytim

edarrSeizures

everitydarr

[30]

Ischem

ia

Hypoxia

Gastro

din

25ndash100120583gmL

Ratcortic

alneuron


[42]

MCA

OGastro

din

50mgkgip10min

before

MCA

OSD

rats

Infarctvolum


Aminoacidsuarr

[41]

MCA

OGastro

din

50or

100m

gkgipattheo

nsetof

MCA

OSD

rats

Infarctvolum

edarrEd

emav

olum

edarr[40]

Transie

ntglob

alisc

hemia

EFMEof

GErhizom

e200or

500m

gkgpo14

days

before

brainisc

hemia

Mon

goliangerbils

Neuronald

amagein

hipp

ocam

palC

A1darr

[39]

Transie

ntglob

alisc

hemia

Vanillin

4-HBA

Land4-HBA

40mgkgip30

min

before

andaft

erisc

hemia

Mon

goliangerbils

Neuronalsurvivalin

hipp

ocam

palC

A1uarr

[38]

Alzh

eimerrsquosdisease

A120573(1ndash

42)

GErhizom

emdashchloroform

extract

20120583gmLfor2

4hPC

12andprim

aryneuron

alcells


[45]

A120573(1ndash

42)

GErhizom

emdashmethano

lextractgastrodin

and4-HBA

10120583gmLfor4

8hBV

2mou

semicroglialcell

Cellviabilityuarr

[48]

A120573(25ndash35)

GErhizom

epow

der

500or

1000

mgkgpofor5

2days

Wistar

rats

Amyloiddepo

sitsdarr

Spatialm

emoryuarr

Cholinea

cetyltransfe

raseuarr

[47]

Parkinsonrsquos

disease

MPP+

Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Cellviabilityuarr

Oxidativ

estre

ssdarr

[54]

MPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

Cellviabilityuarr

Cytotoxicitydarr

[53]

MPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

Cellviabilityuarr

Cytotoxicitydarr

[55]

MPT

PMPP+

Gastro

din

1030and60

mgkgpofor15days

15and25120583M4

hpriortoMPP+

expo

sure

C57B

L6m

ice

SH-SY5

Ycells

Bradykinesiadarr

Motor

impairm

entdarr

Cellviabilityuarr

[52]

4-HBA


l4-HBA


pamineEF

ME

etherfractionof

methano

lextractG

EGastro

diaela

taICR

Instituteo

fCancerR

esearch

KAkainic

acidL-D

OPA

L-34-dihydroxyph

enylalanineMCA

Om

iddlec

erebralarteryo

cclusio

nMPP+1-m

ethyl-4

-phenylpyridiniumM

PTP1-m

ethyl-4

-phenyl-1236-te

trahydropyrid

inePC

pheochrom

ocytom

aPT


Daw

ley


Days 0 1 2 3

Seizure scoring

minus1

TMT (26 mgkg ip)


(a)


Seiz

ure s

core

0

1

2

3

4

5


(ii) Weak tremor



(v) Death

lowast

lowast

lowast

1 2 3


(b)








Hilus

GCL

TMT

GCL

Hilus

0

20

40

60

80

100

120

140

160

Num

ber o

f con

dens

ed n

ucle

iTMT

TMT + vanillin

TMT + vanillin

P lt 001 (n = 10)











Table2Ph


GEandits

compo

nentso

nneurod

egeneration

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Neurotransm

ission

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Recovery

ofbrainGABA

contents

[30]

Neurotransm

ission

Stroking

ofthe

back

Gastro

din

60mgkgpofor1

week

Mon

goliangerbils

Decreased

GABA

-Tim

mun

oreactivity

Decreased

SSADHSSA

Rim

mun

oreactivity

[57]

Neurotransm

ission

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Attenu

ationof

cocaine-indu

cedseizurev

iaGABA

Abut

notG

ABA

Breceptor

activ

ation

[29]

Neurotransm

ission

Pentob

arbital

GErhizom

emdashethano

lextract

2550and100m

gkgpo1h

before

pentob

arbitalinjectio

nICRmiceprim

arycultu

reof

cerebellarg

ranu

lecells

Prolon

gedtotalsleep

time

Redu

cedsle

eplatency

IncreasedGADandGABA

Areceptor

subtype

expressio

n[58]

Neurotransm

ission

andantio

xidatio

nTransie

ntglob

alisc

hemia

Vanillin

4-HBA

Land

4-HBA

40mgkgsc30m

inbefore

and

30min369and

24haft

erisc

hemia

0016008042and

10120583Mfor

2h

Mon

goliangerbilsP

C12

cells

Dow

nregulated

8-OHdG

immun

oreactivity

IncreasedGABA

-Tin

thee

arlysta

geaft

erisc

hemia

Antioxidant

activ

ityon

lipid

peroxidatio

n[38]

Antioxidatio

nGlutamate

Gastro

din

011and10120583M

PC12

cells

InhibitedRO

Sprod

uctio

nInhibitedMDAM

MPandSO

Dlevels

Blockedglutam

ate-indu

ced[Ca2+]Iinflu

xBlockedCa

MKI

IASK

-1and

phosph

orylation

ofMAPK

[59]

Antioxidatio

nMPP

+Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Decreased

ROSprod

uctio

nIndu

cedHO-1expressio

nthroug

hp38

MAPK

Nrf2

signalin

gpathway

[54]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[53]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[55]

Antioxidatio

nA120573(25ndash35)

GErhizom

emdashaqueou

sextract

20120583Mfor

48h

PC12

cells

Decreased

ROSprod

uctio

nUpregulated

enzymaticactiv

ities

ofcatalase

SODand

glutathion

eperoxidase

[60]

Antioxidatio

nMCA

OGErhizom

emdashaqueou

sextract

4-HBA

500m

gkgip

25mgkgip3days

priortoMCA

OSD

rats

Increasedlevelsof

genesrela

tedto

antio

xidant

syste

m(protein

disulfide

isomerasea

nd1-C

ysperoxiredo

xin)

[61]

Anti-infl

ammation

CUS

Gastro

din

50100and

200m

gkgipfor14days

51020and50120583gmL

SDrats

Prim

aryhipp

ocam

palcells

Upregulated

neuralste

mcellproliferatio

nRe


[62]

Anti-infl

ammation

LPS

Gastro

din


Sexpo

sure

BV-2

cells

Decreased

levelsof

proinfl

ammatoryenzymes

(iNOSCO

X-2)

andproinfl

ammatory

cytokines(TN

F-120572IL-1120573)

Redu

cedph

osph

orylationof

ERK1

2JNK

p38

MAPK

and

CREB

[63]

Anti-infl

ammation

Roteno

neGastro

din

02g

kgpo

Wistar

rats

Supp

ressed


Redu


n[64]

Anti-infl

ammation

KAGErhizom

emdashethano

lextract

051gkgpo30m

inpriortoKA

injection

SDrats

Decreased


Redu

cednN

OSactiv

ation

[65]


Table2Con

tinued

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

02505and

1120583gmLfor2

4hRA

W2647cells

InhibitedNOprod

uctio

nRe

ducediN

OSandCO

X-2expressio

n[66]

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

4-HBA

110and

100120583

gmL

50100and

200n

MBV

-2cells

InhibitedJN

KandNF-120581Bsig

nalin

gpathways

InhibitedNOandiN

OS

[18]

4-HBA


l4-HBA



-1apo

ptosissig

nal-regulatingk

inase-1Ca

MKI

ICa2+calmod

ulin-dependent

kinaseIIC

OX-

2cyclo

oxygenase-2CU

Schronicun

predictablestr

essEF

ME

etherfractionof

methano

lextractE

RKextracellu

lars

ignal-regulated

kinaseG

ABA

-Tgam

maam

inob

utyricacid


decarboxylase

GE

Gastro

diaela

taG

REE

Gastro

diaela

tarhizom

eethano

lextractiNOS

indu

ciblenitric

oxidesynthaseJNK

c-junN-te

rminal

kinasesKA

kainicacidL

PSlipop

olysaccharide

MAPK

mito

gen-activ

ated

proteinkinaseM

CAOm

iddlecerebralartery

occlu

sion

MDAm

alon

dialdehydeM

MP

mito

chon

drialm

embranepo

tentialnN

OS

neuron


On

itricoxidePT


OSreactiv

eoxygenspeciesSO

Dsup

eroxided


emialdehyded

ehydrogenaseSSA


eductase










Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +


P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)





SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















elsu

sedto

identifythee

ffectso

fGastro

diaela

ta(G

E)andits

compo

nentso

nneurod

egeneratived

isorders

Mod

elIndu

cer

Extracts

compo

nents

Doserouteregimen

Animalor

cell

Major

finding

Reference

Seizure

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Seizureo

nsettim

euarrSeizured

urationdarr

[29]

KAEF

MEof

GE

200or

500m

gkgpo14

days

before

and4days

after

KAinjection

ICRmice

Onsettim

eofn

eurobehavioral

changeuarr

Severityof

convulsio

nsdarr

Hippo

campaln

euronald

amagedarr

[25]

KAGErhizom

emdashethano

lextract

05or

10gkgpo30

min

before

KAinjection

SDrats

Seizureo

nsettim

euarrSeizure-lik

ebehaviordarr

[24]

KAGErhizom

emdashaqueou

sextract

05or

10gkgpo1w

eekbefore

or2

weeks

after

KAinjection

SDrats

Threetypes

ofseizure(wetdo

gshakespaw

tremorand

facial

myoclo

nia)darr

[26]

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Seizurer

ecoverytim

edarrSeizures

everitydarr

[30]

Ischem

ia

Hypoxia

Gastro

din

25ndash100120583gmL

Ratcortic

alneuron


[42]

MCA

OGastro

din

50mgkgip10min

before

MCA

OSD

rats

Infarctvolum


Aminoacidsuarr

[41]

MCA

OGastro

din

50or

100m

gkgipattheo

nsetof

MCA

OSD

rats

Infarctvolum

edarrEd

emav

olum

edarr[40]

Transie

ntglob

alisc

hemia

EFMEof

GErhizom

e200or

500m

gkgpo14

days

before

brainisc

hemia

Mon

goliangerbils

Neuronald

amagein

hipp

ocam

palC

A1darr

[39]

Transie

ntglob

alisc

hemia

Vanillin

4-HBA

Land4-HBA

40mgkgip30

min

before

andaft

erisc

hemia

Mon

goliangerbils

Neuronalsurvivalin

hipp

ocam

palC

A1uarr

[38]

Alzh

eimerrsquosdisease

A120573(1ndash

42)

GErhizom

emdashchloroform

extract

20120583gmLfor2

4hPC

12andprim

aryneuron

alcells


[45]

A120573(1ndash

42)

GErhizom

emdashmethano

lextractgastrodin

and4-HBA

10120583gmLfor4

8hBV

2mou

semicroglialcell

Cellviabilityuarr

[48]

A120573(25ndash35)

GErhizom

epow

der

500or

1000

mgkgpofor5

2days

Wistar

rats

Amyloiddepo

sitsdarr

Spatialm

emoryuarr

Cholinea

cetyltransfe

raseuarr

[47]

Parkinsonrsquos

disease

MPP+

Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Cellviabilityuarr

Oxidativ

estre

ssdarr

[54]

MPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

Cellviabilityuarr

Cytotoxicitydarr

[53]

MPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

Cellviabilityuarr

Cytotoxicitydarr

[55]

MPT

PMPP+

Gastro

din

1030and60

mgkgpofor15days

15and25120583M4

hpriortoMPP+

expo

sure

C57B

L6m

ice

SH-SY5

Ycells

Bradykinesiadarr

Motor

impairm

entdarr

Cellviabilityuarr

[52]

4-HBA


l4-HBA


pamineEF

ME

etherfractionof

methano

lextractG

EGastro

diaela

taICR

Instituteo

fCancerR

esearch

KAkainic

acidL-D

OPA

L-34-dihydroxyph

enylalanineMCA

Om

iddlec

erebralarteryo

cclusio

nMPP+1-m

ethyl-4

-phenylpyridiniumM

PTP1-m

ethyl-4

-phenyl-1236-te

trahydropyrid

inePC

pheochrom

ocytom

aPT


Daw

ley


Days 0 1 2 3

Seizure scoring

minus1

TMT (26 mgkg ip)


(a)


Seiz

ure s

core

0

1

2

3

4

5


(ii) Weak tremor



(v) Death

lowast

lowast

lowast

1 2 3


(b)








Hilus

GCL

TMT

GCL

Hilus

0

20

40

60

80

100

120

140

160

Num

ber o

f con

dens

ed n

ucle

iTMT

TMT + vanillin

TMT + vanillin

P lt 001 (n = 10)











Table2Ph


GEandits

compo

nentso

nneurod

egeneration

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Neurotransm

ission

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Recovery

ofbrainGABA

contents

[30]

Neurotransm

ission

Stroking

ofthe

back

Gastro

din

60mgkgpofor1

week

Mon

goliangerbils

Decreased

GABA

-Tim

mun

oreactivity

Decreased

SSADHSSA

Rim

mun

oreactivity

[57]

Neurotransm

ission

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Attenu

ationof

cocaine-indu

cedseizurev

iaGABA

Abut

notG

ABA

Breceptor

activ

ation

[29]

Neurotransm

ission

Pentob

arbital

GErhizom

emdashethano

lextract

2550and100m

gkgpo1h

before

pentob

arbitalinjectio

nICRmiceprim

arycultu

reof

cerebellarg

ranu

lecells

Prolon

gedtotalsleep

time

Redu

cedsle

eplatency

IncreasedGADandGABA

Areceptor

subtype

expressio

n[58]

Neurotransm

ission

andantio

xidatio

nTransie

ntglob

alisc

hemia

Vanillin

4-HBA

Land

4-HBA

40mgkgsc30m

inbefore

and

30min369and

24haft

erisc

hemia

0016008042and

10120583Mfor

2h

Mon

goliangerbilsP

C12

cells

Dow

nregulated

8-OHdG

immun

oreactivity

IncreasedGABA

-Tin

thee

arlysta

geaft

erisc

hemia

Antioxidant

activ

ityon

lipid

peroxidatio

n[38]

Antioxidatio

nGlutamate

Gastro

din

011and10120583M

PC12

cells

InhibitedRO

Sprod

uctio

nInhibitedMDAM

MPandSO

Dlevels

Blockedglutam

ate-indu

ced[Ca2+]Iinflu

xBlockedCa

MKI

IASK

-1and

phosph

orylation

ofMAPK

[59]

Antioxidatio

nMPP

+Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Decreased

ROSprod

uctio

nIndu

cedHO-1expressio

nthroug

hp38

MAPK

Nrf2

signalin

gpathway

[54]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[53]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[55]

Antioxidatio

nA120573(25ndash35)

GErhizom

emdashaqueou

sextract

20120583Mfor

48h

PC12

cells

Decreased

ROSprod

uctio

nUpregulated

enzymaticactiv

ities

ofcatalase

SODand

glutathion

eperoxidase

[60]

Antioxidatio

nMCA

OGErhizom

emdashaqueou

sextract

4-HBA

500m

gkgip

25mgkgip3days

priortoMCA

OSD

rats

Increasedlevelsof

genesrela

tedto

antio

xidant

syste

m(protein

disulfide

isomerasea

nd1-C

ysperoxiredo

xin)

[61]

Anti-infl

ammation

CUS

Gastro

din

50100and

200m

gkgipfor14days

51020and50120583gmL

SDrats

Prim

aryhipp

ocam

palcells

Upregulated

neuralste

mcellproliferatio

nRe


[62]

Anti-infl

ammation

LPS

Gastro

din


Sexpo

sure

BV-2

cells

Decreased

levelsof

proinfl

ammatoryenzymes

(iNOSCO

X-2)

andproinfl

ammatory

cytokines(TN

F-120572IL-1120573)

Redu

cedph

osph

orylationof

ERK1

2JNK

p38

MAPK

and

CREB

[63]

Anti-infl

ammation

Roteno

neGastro

din

02g

kgpo

Wistar

rats

Supp

ressed


Redu


n[64]

Anti-infl

ammation

KAGErhizom

emdashethano

lextract

051gkgpo30m

inpriortoKA

injection

SDrats

Decreased


Redu

cednN

OSactiv

ation

[65]


Table2Con

tinued

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

02505and

1120583gmLfor2

4hRA

W2647cells

InhibitedNOprod

uctio

nRe

ducediN

OSandCO

X-2expressio

n[66]

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

4-HBA

110and

100120583

gmL

50100and

200n

MBV

-2cells

InhibitedJN

KandNF-120581Bsig

nalin

gpathways

InhibitedNOandiN

OS

[18]

4-HBA


l4-HBA



-1apo

ptosissig

nal-regulatingk

inase-1Ca

MKI

ICa2+calmod

ulin-dependent

kinaseIIC

OX-

2cyclo

oxygenase-2CU

Schronicun

predictablestr

essEF

ME

etherfractionof

methano

lextractE

RKextracellu

lars

ignal-regulated

kinaseG

ABA

-Tgam

maam

inob

utyricacid


decarboxylase

GE

Gastro

diaela

taG

REE

Gastro

diaela

tarhizom

eethano

lextractiNOS

indu

ciblenitric

oxidesynthaseJNK

c-junN-te

rminal

kinasesKA

kainicacidL

PSlipop

olysaccharide

MAPK

mito

gen-activ

ated

proteinkinaseM

CAOm

iddlecerebralartery

occlu

sion

MDAm

alon

dialdehydeM

MP

mito

chon

drialm

embranepo

tentialnN

OS

neuron


On

itricoxidePT


OSreactiv

eoxygenspeciesSO

Dsup

eroxided


emialdehyded

ehydrogenaseSSA


eductase










Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +


P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)





SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Days 0 1 2 3

Seizure scoring

minus1

TMT (26 mgkg ip)


(a)


Seiz

ure s

core

0

1

2

3

4

5


(ii) Weak tremor



(v) Death

lowast

lowast

lowast

1 2 3


(b)








Hilus

GCL

TMT

GCL

Hilus

0

20

40

60

80

100

120

140

160

Num

ber o

f con

dens

ed n

ucle

iTMT

TMT + vanillin

TMT + vanillin

P lt 001 (n = 10)











Table2Ph


GEandits

compo

nentso

nneurod

egeneration

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Neurotransm

ission

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Recovery

ofbrainGABA

contents

[30]

Neurotransm

ission

Stroking

ofthe

back

Gastro

din

60mgkgpofor1

week

Mon

goliangerbils

Decreased

GABA

-Tim

mun

oreactivity

Decreased

SSADHSSA

Rim

mun

oreactivity

[57]

Neurotransm

ission

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Attenu

ationof

cocaine-indu

cedseizurev

iaGABA

Abut

notG

ABA

Breceptor

activ

ation

[29]

Neurotransm

ission

Pentob

arbital

GErhizom

emdashethano

lextract

2550and100m

gkgpo1h

before

pentob

arbitalinjectio

nICRmiceprim

arycultu

reof

cerebellarg

ranu

lecells

Prolon

gedtotalsleep

time

Redu

cedsle

eplatency

IncreasedGADandGABA

Areceptor

subtype

expressio

n[58]

Neurotransm

ission

andantio

xidatio

nTransie

ntglob

alisc

hemia

Vanillin

4-HBA

Land

4-HBA

40mgkgsc30m

inbefore

and

30min369and

24haft

erisc

hemia

0016008042and

10120583Mfor

2h

Mon

goliangerbilsP

C12

cells

Dow

nregulated

8-OHdG

immun

oreactivity

IncreasedGABA

-Tin

thee

arlysta

geaft

erisc

hemia

Antioxidant

activ

ityon

lipid

peroxidatio

n[38]

Antioxidatio

nGlutamate

Gastro

din

011and10120583M

PC12

cells

InhibitedRO

Sprod

uctio

nInhibitedMDAM

MPandSO

Dlevels

Blockedglutam

ate-indu

ced[Ca2+]Iinflu

xBlockedCa

MKI

IASK

-1and

phosph

orylation

ofMAPK

[59]

Antioxidatio

nMPP

+Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Decreased

ROSprod

uctio

nIndu

cedHO-1expressio

nthroug

hp38

MAPK

Nrf2

signalin

gpathway

[54]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[53]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[55]

Antioxidatio

nA120573(25ndash35)

GErhizom

emdashaqueou

sextract

20120583Mfor

48h

PC12

cells

Decreased

ROSprod

uctio

nUpregulated

enzymaticactiv

ities

ofcatalase

SODand

glutathion

eperoxidase

[60]

Antioxidatio

nMCA

OGErhizom

emdashaqueou

sextract

4-HBA

500m

gkgip

25mgkgip3days

priortoMCA

OSD

rats

Increasedlevelsof

genesrela

tedto

antio

xidant

syste

m(protein

disulfide

isomerasea

nd1-C

ysperoxiredo

xin)

[61]

Anti-infl

ammation

CUS

Gastro

din

50100and

200m

gkgipfor14days

51020and50120583gmL

SDrats

Prim

aryhipp

ocam

palcells

Upregulated

neuralste

mcellproliferatio

nRe


[62]

Anti-infl

ammation

LPS

Gastro

din


Sexpo

sure

BV-2

cells

Decreased

levelsof

proinfl

ammatoryenzymes

(iNOSCO

X-2)

andproinfl

ammatory

cytokines(TN

F-120572IL-1120573)

Redu

cedph

osph

orylationof

ERK1

2JNK

p38

MAPK

and

CREB

[63]

Anti-infl

ammation

Roteno

neGastro

din

02g

kgpo

Wistar

rats

Supp

ressed


Redu


n[64]

Anti-infl

ammation

KAGErhizom

emdashethano

lextract

051gkgpo30m

inpriortoKA

injection

SDrats

Decreased


Redu

cednN

OSactiv

ation

[65]


Table2Con

tinued

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

02505and

1120583gmLfor2

4hRA

W2647cells

InhibitedNOprod

uctio

nRe

ducediN

OSandCO

X-2expressio

n[66]

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

4-HBA

110and

100120583

gmL

50100and

200n

MBV

-2cells

InhibitedJN

KandNF-120581Bsig

nalin

gpathways

InhibitedNOandiN

OS

[18]

4-HBA


l4-HBA



-1apo

ptosissig

nal-regulatingk

inase-1Ca

MKI

ICa2+calmod

ulin-dependent

kinaseIIC

OX-

2cyclo

oxygenase-2CU

Schronicun

predictablestr

essEF

ME

etherfractionof

methano

lextractE

RKextracellu

lars

ignal-regulated

kinaseG

ABA

-Tgam

maam

inob

utyricacid


decarboxylase

GE

Gastro

diaela

taG

REE

Gastro

diaela

tarhizom

eethano

lextractiNOS

indu

ciblenitric

oxidesynthaseJNK

c-junN-te

rminal

kinasesKA

kainicacidL

PSlipop

olysaccharide

MAPK

mito

gen-activ

ated

proteinkinaseM

CAOm

iddlecerebralartery

occlu

sion

MDAm

alon

dialdehydeM

MP

mito

chon

drialm

embranepo

tentialnN

OS

neuron


On

itricoxidePT


OSreactiv

eoxygenspeciesSO

Dsup

eroxided


emialdehyded

ehydrogenaseSSA


eductase










Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +


P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)





SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Hilus

GCL

TMT

GCL

Hilus

0

20

40

60

80

100

120

140

160

Num

ber o

f con

dens

ed n

ucle

iTMT

TMT + vanillin

TMT + vanillin

P lt 001 (n = 10)











Table2Ph


GEandits

compo

nentso

nneurod

egeneration

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Neurotransm

ission

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Recovery

ofbrainGABA

contents

[30]

Neurotransm

ission

Stroking

ofthe

back

Gastro

din

60mgkgpofor1

week

Mon

goliangerbils

Decreased

GABA

-Tim

mun

oreactivity

Decreased

SSADHSSA

Rim

mun

oreactivity

[57]

Neurotransm

ission

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Attenu

ationof

cocaine-indu

cedseizurev

iaGABA

Abut

notG

ABA

Breceptor

activ

ation

[29]

Neurotransm

ission

Pentob

arbital

GErhizom

emdashethano

lextract

2550and100m

gkgpo1h

before

pentob

arbitalinjectio

nICRmiceprim

arycultu

reof

cerebellarg

ranu

lecells

Prolon

gedtotalsleep

time

Redu

cedsle

eplatency

IncreasedGADandGABA

Areceptor

subtype

expressio

n[58]

Neurotransm

ission

andantio

xidatio

nTransie

ntglob

alisc

hemia

Vanillin

4-HBA

Land

4-HBA

40mgkgsc30m

inbefore

and

30min369and

24haft

erisc

hemia

0016008042and

10120583Mfor

2h

Mon

goliangerbilsP

C12

cells

Dow

nregulated

8-OHdG

immun

oreactivity

IncreasedGABA

-Tin

thee

arlysta

geaft

erisc

hemia

Antioxidant

activ

ityon

lipid

peroxidatio

n[38]

Antioxidatio

nGlutamate

Gastro

din

011and10120583M

PC12

cells

InhibitedRO

Sprod

uctio

nInhibitedMDAM

MPandSO

Dlevels

Blockedglutam

ate-indu

ced[Ca2+]Iinflu

xBlockedCa

MKI

IASK

-1and

phosph

orylation

ofMAPK

[59]

Antioxidatio

nMPP

+Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Decreased

ROSprod

uctio

nIndu

cedHO-1expressio

nthroug

hp38

MAPK

Nrf2

signalin

gpathway

[54]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[53]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[55]

Antioxidatio

nA120573(25ndash35)

GErhizom

emdashaqueou

sextract

20120583Mfor

48h

PC12

cells

Decreased

ROSprod

uctio

nUpregulated

enzymaticactiv

ities

ofcatalase

SODand

glutathion

eperoxidase

[60]

Antioxidatio

nMCA

OGErhizom

emdashaqueou

sextract

4-HBA

500m

gkgip

25mgkgip3days

priortoMCA

OSD

rats

Increasedlevelsof

genesrela

tedto

antio

xidant

syste

m(protein

disulfide

isomerasea

nd1-C

ysperoxiredo

xin)

[61]

Anti-infl

ammation

CUS

Gastro

din

50100and

200m

gkgipfor14days

51020and50120583gmL

SDrats

Prim

aryhipp

ocam

palcells

Upregulated

neuralste

mcellproliferatio

nRe


[62]

Anti-infl

ammation

LPS

Gastro

din


Sexpo

sure

BV-2

cells

Decreased

levelsof

proinfl

ammatoryenzymes

(iNOSCO

X-2)

andproinfl

ammatory

cytokines(TN

F-120572IL-1120573)

Redu

cedph

osph

orylationof

ERK1

2JNK

p38

MAPK

and

CREB

[63]

Anti-infl

ammation

Roteno

neGastro

din

02g

kgpo

Wistar

rats

Supp

ressed


Redu


n[64]

Anti-infl

ammation

KAGErhizom

emdashethano

lextract

051gkgpo30m

inpriortoKA

injection

SDrats

Decreased


Redu

cednN

OSactiv

ation

[65]


Table2Con

tinued

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

02505and

1120583gmLfor2

4hRA

W2647cells

InhibitedNOprod

uctio

nRe

ducediN

OSandCO

X-2expressio

n[66]

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

4-HBA

110and

100120583

gmL

50100and

200n

MBV

-2cells

InhibitedJN

KandNF-120581Bsig

nalin

gpathways

InhibitedNOandiN

OS

[18]

4-HBA


l4-HBA



-1apo

ptosissig

nal-regulatingk

inase-1Ca

MKI

ICa2+calmod

ulin-dependent

kinaseIIC

OX-

2cyclo

oxygenase-2CU

Schronicun

predictablestr

essEF

ME

etherfractionof

methano

lextractE

RKextracellu

lars

ignal-regulated

kinaseG

ABA

-Tgam

maam

inob

utyricacid


decarboxylase

GE

Gastro

diaela

taG

REE

Gastro

diaela

tarhizom

eethano

lextractiNOS

indu

ciblenitric

oxidesynthaseJNK

c-junN-te

rminal

kinasesKA

kainicacidL

PSlipop

olysaccharide

MAPK

mito

gen-activ

ated

proteinkinaseM

CAOm

iddlecerebralartery

occlu

sion

MDAm

alon

dialdehydeM

MP

mito

chon

drialm

embranepo

tentialnN

OS

neuron


On

itricoxidePT


OSreactiv

eoxygenspeciesSO

Dsup

eroxided


emialdehyded

ehydrogenaseSSA


eductase










Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +


P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)





SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table2Ph


GEandits

compo

nentso

nneurod

egeneration

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Neurotransm

ission

PTZ

EFMEof

GErhizom

e500m

gkgpofor10days

SDrats

Recovery

ofbrainGABA

contents

[30]

Neurotransm

ission

Stroking

ofthe

back

Gastro

din

60mgkgpofor1

week

Mon

goliangerbils

Decreased

GABA

-Tim

mun

oreactivity

Decreased

SSADHSSA

Rim

mun

oreactivity

[57]

Neurotransm

ission

Cocaine

GErhizom

emdashmethano

lextract

500or

1000

mgkgpo5tim

esevery

12hbefore

cocainetreatment

C57B

L6Jmice

Attenu

ationof

cocaine-indu

cedseizurev

iaGABA

Abut

notG

ABA

Breceptor

activ

ation

[29]

Neurotransm

ission

Pentob

arbital

GErhizom

emdashethano

lextract

2550and100m

gkgpo1h

before

pentob

arbitalinjectio

nICRmiceprim

arycultu

reof

cerebellarg

ranu

lecells

Prolon

gedtotalsleep

time

Redu

cedsle

eplatency

IncreasedGADandGABA

Areceptor

subtype

expressio

n[58]

Neurotransm

ission

andantio

xidatio

nTransie

ntglob

alisc

hemia

Vanillin

4-HBA

Land

4-HBA

40mgkgsc30m

inbefore

and

30min369and

24haft

erisc

hemia

0016008042and

10120583Mfor

2h

Mon

goliangerbilsP

C12

cells

Dow

nregulated

8-OHdG

immun

oreactivity

IncreasedGABA

-Tin

thee

arlysta

geaft

erisc

hemia

Antioxidant

activ

ityon

lipid

peroxidatio

n[38]

Antioxidatio

nGlutamate

Gastro

din

011and10120583M

PC12

cells

InhibitedRO

Sprod

uctio

nInhibitedMDAM

MPandSO

Dlevels

Blockedglutam

ate-indu

ced[Ca2+]Iinflu

xBlockedCa

MKI

IASK

-1and

phosph

orylation

ofMAPK

[59]

Antioxidatio

nMPP

+Gastro

din

15and25120583M4

hpriortoMPP+

expo

sure

SH-SY5

Ycells

Decreased

ROSprod

uctio

nIndu

cedHO-1expressio

nthroug

hp38

MAPK

Nrf2

signalin

gpathway

[54]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

10100and

200120583

gmL4h

priorto

MPP+expo

sure

SH-SY5

Ycells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[53]

Antioxidatio

nMPP+

GErhizom

emdashethano

lextract

Vanillylalcoh

ol10100and

200120583

gmL

110and

100120583

MMN9D

cells

InhibitedRO

Sprod

uctio

nInhibitedBa

xBc

l-2ratio

cleaved

caspase-3

andPA

RPproteolysis

[55]

Antioxidatio

nA120573(25ndash35)

GErhizom

emdashaqueou

sextract

20120583Mfor

48h

PC12

cells

Decreased

ROSprod

uctio

nUpregulated

enzymaticactiv

ities

ofcatalase

SODand

glutathion

eperoxidase

[60]

Antioxidatio

nMCA

OGErhizom

emdashaqueou

sextract

4-HBA

500m

gkgip

25mgkgip3days

priortoMCA

OSD

rats

Increasedlevelsof

genesrela

tedto

antio

xidant

syste

m(protein

disulfide

isomerasea

nd1-C

ysperoxiredo

xin)

[61]

Anti-infl

ammation

CUS

Gastro

din

50100and

200m

gkgipfor14days

51020and50120583gmL

SDrats

Prim

aryhipp

ocam

palcells

Upregulated

neuralste

mcellproliferatio

nRe


[62]

Anti-infl

ammation

LPS

Gastro

din


Sexpo

sure

BV-2

cells

Decreased

levelsof

proinfl

ammatoryenzymes

(iNOSCO

X-2)

andproinfl

ammatory

cytokines(TN

F-120572IL-1120573)

Redu

cedph

osph

orylationof

ERK1

2JNK

p38

MAPK

and

CREB

[63]

Anti-infl

ammation

Roteno

neGastro

din

02g

kgpo

Wistar

rats

Supp

ressed


Redu


n[64]

Anti-infl

ammation

KAGErhizom

emdashethano

lextract

051gkgpo30m

inpriortoKA

injection

SDrats

Decreased


Redu

cednN

OSactiv

ation

[65]


Table2Con

tinued

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

02505and

1120583gmLfor2

4hRA

W2647cells

InhibitedNOprod

uctio

nRe

ducediN

OSandCO

X-2expressio

n[66]

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

4-HBA

110and

100120583

gmL

50100and

200n

MBV

-2cells

InhibitedJN

KandNF-120581Bsig

nalin

gpathways

InhibitedNOandiN

OS

[18]

4-HBA


l4-HBA



-1apo

ptosissig

nal-regulatingk

inase-1Ca

MKI

ICa2+calmod

ulin-dependent

kinaseIIC

OX-

2cyclo

oxygenase-2CU

Schronicun

predictablestr

essEF

ME

etherfractionof

methano

lextractE

RKextracellu

lars

ignal-regulated

kinaseG

ABA

-Tgam

maam

inob

utyricacid


decarboxylase

GE

Gastro

diaela

taG

REE

Gastro

diaela

tarhizom

eethano

lextractiNOS

indu

ciblenitric

oxidesynthaseJNK

c-junN-te

rminal

kinasesKA

kainicacidL

PSlipop

olysaccharide

MAPK

mito

gen-activ

ated

proteinkinaseM

CAOm

iddlecerebralartery

occlu

sion

MDAm

alon

dialdehydeM

MP

mito

chon

drialm

embranepo

tentialnN

OS

neuron


On

itricoxidePT


OSreactiv

eoxygenspeciesSO

Dsup

eroxided


emialdehyded

ehydrogenaseSSA


eductase










Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +


P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)





SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table2Con

tinued

Targetpathway

Indu

cer(s)

Extracts

compo

nents

Doserouteregimen

Animalso

rcells


nRe

ferences

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

02505and

1120583gmLfor2

4hRA

W2647cells

InhibitedNOprod

uctio

nRe

ducediN

OSandCO

X-2expressio

n[66]

Anti-infl

ammation

andantio

xidatio

nLP

SGErhizom

emdashethano

lextract

4-HBA

110and

100120583

gmL

50100and

200n

MBV

-2cells

InhibitedJN

KandNF-120581Bsig

nalin

gpathways

InhibitedNOandiN

OS

[18]

4-HBA


l4-HBA



-1apo

ptosissig

nal-regulatingk

inase-1Ca

MKI

ICa2+calmod

ulin-dependent

kinaseIIC

OX-

2cyclo

oxygenase-2CU

Schronicun

predictablestr

essEF

ME

etherfractionof

methano

lextractE

RKextracellu

lars

ignal-regulated

kinaseG

ABA

-Tgam

maam

inob

utyricacid


decarboxylase

GE

Gastro

diaela

taG

REE

Gastro

diaela

tarhizom

eethano

lextractiNOS

indu

ciblenitric

oxidesynthaseJNK

c-junN-te

rminal

kinasesKA

kainicacidL

PSlipop

olysaccharide

MAPK

mito

gen-activ

ated

proteinkinaseM

CAOm

iddlecerebralartery

occlu

sion

MDAm

alon

dialdehydeM

MP

mito

chon

drialm

embranepo

tentialnN

OS

neuron


On

itricoxidePT


OSreactiv

eoxygenspeciesSO

Dsup

eroxided


emialdehyded

ehydrogenaseSSA


eductase










Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +


P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)





SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























Iba1

0

05

1

15

2

25

3

35

Fold

incr

ease

120573-actin

Control

Control

Vanillin TMT TMT +


P lt 001P lt 001

vanillin

(a)CA1DG CA3

HilusCA3

CA1

DG

Control

Vanillin

TMT

HilusCA3

CA1

DG

HilusCA3

CA1

DG

HilusCA3

CA1

DG

TMT +

vanillin

(b)





SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















SSADH


GABA

Glutamate

SSA GABA-TGABA

vesicle


nNOS

NO

MAPK CaMKII ASK-1

Bax caspase-3

Oxidative stress

Presynaptic

Postsynaptic

iNOSCOX-2

Neuron



MAPK

HO-1

Catalase

GAD

GABAA receptor

[Ca2+]I

OH∙

IL-1120573TNF-120572

activation

H2O2

SOD

Downregulation of

Microglial


Synaptic

NF-120581B



4 Conclusion






Acknowledgments


References




















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article neuropharmacological potential of gastrodia elata...

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