Natural Compounds for the Management of Parkinson’s...

Review ArticleNatural Compounds for the Management of ParkinsonrsquosDisease and Attention-DeficitHyperactivity Disorder

Juan Carlos Corona

Laboratory of Neurosciences Hospital Infantil de Mexico Federico Gomez Mexico

Correspondence should be addressed to Juan Carlos Corona jcoronahimfgedumx

Received 28 June 2018 Revised 31 October 2018 Accepted 11 November 2018 Published 22 November 2018

Guest Editor Francesco Facchiano

Copyright copy 2018 Juan Carlos CoronaThis 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

Parkinsonrsquos disease (PD) is the second most common neurodegenerative disorder with an unknown aetiology The pathogenicmechanisms include oxidative stress mitochondrial dysfunction protein dysfunction inflammation autophagy apoptosis andabnormal deposition of 120572-synuclein Currently the existing pharmacological treatments for PD cannot improve fundamentally thedegenerative process of dopaminergic neurons and have numerous side effects On the other hand attention-deficithyperactivitydisorder (ADHD) is the most common neurodevelopmental disorder of childhood and is characterised by hyperactivity impulsiv-ity and inattention The aetiology of ADHD remains unknown although it has been suggested that its pathophysiology involvesabnormalities in several brain regions disturbances of the catecholaminergic pathway and oxidative stress Psychostimulants andnonpsychostimulants are the drugs prescribed for the treatment of ADHD however they have been associated with increased riskof substance use and have several side effects Today there are very few tools available to prevent or to counteract the progressionof such neurological disorders Thus therapeutic approaches with high efficiency and fewer side effects are needed This reviewpresents a brief overview of the two neurological disorders and their current treatments followed by a discussion of the naturalcompounds which have been studied as therapeutic agents and the mechanisms underlying the beneficial effects in particular thedecrease in oxidative stress

1 Introduction

For many years natural compounds have provided an effi-cient resource for the discovery of potential therapeuticagents Among them many natural products possess antiox-idative antiapoptotic and anti-inflammatory activities In thisreview we summarize the role of natural compounds andtheir therapeutic use for the management of dopamine-related diseases divided into part 1 for Parkinsonrsquos disease andpart 2 for attention-deficithyperactivity disorder In addi-tion the current knowledge of the mechanisms underlyingthe potential beneficial effects of diverse natural compoundscapable of counteracting the progression of this type of dis-eases is reviewed as demonstrated by their antioxidativeeffects

2 Parkinsonrsquos Disease

Parkinsonrsquos disease (PD) is the second most commonprogressive and chronic neurodegenerative disorder

characterised by the progressive loss of dopaminergicneurons in the substantia nigra (SN) and their projections tothe striatum Thus the function of the nigrostriatal pathwaybecomes reduced and causes the development of movementdisorder [1] The basic characteristics of PD include tremorrigidity bradykinesia and impaired balance depression isalso present in patients affecting the quality of life Oneof the pathological features of PD is the presence of Lewybodies which are intraneuronal proteinaceous cytoplasmicinclusions and include 120572-synuclein ubiquitin and neuro-filaments found in all affected brain regions [2] Thepathogenic mechanisms of PD include oxidative stressmitochondrial dysfunction protein dysfunction inflam-mation autophagy and apoptosis [3] PD occurs 95 asa sporadic form while familial forms involve mutations inproteins that include PINK1 DJ-1 PARKIN FBXO7 andLRRK2 [4] even though pesticides chemicals and metalsmay increase the risk of developing PD Currently thetreatment of PD includes drugs such as L-DOPA which iscatalysed primarily by dopa decarboxylase in the brain and is

HindawiBioMed Research InternationalVolume 2018 Article ID 4067597 12 pageshttpsdoiorg10115520184067597

2 BioMed Research International

converted into dopamine producing its therapeutic effectsAnother treatment includes anticholinergic drugs that canblock striatal cholinergic receptors inhibiting the excitabilityof cholinergic nerves it has also been demonstrated thatthey can inhibit dopamine reuptake to enhance the functionof dopaminergic neurons [5] At present there are alsoother drugs in Phase III clinical trials Nevertheless thecurrent drugs used for the PD treatment have some sideeffects limiting their clinical applications [6] Drugs usedfor the PD treatment and their side effects are shown inTable 1 Thus the growing interest in alternative therapiesfor neurodegenerative disorders including PD has focusedon the neuroprotective and antioxidant effects of naturalproducts that may provide alternatives since they can havehigh efficiency and fewer side effects Natural compoundsused as alternative therapies for the management of PD areshown in Table 2

21 Ginkgo biloba Ginkgo biloba is an ancient tree native toChina and has been extensively used in traditional Chinesemedicine to manage symptoms associated with dysfunctionsof the heart and lungs G biloba usually contains three ingre-dients which include flavonoids terpenoids and ginkgolicacid [81] Ginkgolides well-known plant extracts obtainedfrom leaves from G biloba especially in the preparationEGb761 which contains ginkgolide B and bilobalide haveemerged as natural therapeutic compounds in part due totheir antioxidant activity These effects have been observed inthe 1-methyl-4-phenyl-1236-tetrahydropyridine- (MPTP-)treated mouse model of PD where chronic ingestion ofEGb761 preventedMPTP-induced reduction in the dopamin-ergic nerve endings [9] In addition EGb761 administeredbefore or after MPTP treatment protected against MPTP-induced dopaminergic neurotoxicity [10] Moreover EGb761attenuated the neurotoxic effect of levodopa in the 6-hydroxydopamine (6-OHDA) model of PD indicated thatlevodopa is neurotoxic and that EGb761 may decrease thistoxicity [11] The neuroprotective effects of EGb761 weredemonstrated in the 6-OHDA rat model as indicated by thereduction in the behavioural deficit in the rat [12] Paraquat isa pesticide that has been linked to PD and it has been demon-strated that EGb761 protects against paraquat-induced apop-tosis of PC12 cells by increasing bcl-2 activation maintainingofmitochondrial membrane potential ( Ψm) and decreasingcaspase-3 activation through the mitochondria-dependentpathway [13] The neuroprotective effect of EGb761 againstMPTP neurotoxicity is associated with the blockade of lipidperoxidation reduction of oxidative stress and attenuation ofMPTP-induced neurodegeneration of the nigrostriatal path-way [14] Also it was demonstrated in an extensive review thatEGb761 may exert therapeutic actions in an animal modelof PD via the antioxidant effects [82] Ginkgetin a naturalbiflavonoid isolated from leaves of G biloba protectedagainst 1-methyl-4-phenylpyridinium ion- (MPP+-) inducedcell damage in vitro by decreasing the levels of intracellularreactive oxygen species (ROS) and by maintaining Ψmand also improved the sensorimotor coordination in amousePD model induced by MPTP suggesting that the neuro-protective mechanism of ginkgetin occurs via regulating

iron homeostasis [16] In low-dose whole-body 120574-irradiationin the reserpine model of PD EGb761 was protective byameliorating the reserpine-induced state of oxidative stressmitochondrial dysfunction and apoptosis in the brain [15]The pretreatment with ginkgolide B or bilobalide protectedSH-SY5Y cells against 120572-synuclein-induced cell injury andapoptosis [17] Ultimately the G biloba extract treatmentimproved locomotor activity decreased oxidative damagemaintained the dopamine homeostasis and inhibited thedevelopment of PD inA53T120572-synuclein transgenicmice [18]

22 Ginseng Ginseng is a traditional Chinese herb con-taining more than 30 ginsenosides the active ingredientsof ginseng Ginsenosides Rb1 and Rg1 are regarded as themain compounds responsible for the therapeutic actionsof ginseng Previous studies have shown that in SN-K-SHcells both ginsenosides Rb1 and Rg1 reversedMPTP-inducedcell death [19] The protective effect of Rg1 against MPTP-induced apoptosis was attributed to enhancing Bcl-2 andBcl-xl expression reducing Bax and iNOS expression andinhibiting activation of caspase-3 [20] The ginseng extractG115 significantly blocked tyrosine hydroxylase- (TH-)positive cell loss in the SN and reduced the appearance oflocomotor dysfunction in two rodent models of PD [21]Pretreatments of Rg1 or N-acetylcysteine were found toprotect against MPTP-induced SN neuron loss by preventingglutathione (GSH) reduction attenuate the phosphorylationsof JNK and c-Jun and activate superoxide dismutase (SOD)[22] MPP+-induced cytotoxicity in SH-SY5Y was inhibitedbywater extract of ginseng as demonstrated by the inhibitoryeffect on cell death overproduction of ROS elevated BaxBcl-2 ratio release of cytochrome c and activation of caspase-3 expression [23] It was demonstrated that ginsenosidesprotect by reducing intracellular ROS levels enhancingantioxidant activity preserving the activity of complex I sta-bilising the Ψm and increasing intracellular ATP levels Rg1treatment restored motor functions in MPTP-treated miceand these behavioural ameliorations were accompanied byrestoration of dopaminergic neurons in the SN and striatum[24] Additionally the ginsenoside Rb1 exhibited a strongability to disaggregate fibrils and to inhibit the polymerisationof 120572-synuclein [25] Rg1 treatment inhibited the activation ofmicroglia and reduced the infiltration of CD3+ and T cellsand also protected TH-positive cells in the SN and reducedthe serum concentrations of proinflammatory cytokinesTNF120572 IFN120574 IL-1120573 and IL-6 in MPTP mouse models [26]Also using in vivo and in vitro models of PD it was demon-strated that ginsenoside Rg1 may exert therapeutic effects onPD via the Wnt120573-catenin signalling pathway [27] In theMPTP-probenecidmousemodel the oral treatment with Rg1significantly attenuated MPTP-induced mortality behaviourdefects and loss of dopaminergic neurons The protectiveeffect of Rg1 may be mediated by reducing aberrant 120572-synuclein-mediated neuroinflammation [28]Theneurotoxinrotenone is an inhibitor of complex I and has been widelyused in vivo and in vitro tomodel PDThus cotreatment withginsenosides Rd and Re inhibited the increased intracellularROS production and lipid peroxidation accumulation causedby rotenone Besides the major ginsenosides Rd and Re

BioMed Research International 3

Table1Drugs

used

inPD

andADHDandtheirsidee

ffects

Drugs

forP

D[7]

Mecha

nism

Side

effects

L-DOPA

and

Carbido

paAprecursortodo

paminecombinedwith

carbidop

awhich

blocks

arom

aticam

inoacid

decarboxylase

Nauseavomiting

insom

niapsycho

sishallucinatio

nshypotensio

narrhythm

iasom

nolencenigh

tmares

Selegilin

eRa

sagilin

eSafin

amide

Mon

oamineo

xidase

Binhibitors(M

AO-B)increase

thes

ynaptic

availabilityof

dopaminesafin

amidea

lsoinhibitsglutam

aterelease

Abno

rmalmovem

ents

dizzinessnauseavom

iting

dry

mou

th

persistentd

iarrho

eacon

stipatio

nwe

ight

loss

Entacapo

neand

Tolcapon

eCatecho

l-O-m

ethyltransfe

raseinhibitors(C

OMT)IncreaseC

NS

L-DOPA

bioavailabilityby

decreasin

gperip

heralL

-DOPA

metabolism

Dyskinesia

nauseasle

epdistu

rbancesarteria

lhypotensio

nliver

toxicityvom

iting

dizziness

Pram

ipexole

Ropinirole

Rotig

otine

Apom

orph

ine

Dop

aminea

gonists

stim

ulatethe

actio

nof

dopaminea

tpostsy

naptic

receptors

Nauseadyskinesiah

allucinatio

nssleepinesssle

epattacksconfusion

ankleo

edem

aorthostatic

hypo

tension

constip

ation

Trihexyphenidyl

and

Benztro

pine

Anticho

linergicsblock

acetylcholineinthes

triatum

Dry

mou

thu

riner

etentio

nhallu

cinatio

nsdry

eyescon

stipatio

nblurredvisio

nlossof

mem

oryandconfusion

somno

lencedizziness

Amantadine

Isan

antagonistof

theN

MDAtype

glutam

atereceptora

ndalso

stimulates

dopaminer

elease

Oedem

ahallu

cinatio

nsinsom

niaconfusion

Drugs

ForA

DHD

[8]

Mecha

nism

Side

effects

Methylphenidate

Inhibitsreup

take

ofdo

paminea

ndno

repineph

rine

Anx

ietyagitatio

ninsomniadecrease

appetitewe

ight

lossirritability

hypertensio

nheadachestomachpainn

umbn

ess

Amph

etam

ines

Inhibitreuptakeo

fdop

aminea

ndno

repineph

rine

Decreasea

ppetitew

eigh

tlossirr

itabilityhypertensio

nanxiety

agitatio

nnervou

snessdepressio

n

Atom

oxetine

Selectiven

orepinephriner

euptakeinh

ibito

rDry

mou

thsedation

fatig

ueincreased

sweatin

ghypertensio

ndecrease

appetitedizzinessdrow

sinessinsomniaitching

impo

tence

unusually

fastor

irregular

heartbeatincreasedsuicidality

Imipramine

Nortriptylin

eAmitriptylin

eDesipramine

Tricyclic

antid

epressants

Inhibitreuptakeo

fdop

aminea

ndno

repineph

rine

Dry

mou

thswe

atingabno

rmalitiesdrowsin

esssedatio

nincreased

suicidality

Clon

idinea

ndGuanfacine

Agonists

ofthe120572

-2and120572-2Aadrenergicreceptorsinthep

refro

ntal

cortex

Dry

mou

thfatiguedizzinessprofoun

dwith

draw

aleffects


Table2Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forP

D

Source

Com

poun

dAc

tionmecha

nism

Refs

Ginkgobiloba

EGb761

Antioxidantinh

ibitedtoxice

ffectof

levodo

painh

ibitedMAO

activ

itydarrbehaviou

raldeficit

anti-apop

totic

maintainΔΨmuarrbcl-2

darrcaspase-3darrlip

idperoxidatio

ndarroxidatives

tress

[9ndash15]

Ginkgobiloba

Ginkgetin

darrRO

SmaintainΔΨm

[16]

Ginkgobiloba

GinkgolideBand

Bilobalid

edarr120572-synucleinanti-a

poptotic

[17]

Ginkgobiloba

Ginkgobiloba

extract

uarrSO

DuarrGHSdarrmalon

dialdehyde

[18]

Ginseng

Ginseno

sides

Rb1a

ndRg

1Antioxidantanti-a

poptoticuarrbcl-2

darrBa

xdarriN

OSdarrcaspase-3uarrSO

DuarrGHSdarr120572-synuclein

fibrilsdarrTN

F-120572darrIFN-120574darrIL-1120573darrIL-6uarrWnt-1uarr120573-cateninuarrGSK

-3120573m

aintainΔΨm

darrcytochromec

release

[19ndash28]

Ginseng

Ginseno

sides

RdandRe

Antioxidantanti-a

poptoticimproved

mito

chon

drialfun

ction

[2930]

Flavon

oid

Baicalein

darrlip

idperoxidatio

nuarrserotonindarrdo

paminelevelsdarroxidatives

tressdarr120572-synuclein

aggregation

uarrDJ-1darrNF-120581BdarrER

KdarrJN

K[31ndash40

]

Flavon

oid

Luteolin

darrInflammationdarrRO

Sdarroxidatives

tress

[41ndash43]

Flavon

oid

Quercetin

AntioxidantuarrSO

DuarrGPx

darroxidatives

tressuarrAT

Paseuarrcatalaseuarrcomplex

IactivityuarrPK

D1

uarrAktuarrCR

EBuarrBD

NF

[44ndash

47]

Flavon

oid

Kaem

pferol

uarrSO

DuarrGHSdarrlip

idperoxidatio

nuarrautoph

agy

[4849]

Flavon

oid

Rutin

darroxidatives

tressuarrSO

DuarrGPx

darroxidatives

tressdarrlip

idperoxidatio

nuarrcatalase

[5051]

Flavon

oid

Isoq

uercitrin

darroxidatives

tress

[52]

Flavon

oid

Apigenin


S[4353]

Flavon

oid

Troxerutin

darrlip

idperoxidatio

ndarrRO

SdarrDNAfragmentatio

n[54]

Flavon

oid

Hesperid

inAntioxidant

[5556]

Valeria

naoffi

cinalis

Extracto

fvalerian

Normalise

dSO

Dandcatalase

mRN

As

[57]

Valeria

nawallichii

Valeria

nawallichii

darrRO

SdarrInflammationdarrlip

idperoxidatio

n[58]

Passifloraincarnata

Extracto

fpassio

nflo

wer

Antioxidant

[59]

Passiflorac

incinn

ata

Passiflorac

incinn

ata

Antioxidant

[60]

Hypericum

perfo

ratum

Extracto

fStJohn

rsquoswo

rtAntioxidantanti-a

poptoticuarrGHSuarrcatalasedarrmalon

dialdehydedarrDNAfragmentatio

n[6162]


upregulate SOD and aconitase activities and GSH alsoattenuates the depolarisation of Ψm and restores Ca2+levels and moreover prevents apoptosis by modulating Baxand Bcl-2 and inhibiting cytochrome c release and caspase-3 activation [29] Additionally ginsenoside Rd reversed theloss of TH-positive cells in SN in vivo and in vitro PDmodelswhich may involve its antioxidant effects and mitochondrialfunction preservation [30]

23 Flavonoids Flavonoids are part of a large group ofnatural polyphenol phytochemicals with a long history ofuse as therapeutic agents Baicalin a flavonoid isolated fromScutellaria baicalensis is themainmetabolite of baicaleinTheneuroprotective efficacy of baicalein has been shown in an invivo model of PD using the neurotoxin 6-OHDA where theprotective effects on dopaminergic dysfunction and lipid per-oxidation were seen [31] Other reports showed that baicaleinprevented abnormal behaviour by increasing dopaminergicneurons and dopamine and serotonin levels in the striatumand also inhibited oxidative stress and astroglial response[32] Luteolin and apigenin are flavones with similar struc-ture luteolin is found in celery broccoli parsley thyme andolive oil and apigenin is present in vegetables several fruitsand herbs Luteolin protects dopaminergic neurons againstinflammation-induced neurotoxicity by inhibiting microglialactivation [41]Moreover baicalein exerts protective effects invivo and in vitro against 6-OHDA [33] In addition baicaleinprotects cells against the toxicity of a point mutation in 120572-synuclein [34] Baicalein also inhibited the formation of 120572-synuclein oligomers and consequently prevents its oligomeri-sation [35] Quercetin is the aglycone form of a numberof other flavonoid glycosides such as rutin and quercitrinand is found in citrus fruit onions and grains In the 6-OHDA rat model treatment of quercetin increased levels ofantioxidant and striatal dopamine and reduced dopaminergicneuronal loss [44] Kaempferol is a natural flavonoid whichhas been found in grapefruit and other plant sources Itimproves motor coordination raises striatal dopamine andits metabolite levels increases SOD and GSH activity andreduces the content of lipid peroxidation also preventing theloss of TH-positive neurons induced by MPTP [48] There isalso evidence of neuroprotection by kaempferol by autophagyin SH-SY5Y cells and primary neurons against rotenonetoxicity [49] It has been demonstrated that rutin pro-tects dopaminergic neurons against oxidative stress inducedby 6-OHDA [50] Furthermore it has been shown thatquercetin protects against oxidative stress and increases activ-ities of glutathione peroxidase (GPx) SOD ATPase AchEand dopamine depletion in MPTP-treated mice [45] Thebioflavonoid rutin inhibits 6-OHDA-induced neurotoxicityin PC12 cells by activation of SOD catalase GPx and totalGSH and by inhibition of lipid peroxidation [51] Moreoverin a rotenone model quercetin has been shown to upregulatemitochondrial complex I activity and increase catalase andSOD activity [46] Mitochondrial dysfunction in SH-SY5Ycells and upregulation of DJ-1 protein expression inducedby 6-OHDA is prevented by baicalein [36] The flavonolisoquercitrin protects PC12 cells against 6-OHDA-inducedoxidative stress [52] Baicalein downregulates the activation

of NF-120581B ERK and JNK and attenuates astrocyte activationin MPTP mice [37] Baicalein inhibits the upregulationof proinflammatory cytokines in the SN and striatum inPD mice models [38] Luteolin also reduces cytotoxicityinduced by 6-OHDA and ROS production in neuronal PC12cells by modulating changes in the stress response pathway[42] In MPTP-treated mice luteolin and apigenin protectdopaminergic neurons by reducing oxidative damage neu-roinflammation and microglial activation and also improvemuscular and locomotor activity [43] The flavonoids andtheir metabolites can interact with neuronal receptors andmodulate kinase signalling pathways transcription factorsand gene andor protein expression which control memoryand learning processes in the hippocampus [83] Naringinis a flavonoid glycoside that is contained abundantly in theskin of grapefruit and orange and is the origin of theirbitterness It protects dopaminergic neurons by induction ofthe activation of mammalian target of rapamycin complex 1(mTORC1) and inhibited microglial activation in the SN ofthe mouse treated with 6-OHDA [84] In a rotenone mousemodel baicalein prevented the progression of 120572-synucleinaccumulation and protected dopaminergic neurons and alsoinhibited the formation of 120572-synuclein oligomers [39] It hasbeen shown that baicalein inhibits 120572-synuclein aggregatesand autophagy in rats treated withMPP+ [40] Besides in thesame model apigenin ameliorated dopaminergic neuronalloss and improved behavioural biochemical and mitochon-drial enzyme activities such effects were associated withthe suppression of oxidative stress and neuroinflammation[53] Recently it was demonstrated that quercetin improvedmitochondrial biogenesis and induced the activation oftwo major cell survival kinases PKD1 and Akt and alsoenhanced CREB and BDNF (a CREB target gene) in MN9Dcells against 6-OHDA-induced neurotoxicity and in theMitoPark transgenicmousemodel of PD quercetin improvedbehavioural deficits and reduced TH cell loss [47] Troxerutin(also known as vitamin P4) is a natural derivative of thebioflavonoid rutin that is present in coffee cereal grains teaand vegetables Theneuroprotective effects of troxerutin werereported in a 6-OHDA rat model to reduce striatal lipid per-oxidation ROS GFAP and DNA fragmentation Meanwhiletroxerutin was capable of preventing loss of TH-positiveneurons in the SN [54] The bioflavonoid hesperidin is aspecific flavonoid glycoside frequently found in oranges andlemons Hesperidin protects against iron-induced oxidativedamage and dopamine depletion inDrosophila melanogastermodel of PD [55] In addition in 6-OHDA-treated micehesperidin protects by reducing oxidative damage increasingthe dopamine levels and also improving the behaviouralparameters [56]

24 Valeriana officinalis Valeriana officinalis (Valerian) isa plant with sedative and antispasmodic effect traditionallyused in the treatment of insomnia anxiety and restlessnessThe effects of valerian on rotenone-induced cell death in SH-SY5Y cells have been demonstrated [85] Moreover extractof valerian was effective in reducing the toxicity induced byrotenone in Drosophila melanogaster as confirmed by thenormalisation in the expression of SOD and catalase mRNAs


suggesting that the effects of valerian are at least in partassociated with the antioxidant properties of the plant dueto its phenolic and flavonoid constituents [57] Valerianawallichii also known as Indian valerian or Tagar-Ganthodabelongs to the family Valerianaceae and is considered as animportant Asian counterpart of the European valerian Thusvaleriana wallichii treatment significantly recuperated thealtered behaviour striatal dopamine levels increased GFAPexpression and the histopathological changes observedin mice treated with MPTP Likewise it ameliorated theincreased levels of ROS inflammatory cytokines and lipidperoxidation and also ameliorated the diminished levels ofantioxidants [58]

25 Passion Flower Passion flower commonly known asPassiflora incarnata (Passifloraceae) contains flavonoids gly-cosides alkaloids and phenolic compounds Also it hasbeen used for the treatment of anxiety insomnia epilepsymuscular spasms and other diseases [86] Therefore thebiological effects of passion flower have been investigated inPDThe extract of passion flower reduced the number of jawmovements induced by tacrine which is a widely used animalmodel of PD tremors In addition the model showed cog-nitive improvement with significantly reduced duration ofhaloperidol-induced catalepsy The passion flower possessesantioxidant activity as shown by its significant scavengingability [59] Passiflora cincinnata is a Brazilian native speciesof passion flower and its possible biological effects have beeninvestigated Thus in a model of PD induced by reserpinePassiflora cincinnata extract prevented the decrease in THin the SN induced by reserpine delayed the onset of motorimpairments and prevented the occurrence of increasedcatalepsy behaviour However the extract did not modifyreserpine-induced cognitive impairments [60]

26 St Johnrsquos Wort The use of St Johnrsquos wort known asHypericum perforatum dates back to the time of the ancientGreeks Active compounds of St Johnrsquos wort have beenidentified and include naphthodianthrones phloroglucinolsand flavonoids (such as phenylpropanes flavonol glycosidesand biflavones) as well as essential oils Therefore theactive compounds provide antioxidant and neuroprotectiveeffects [87] Two standardised extracts of St Johnrsquos wort havebeen tested on the neurodegeneration induced by chronicadministration of rotenone in rats Accordingly St Johnrsquoswort reduced neuronal damage and inhibited the apoptoticcascade by decreasing Bax levels [61] Besides intrastriatal6-OHDA-lesioned rats were treated with an the extract ofSt Johnrsquos wort and showed lowered striatal level of malondi-aldehyde enhanced catalase activity reduced GSH contentnormalised expression of GFAP and TNF120572 lowered DNAfragmentation and prevention of damage to dopaminergicneurons [62]

3 Attention-DeficitHyperactivity Disorder

Attention-deficithyperactivity disorder (ADHD) is the mostcommon neurodevelopmental disorder in childhood and

is characterised by inattention impulsivity and hyperactiv-ity The worldwide prevalence of ADHD in children andadolescents is 53 [88] across cultures the prevalence isestimated to range from 5 to 7 [88 89] ADHD hashigh impact on school performance and causes impairmentsin personal social or occupational function leading toisolation poorer grades and in adolescence there is increasedrisk of depression delinquent and antisocial behaviourincurring comorbid conditions and later substance abuse[90] ADHD has been associated with deregulation of thecatecholaminergic pathway in the brain [91] although exten-sive data point to oxidative stress as potential contributorto the pathophysiology in ADHD [92] Currently ADHDtreatment is pharmacologic and improves the attentionreducing distractibility and impulsive behaviour Pharma-cologic agents used for the treatment of ADHD increaselevels of catecholamines in the brain alleviating ADHDsymptoms and can be divided into two psychostimulantsand nonpsychostimulants [93] Methylphenidate (MPH) is apsychostimulant that increases extracellular dopamine andnorepinephrine levels thereby correcting the underlyingabnormalities in catecholaminergic functions and restoringneurotransmitter imbalance [94] Atomoxetine (ATX) isa nonpsychostimulant a norepinephrine specific reuptakeinhibitor that increases catecholamine levels in the brainresulting in behavioural improvement [94 95] ADHD is aheterogeneous disorder and is categorized into three sub-types hyperactiveimpulsive inattentive and the combinedsubtype [89 90] There may be also differences in terms oftreatment responses for example the hyperactiveimpulsivesubtype responds well to MPH the inattentive subtyperesponds better to ATX and the combined type respondswell to ATX and MPH although controversy still persistsabout which is the best treatment for each subtype Howeverit has been demonstrated that the pharmacological treat-ments to improve ADHD symptoms have some side effectswhich include nausea headache insomnia abdominal paindecreased appetite and motor tics [96] Drugs used for theADHD treatment and their side effects are shown in Table 1Moreover the use of psychostimulant medications in ADHDhas been also associated with increased risk of substanceuse disorder [97] Thus there has been growing interest inalternative treatments for ADHD including natural com-pounds because of their antioxidant properties [98] Naturalcompounds used as alternative therapies for the managementof ADHD are shown in Table 3

31 Ginkgo biloba The extract fromG biloba leaves has beenused as a herbal medicine for dementia [81 99] Thereforeseveral reports indicate that G biloba may have therapeuticbenefits in ADHD given that the cotreatment with G bilobaand ginseng were found to alleviate ADHD symptoms inchildren with minor side effects observed [63] Moreoverin a double-blind randomised trial the administration of Gbiloba was less effective thanMPH in the treatment of ADHD[64] G biloba extract treatment at a maximal dosage of 240mg improved the behavioural ratings of ADHD symptomsand the electrical brain activity in children suggesting thatG biloba extract seems to be well tolerated in the short term


Table3Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forA

DHD

Com

poun

dOutcome

Refs

Ginkgobiloba

AlleviatesADHDsymptom

sinchild

renandhasm

inor

sidee

ffects

[63]

Ginkgobiloba

Dou

bleb

lindrand

omise

dtrialwas

lesseffectiv

ethanMPH

inchild

renwith

ADHD

[64]

Ginkgobiloba

Improved

behaviou

ralratings

ofADHDsymptom

sand

thee

lectric

albrainactiv

ityin

child

ren

[65]

Ginkgobiloba

Rand

omise

dplacebo-controlledtrialther

espo

nser

atew

ashigh

er[66]

Ginseng

Opentrialim

proved

theinatte

ntionandhyperactiveim

pulsive

scoreinchild

renwith

ADHD

[67]

Ginseng

Observatio

nalclin

icalstu

dyimproved

inattentivenessinchild

renwith

ADHD

[68]

Ginseng

Dou

ble-blindrand

omise

dplacebo-controlledtrialdarrinattentionandhyperactivity

scores

inchild

renwith

ADHD

[69]

Ginseno

sideR

g3and

Ginkgobiloba

darrRO

SuarrBD

NFlevelsuarrp-TrkB

uarrBD

NFuarrdo

paminetranspo

rteruarrno

repineph

rinetranspo

rter

[70]

Flavon

oid

darrhyperactivityimproved

attentionandvisual-m

otor

coordinatio

nandconcentrationof

child

renwith

ADHD

[71]

Flavon

oid

Rand

omise

ddo

uble-blin

dandplacebocontrolledstu

dyn

ormalise

dtotalantioxidant

statusdarroxidatived

amagetoDNAand

improved

attentionin

child

renwith

ADHD

[72]

Flavon

oid

Rand

omise

ddo

uble-blin

dcontrolleddesig

ndarrhyperactivitynormalise

dcatecholam

inec

oncentratio

nsanddarroxidatives

tress

inchild

renwith

ADHD

[73]

Flavon

oid

uarrdo

paminergicn

eurotransm

ission

improved

synaptosom

alAT

Paseregulated

motor

abilitylearningandmem

ory

darrhyperactivityinatte

ntionandim

pulsivity

intheS

HRmod

el[74ndash

76]

Valeria

naoffi

cinalis

doub

le-blin

dplacebo-controlledpilotstudyimproved

ADHDsymptom

s[77]

Passifloraincarnata

Rand

omise

dstu

dyalleviated

ADHDsymptom

sand

hastolerablesid

eeffect

[78]

Hypericum

perfo

ratum

Rand

omise

dcontrolledtrialdidno

timproves

ymptom

sinchild

renwith

ADHD

[79]

Hypericum

perfo

ratum

Aprelim

inarystu

dyimproved

somes

ymptom

sinADHDpatie

nts

[80]


and may be a useful treatment [65] Lately in a randomisedplacebo-controlled trial the response rate was higher with Gbiloba treatment compared to placebo Thus G biloba couldbe an effective complementary treatment for ADHD [66]

32 Ginseng Ginseng contains a class of phytochemicalscalled ginsenosides which are known as potent antioxidantsand for their neuroprotective properties Ginseng has beenshown to alleviate effectively symptoms of ADHD In anopen trial ginseng medication improved the inattention andhyperactiveimpulsive score in children with ADHD [67]Indeed an observational clinical study showed that ginsenggiven at 1000 mg for 8 weeks improved inattentivenessin children with ADHD [68] A double-blind randomisedplacebo-controlled trial reported that ginseng decreasedinattention and hyperactivity scores in children with ADHD[69] Hence ginseng has the potential to be used as analternative therapy for ADHD On the ADHD-like conditioninduced by Aroclor1254 YY162 which consists of terpenoid-strengthened G biloba and ginsenoside Rg3 attenuatedthe increase in ROS and decrease in BDNF levels in SH-SY5Y cells Moreover YY162 attenuated reductions in p-TrkB BDNF dopamine transporter and norepinephrinetransporter expression [70]

33 Flavonoids Pycnogenol is a herbal dietary supplementextracted from French maritime pine bark whose mainingredient is procyanidin Procyanidins are members of theproanthocyanidin a class of flavonoids and are powerfulantioxidants also found in food such as grapes berriespomegranates red wine and nuts The treatment of 1-monthpycnogenol administration resulted in a significant reduc-tion in hyperactivity improved attention and visual-motorcoordination and concentration in children with ADHD [71]Moreover pycnogenol reduced oxidative damage to DNAnormalised total antioxidant status and improved attentionas demonstrated in a randomised double-blind placebo-controlled study [72] Also the administration of pycnogenolin children with ADHD normalised catecholamine concen-trations leading to less hyperactivity and reduced oxidativestress in a randomised double-blind controlled design [73]St Johnrsquoswort and pycnogenol have been tested as therapeuticalternatives to treat ADHD A significant increase of SH-SY5Y cell survival was induced by pycnogenol which didnot cause any cytotoxic effect when used in therapeuticallyrelevant concentrations also treatment with St Johnrsquos wortsignificantly increased ATP levels [100] Oroxylin A is aflavonoid isolated from the root of Scutellaria baicalensisGeorgi a herb found in East Asia It has been observedthat oroxylin A is an antagonist of the GABA-A receptorand its neuroprotective actions include antioxidant anti-inflammatory and memory-enhancing effects On the otherhand spontaneously hypertensive rats (SHRs) display somesymptoms of ADHD which makes them a model of thedisorder It was demonstrated that oroxylin A improvedADHD-like behaviours via enhancement of dopaminergicneurotransmission and not the modulation of the GABApathway in the SHR [74] Furthermore an oroxylin Aanalogue reduced hyperactivity sustained inattention and

impulsivity in the SHR [75] Baicalin regulated the motorability and learning andmemory abilities in the SHR and thuscontrolled the core symptoms of ADHD [76] Also baicalinimproved synaptosomal ATPase and LDH activities in theSHR suggesting that baicalin exerts its therapeutic effect byupregulating the ACcAMPPKA signalling pathway [101] Arandomised double-blind trial to investigate the therapeuticbenefit of pycnogenol in ADHD patients is in progress [102]

34 Valeriana officinalis The efficacy of valerian has beenevaluated in a double-blind placebo-controlled pilot studywhere valerian showed improvement in ADHD symptomsin particular sustained inattention anxiety and impulsivityandor hyperactivity [77] The GABA- A receptors are thesubstrate for the anxiolytic action of valerenic acid a majorconstituent of valerian root extracts [103] GABA is the maininhibitory neurotransmitter in the CNS and its deficiencycauses anxiety restlessness and obsessive behaviour symp-toms often seen in ADHD The European Medicine Agencydeemed that root extracts of valerian could be used for therelief of mild nervous tension and sleep disorders Howevermore research is required to support the efficacy of valerianin the treatment ADHD

35 Passion Flower The effect of passion flower in alleviatingADHD symptoms was tested in a randomised study Inaddition a tolerable side effect profile may be consideredas one of the advantages of passion flower as comparedwith MPH [78] It seems that the mechanism of action ofpassion flower is mediated via modulation of the GABA-Aand GABA-B receptors and its effects on GABA uptake [104]Although the passion flower has shown pharmacologicalactivity in preclinical experiments including sedative anxi-olytic antitussive antiasthmatic and antidiabetic activitiesits supposed efficacy does not appear to be adequately cor-roborated in the literature since clinical studies often presentmethodologies and procedures with weaknesses [105]

36 St Johnrsquos Wort St Johnrsquos wort produces its therapeuticeffects by involving inhibition of the reuptake of dopamineserotonin and norepinephrine [106] In a randomised con-trolled trial the use of St Johnrsquos wort for the treatmentof ADHD over the course of eight weeks did not improvesymptoms [79] However a preliminary study reported thattreatment with St Johnrsquos wort improved some symptoms inADHD patients [80] Because of findings that St Johnrsquos worthas no adverse effects more studies are required to determineefficacy in the treatment of ADHD

4 Conclusions

The natural compounds discussed in this review appear tobe promising for the treatment of PD and ADHD There-fore these compounds can lay the foundation for a newtherapeutic approach for the treatment of these disordersNatural compounds are more easily accepted by patientssince they are considered healthier than synthetic drugsAlthough the use of natural compounds for the neurological


disorders has been considered as a safe approach they arestill far from being standard treatments due to the lackof controlled clinical studies that could corroborate boththeir high efficacy and safety Hence better designed andmore rigorous clinical trials are required before they canbe established as therapeutic compounds Neither PD norADHD until today have a therapeutic option capable ofcounteracting the progression of the disease and naturalcompounds are often able to modulate the progression ofthis type of disorder as demonstrated by their decreasing ofoxidative stress

Conflicts of Interest

The author declares that there are no conflicts of interest

Acknowledgments

This work was supported by Fondos Federales HIM 2015022SSA 1160

References

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

[2] CW Olanow D R Wakeman and J H Kordower ldquoPeripheralalpha-synuclein and Parkinsonrsquos diseaserdquoMovement Disordersvol 29 no 8 pp 963ndash966 2014

[3] J C Corona andM R Duchen ldquoPPARgamma and PGC-1alphaas therapeutic targets in Parkinsonrsquosrdquo Neurochemical Researchvol 40 no 2 pp 308ndash316 2015

[4] H Deng P Wang and J Jankovic ldquoThe genetics of Parkinsondiseaserdquo Ageing Research Reviews vol 42 pp 72ndash85 2018

[5] L Brichta P Greengard and M Flajolet ldquoAdvances in thepharmacological treatment of Parkinsonrsquos disease targetingneurotransmitter systemsrdquo Trends in Neurosciences vol 36 no9 pp 543ndash554 2013

[6] B K Young R Camicioli and L Ganzini ldquoNeuropsychiatricadverse effects of antiparkinsonian drugs Characteristics eval-uation and treatmentrdquoDrugsampAging vol 10 no 5 pp 367ndash3831997

[7] H Homayoun ldquoParkinson Diseaserdquo Annals of InternalMedicine vol 169 no 5 pp ITC33ndashITC48 2018

[8] R D White G D Harris and M E Gibson ldquoAttention DeficitHyperactivity Disorder and Athletesrdquo Sports Health vol 6 no2 pp 149ndash156 2014

[9] C Ramassamy F Clostre Y Christen and J CostentinldquoPrevention by a Ginkgo biloba Extract (GBE 761) of theDopaminergic Neurotoxicity of MPTPrdquo Journal of Pharmacyand Pharmacology vol 42 no 11 pp 785ndash789 1990

[10] W-R Wu and X-Z Zhu ldquoInvolvement of monoamine oxidaseinhibition in neuroprotective and neurorestorative effects ofGinkgo biloba extract against MPTP-induced nigrostriataldopaminergic toxicity in C57 micerdquo Life Sciences vol 65 no2 pp 157ndash164 1999

[11] F Cao S Sun andE T Tong ldquoExperimental study on inhibitionof neuronal toxical effect of levodopa by ginkgo biloba extracton Parkinson disease in ratsrdquo Journal of Huazhong Universityof Science and Technology - Medical Sciences vol 23 no 2 pp151ndash153 2003

[12] M-S Kim J-I LeeW-Y Lee and S-E Kim ldquoNeuroprotectiveeffect of Ginkgo biloba L extract in a rat model of parkinsonrsquosdiseaserdquo Phytotherapy Research vol 18 no 8 pp 663ndash6662004

[13] X Kang J Chen Z Xu H Li and B Wang ldquoProtective effectsofGinkgobiloba extract onparaquat-induced apoptosis of PC12cellsrdquo Toxicology in Vitro vol 21 no 6 pp 1003ndash1009 2007

[14] P Rojas N Serrano-Garcıa J J Mares-Samano O N Medina-Campos J Pedraza-Chaverri and S O Ogren ldquoEGb761 pro-tects against nigrostriatal dopaminergic neurotoxicity in 1-methyl-4-phenyl-123 6-tetrahydropyridine-induced Parkin-sonism in mice Role of oxidative stressrdquo European Journal ofNeuroscience vol 28 no 1 pp 41ndash50 2008

[15] M A El-Ghazaly N A Sadik E R Rashed and A A Abd-El-Fattah ldquoNeuroprotective effect of EGb761(R) and low-dosewhole-body gamma-irradiation in a rat model of ParkinsonrsquosdiseaserdquoToxicology amp Industrial Health vol 31 no 12 pp 1128ndash1143 2015

[16] Y QWangM YWang X R Fu et al ldquoNeuroprotective effectsof ginkgetin against neuroinjury in Parkinsonrsquos disease modelinduced byMPTP via chelating ironrdquo Free Radical Research vol49 no 9 pp 1069ndash1080 2015

[17] J Hua N Yin B Yang et al ldquoGinkgolide B and bilobalideameliorate neural cell apoptosis in 120572-synuclein aggregatesrdquoBiomedicine amp Pharmacotherapy vol 96 pp 792ndash797 2017

[18] S Kuang L Yang Z Rao et al ldquoEffects ofGinkgoBiloba Extracton A53T 120572-Synuclein Transgenic Mouse Models of ParkinsonrsquosDiseaserdquo Canadian Journal of Neurological Sciences vol 45 no2 pp 182ndash187 2018

[19] M Rudakewich F Ba and C G Benishin ldquoNeurotrophic andneuroprotective actions of ginsenosides Rb(1) andRg(1)rdquoPlantaMedica vol 67 no 6 pp 533ndash537 2001

[20] X-C Chen Y Chen Y-G Zhu F Fang and L-M ChenldquoProtective effect of ginsenoside Rg1 against MPTP-inducedapoptosis in mouse substantia nigra neuronsrdquo Acta Pharmaco-logica Sinica vol 23 no 9 pp 829ndash834 2002

[21] J Van Kampen H Robertson T Hagg and R DrobitchldquoNeuroprotective actions of the ginseng extract G115 in tworodent models of Parkinsonrsquos diseaserdquo Experimental Neurologyvol 184 no 1 pp 521ndash529 2003

[22] X-C Chen Y-C Zhou F Fang Y Chen Y-G Zhu and L-M Chen ldquoGinsenoside Rg1 reduces MPTP-induced substantianigra neuron loss by suppressing oxidative stressrdquo Acta Phar-macologica Sinica vol 26 no 1 pp 56ndash62 2005

[23] S Hu R Han S Mak andY Han ldquoProtection against 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis by waterextract of ginseng (Panax ginseng CA Meyer) in SH-SY5Ycellsrdquo Journal of Ethnopharmacology vol 135 no 1 pp 34ndash422011

[24] W Jiang Z Wang Y Jiang M Lu and X Li ldquoGinsenoside Rg1ameliorates motor function in an animal model of Parkinsonrsquosdiseaserdquo Pharmacology vol 96 no 1-2 pp 25ndash31 2015

[25] M T Ardah K E Paleologou G Lv et al ldquoGinsenosideRb1 inhibits fibrillation and toxicity of alpha-synuclein anddisaggregates preformed fibrilsrdquo Neurobiology of Disease vol74 pp 89ndash101 2015

[26] T-T Zhou G Zu X Wang et al ldquoImmunomodulatory andneuroprotective effects of ginsenoside Rg1 in the MPTP(1-methyl-4-phenyl-1236-tetrahydropyridine) -induced mousemodel of Parkinsonrsquos diseaserdquo International Immunopharmacol-ogy vol 29 no 2 pp 334ndash343 2015


[27] T Zhou G Zu X Zhang et al ldquoNeuroprotective effects ofginsenoside Rg1 through the Wnt120573-catenin signaling pathwayin both in vivo and in vitro models of Parkinsonrsquos diseaserdquoNeuropharmacology vol 101 no 5 pp 480ndash489 2016

[28] Y Heng Q-S Zhang Z Mu J-F Hu Y-H Yuan and N-H Chen ldquoGinsenoside Rg1 attenuates motor impairment andneuroinflammation in the MPTP-probenecid-induced parkin-sonismmouse model by targeting 120572-synuclein abnormalities inthe substantia nigrardquo Toxicology Letters vol 243 pp 7ndash21 2016

[29] E Gonzalez-Burgos C Fernandez-Moriano R Lozano IIglesias andM P Gomez-Serranillos ldquoGinsenosides Rd and Reco-treatments improve rotenone-induced oxidative stress andmitochondrial impairment in SH-SY5Y neuroblastoma cellsrdquoFood and Chemical Toxicology vol 109 pp 38ndash47 2017

[30] Y Liu R-Y Zhang J Zhao et al ldquoGinsenoside Rd protectsSH-SY5Y cells against 1-methyl-4-phenylpyridinium inducedinjuryrdquo International Journal of Molecular Sciences vol 16 no7 pp 14395ndash14408 2015

[31] H-I ImW S Joo ENam E-S Lee Y-J Hwang andY S KimldquoBaicalein prevents 6-hydroxydopamine-induced dopaminer-gic dysfunction and lipid peroxidation in micerdquo Journal ofPharmacological Sciences vol 98 no 2 pp 185ndash189 2005

[32] Y Cheng G He X Mu et al ldquoNeuroprotective effect ofbaicalein against MPTP neurotoxicity Behavioral biochemicaland immunohistochemical profilerdquo Neuroscience Letters vol441 no 1 pp 16ndash20 2008

[33] X Mu G He Y Cheng X Li B Xu and G Du ldquoBaicaleinexerts neuroprotective effects in 6-hydroxydopamine-inducedexperimental parkinsonism in vivo and in vitrordquo PharmacologyBiochemistry amp Behavior vol 92 no 4 pp 642ndash648 2009

[34] M Jiang Y Porat-Shliom Z Pei et al ldquoBaicalein reduces E46K120572-synuclein aggregation in vitro and protects cells against E46K120572-synuclein toxicity in cell models of familiar ParkinsonismrdquoJournal of Neurochemistry vol 114 no 2 pp 419ndash429 2010

[35] J-H Lu M T Ardah S S K Durairajan et al ldquoBaicaleinInhibits Formation of 120572-Synuclein Oligomers within LivingCells and Prevents A120573 Peptide Fibrillation and Oligomerisa-tionrdquo ChemBioChem vol 12 no 4 pp 615ndash624 2011

[36] Y-H Wang H-T Yu X-P Pu and G-H Du ldquoBaicalein pre-vents 6-hydroxydopamine-induced mitochondrial dysfunctionin SH-SY5Y cells via inhibition of mitochondrial oxidation andup-regulation of DJ-1 protein expressionrdquoMolecules vol 18 no12 pp 14726ndash14738 2013

[37] E LeeH R Park S T Ji Y Lee and J Lee ldquoBaicalein attenuatesastroglial activation in the 1-methyl-4-phenyl-1234-tetrahy-dropyridine-induced Parkinsonrsquos disease model by downreg-ulating the activations of nuclear factor-120581B ERK and JNKrdquoJournal of Neuroscience Research vol 92 no 1 pp 130ndash139 2014

[38] X Xue H Liu L Qi et al ldquoBaicalein ameliorated the upregula-tion of striatal glutamatergic transmission in the mice model ofParkinsonrsquos diseaserdquo Brain Research Bulletin vol 103 pp 54ndash592014

[39] Q Hu V N Uversky M Huang et al ldquoBaicalein inhibitsalpha-synuclein oligomer formation and prevents progressionof alpha-synuclein accumulation in a rotenonemouse model ofParkinsonrsquos diseaserdquo Biochim Biophys Acta vol 1862 no 10 pp1883ndash1890 2016

[40] K-C Hung H-J Huang Y-T Wang and A M-Y LinldquoBaicalein attenuates 120572-synuclein aggregation inflammasomeactivation and autophagy in the MPP+-treated nigrostriataldopaminergic system in vivordquo Journal of Ethnopharmacologyvol 194 pp 522ndash529 2016

[41] H-Q Chen Z-Y Jin X-J Wang X-M Xu L Deng andJ-W Zhao ldquoLuteolin protects dopaminergic neurons frominflammation-induced injury through inhibition of microglialactivationrdquo Neuroscience Letters vol 448 no 2 pp 175ndash1792008

[42] L Hu J Yen Y Shen KWuMWu and Y Ho ldquoLuteolinMod-ulates 6-Hydroxydopamine-Induced Transcriptional Changesof Stress Response Pathways in PC12 Cellsrdquo PLoS ONE vol 9no 5 p e97880 2014

[43] S P Patil P D Jain J S Sancheti P J Ghumatkar R Tambeand S Sathaye ldquoNeuroprotective and neurotrophic effects ofApigenin and Luteolin in MPTP induced parkinsonism inmicerdquoNeuropharmacology vol 86 pp 192ndash202 2014

[44] N Haleagrahara C J Siew N K Mitra and M KumarildquoNeuroprotective effect of bioflavonoid quercetin in 6-hydroxydopamine-induced oxidative stress biomarkers in therat striatumrdquo Neuroscience Letters vol 500 no 2 pp 139ndash1432011

[45] C Lv T Hong Z Yang et al ldquoEffect of quercetin in the 1-methyl-4-phenyl-1 2 3 6-tetrahydropyridine-induced mousemodel of parkinsonrsquos diseaserdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 928643 6 pages2012

[46] S S Karuppagounder S K Madathil M Pandey R HaobamU Rajamma and K P Mohanakumar ldquoQuercetin up-regulatesmitochondrial complex-I activity to protect against pro-grammed cell death in rotenone model of Parkinsonrsquos diseasein ratsrdquo Neuroscience vol 236 pp 136ndash148 2013

[47] M Ay J Luo M Langley et al ldquoMolecular mechanisms under-lying protective effects of quercetin against mitochondrialdysfunction and progressive dopaminergic neurodegenerationin cell culture and MitoPark transgenic mouse models ofParkinsonrsquos Diseaserdquo Journal of Neurochemistry vol 141 no 5pp 766ndash782 2017

[48] S Li and X-P Pu ldquoNeuroprotective effect of kaempferolagainst a 1-methyl-4-phenyl-1236-tetrahydropyridine-in-duced mouse model of Parkinsonrsquos diseaserdquo Biological ampPharmaceutical Bulletin vol 34 no 8 pp 1291ndash1296 2011

[49] G Filomeni I Graziani D de Zio et al ldquoNeuroprotectionof kaempferol by autophagy in models of rotenone-mediatedacute toxicity possible implications for Parkinsonrsquos diseaserdquoNeurobiology of Aging vol 33 no 4 pp 767ndash785 2012

[50] MMKhan S S RazaH Javed et al ldquoRutin protects dopamin-ergic neurons from oxidative stress in an animal model ofParkinsonrsquos diseaserdquo Neurotoxicity Research vol 22 no 1 pp1ndash15 2012

[51] K B Magalingam A Radhakrishnan and N HaleagraharaldquoRutin a bioflavonoid antioxidant protects rat pheochromo-cytoma (PC-12) cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicityrdquo International Journal of MolecularMedicine vol 32 no 1 pp 235ndash240 2013

[52] K B Magalingam A Radhakrishnan and N Haleagra-hara ldquoProtective effects of flavonol isoquercitrin against 6-hydroxydopamine (6-OHDA)-induced toxicity in PC12 cellsrdquoBMC Research Notes vol 7 p 49 2014

[53] C Anusha T Sumathi and L D Joseph ldquoProtective roleof apigenin on rotenone induced rat model of Parkinsonrsquosdisease Suppression of neuroinflammation and oxidative stressmediated apoptosisrdquo Chemico-Biological Interactions vol 269pp 67ndash79 2017

[54] T Baluchnejadmojarad N Jamali-Raeufy S Zabihnejad NRabiee and M Roghani ldquoTroxerutin exerts neuroprotection


in 6-hydroxydopamine lesion rat model of Parkinsonrsquos diseasePossible involvement of PI3KER120573 signalingrdquo European Journalof Pharmacology vol 801 pp 72ndash78 2017

[55] M R Poetini S M Araujo M Trindade de Paula et alldquoHesperidin attenuates iron-induced oxidative damage anddopamine depletion in Drosophila melanogaster model ofParkinsonrsquos diseaserdquo Chemico-Biological Interactions vol 279pp 177ndash186 2018

[56] M S Antunes A T R Goes S P Boeira M Prigol and C RJesse ldquoProtective effect of hesperidin in a model of Parkinsonrsquosdisease induced by 6-hydroxydopamine in aged micerdquo Nutri-tion Journal vol 30 no 11-12 pp 1415ndash1422 2014

[57] J H Sudati F A Vieira and S S Pavin ldquoValeriana offici-nalis attenuates the rotenone-induced toxicity in Drosophilamelanogasterrdquo NeuroToxicology vol 37 pp 118ndash126 2013

[58] S Sridharan K Mohankumar S P Jeepipalli et al ldquoNeuropro-tective effect of Valeriana wallichii rhizome extract against theneurotoxin MPTP in C57BL6 micerdquo NeuroToxicology vol 51pp 172ndash183 2015

[59] S Ingale and S Kasture ldquoProtective effect of standardizedextract of Passiflora incarnata flower in parkinsonrsquos andalzheimerrsquos diseaserdquo Ancient Science of Life vol 36 no 4 pp200ndash206 2017

[60] L E M Brandao and D Noga ldquoPassiflora cincinnata extractdelays the development of motor signs and prevents dopamin-ergic loss in a mice model of parkinsonrsquos diseaserdquo Evidence-Based Complementary and Alternative Medicine vol 2017Article ID 8429290 11 pages 2017

[61] M AGomez del RioM I Sanchez-Reus I Iglesias et al ldquoNeu-roprotective properties of standardized extracts of hypericumperforatumon rotenonemodel of parkinsonrsquos diseaserdquoCNS andNeurological Disorders - Drug Targets vol 12 no 5 pp 665ndash6792013

[62] Z Kiasalari T Baluchnejadmojarad and M Roghani ldquoHy-pericum perforatum hydroalcoholic extract mitigates motordysfunction and is neuroprotective in intrastriatal 6-hydrox-ydopamine rat model of parkinsonrsquos diseaserdquo Cellular andMolecular Neurobiology vol 36 no 4 pp 521ndash530 2016

[63] M R Lyon J C Cline J T De Zepetnek J J Shan P Pangand C Benishin ldquoEffect of the herbal extract combinationPanax quinquefolium and Ginkgo biloba on attention-deficithyperactivity disorder a pilot studyrdquo Journal of Psychiatry ampNeuroscience vol 26 no 3 pp 221ndash228 2001

[64] B Salehi R Imani M RMohammadi et al ldquoGinkgo biloba forattention-deficithyperactivity disorder in children and adoles-cents a double blind randomized controlled trialrdquo Progress inNeuro-Psychopharmacology amp Biological Psychiatry vol 34 no1 pp 76ndash80 2010

[65] H Uebel-von Sandersleben A Rothenberger B Albrecht L GRothenberger S Klement and N Bock ldquoGinkgo biloba extractEGb 761 in children with ADHDrdquo Zeitschrift fur Kinder- undJugendpsychiatrie und Psychotherapie vol 42 no 5 pp 337ndash3472014

[66] F Shakibaei M Radmanesh E Salari and B Mahaki ldquoGinkgobiloba in the treatment of attention-deficithyperactivity dis-order in children and adolescents A randomized placebo-controlled trialrdquo Complementary Therapies in Clinical Practicevol 21 no 2 pp 61ndash67 2015

[67] H Niederhofer ldquoPanax ginseng may improve some symptomsof attention-deficit hyperactivity disorderrdquo Journal of DietarySupplements vol 6 no 1 pp 22ndash27 2009

[68] S H Lee W S Park and M H Lim ldquoClinical effects ofkorean red ginseng on attention deficit hyperactivity disorderin children an observational studyrdquo Journal of GinsengResearchvol 35 no 2 pp 226ndash234 2011

[69] H-J Ko I Kim J-B Kim et al ldquoEffects of Korean red ginsengextract on behavior in children with symptoms of inatten-tion and hyperactivityimpulsivity a double-blind randomizedplacebo-controlled trialrdquo Journal of Child and Adolescent Psy-chopharmacology vol 24 no 9 pp 501ndash508 2014

[70] Y Nam E-J Shin S W Shin et al ldquoYY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aro-clor1254 via interactive signaling between antioxidant potentialBDNFTrkBDATandNETrdquoFoodandChemical Toxicology vol65 pp 280ndash292 2014

[71] J Trebaticka S Kopasova Z Hradecna et al ldquoTreatment ofADHD with French maritime pine bark extract PycnogenolrdquoEuropeanChild andAdolescent Psychiatry vol 15 no 6 pp 329ndash335 2006

[72] Z Chovanova J Muchova M Sivonova et al ldquoEffect ofpolyphenolic extract Pycnogenol on the level of 8-oxoguaninein children suffering from attention deficithyperactivity disor-derrdquo Free Radical Research vol 40 no 9 pp 1003ndash1010 2006

[73] M Dvorakova M Sivonova J Trebaticka et al ldquoThe effectof polyphenolic extract from pine bark Pycnogenol on thelevel of glutathione in children suffering from attention deficithyperactivity disorder (ADHD)rdquoRedoxReport vol 11 no 4 pp163ndash172 2006

[74] S Y Yoon I D Pena S M Kim et al ldquoOroxylin A improvesattention deficit hyperactivity disorder-like behaviors in thespontaneously hypertensive rat and inhibits reuptake of dopam-ine in vitrordquo Archives of Pharmacal Research vol 36 no 1 pp134ndash140 2013

[75] I C Dela Pena S Y Yoon Y Kim et al ldquo57-Dihydroxy-6-methoxy-41015840-phenoxyflavone a derivative of oroxylin Aimproves attention-deficithyperactivity disorder (ADHD)-likebehaviors in spontaneously hypertensive ratsrdquoEuropean Journalof Pharmacology vol 715 no 1ndash3 pp 337ndash344 2013

[76] R Zhou X Han J Wang and J Sun ldquoEffect of baicalinon behavioral characteristics of rats with attention deficithyperactivity disorderrdquo Zhongguo Dang Dai Er Ke Za Zhi vol19 no 8 pp 930ndash937 2017

[77] R Razlog J Pellow and S JWhite ldquoA pilot study on the efficacyofValeriana officinalismother tincture and Valeriana officinalis3X in the treatment of attention deficit hyperactivity disorderrdquoHealth SA Gesondheid vol 17 no 1 pp 1ndash7 2012

[78] S Akhondzadeh M R Mohammadi and F Momeni ldquoPassi-flora incarnata in the treatment of attention-deficit hyperactiv-ity disorder in children and adolescentsrdquoTherapy vol 2 no 4pp 609ndash614 2005

[79] W Weber A Vander Stoep R L McCarty N S Weiss JBiederman and JMcClellan ldquoHypericumperforatum(St JohnrsquosWort) for attention-deficithyperactivity disorder in childrenand adolescents a randomized controlled trialrdquo The Journal ofthe American Medical Association vol 299 no 22 pp 2633ndash2641 2008

[80] H Niederhofer ldquoSt Johnrsquos wort may improve some symptomsof attention-deficit hyperactivity disorderrdquo Natural ProductResearch vol 24 no 3 pp 203ndash205 2010

[81] F V DeFeudis and K Drieu ldquoGinkgo biloba extract (EGb 761)and CNS functions basic studies and clinical applicationsrdquoCurrent Drug Targets vol 1 no 1 pp 25ndash58 2000


[82] P Rojas P Montes C Rojas N Serrano-Garcıa and J C Rojas-Castaneda ldquoEffect of a phytopharmaceutical medicine Ginkobiloba extract 761 in an animal model of Parkinsonrsquos diseaseTherapeutic perspectivesrdquo Nutrition Journal vol 28 no 11-12pp 1081ndash1088 2012

[83] C Rendeiro J S Rhodes and J P E Spencer ldquoThemechanismsof action of flavonoids in the brain Direct versus indirecteffectsrdquoNeurochemistry International vol 89 pp 126ndash139 2015

[84] H D Kim K H Jeong U J Jung and S R Kim ldquoNaringintreatment induces neuroprotective effects in a mouse modelof Parkinsonrsquos disease in vivo but not enough to restorethe lesioned dopaminergic systemrdquo The Journal of NutritionalBiochemistry vol 28 pp 140ndash146 2016

[85] D M de Oliveria G Barreto D V G de Andrade et alldquoCytoprotective effect of valeriana officinalis extract on an invitro experimental model of parkinson diseaserdquoNeurochemicalResearch vol 34 no 2 pp 215ndash220 2009

[86] K Dhawan S Dhawan and A Sharma ldquoPassiflora a reviewupdaterdquo Journal of Ethnopharmacology vol 94 no 1 pp 1ndash232004

[87] J Barnes L A Anderson and J D Phillipson ldquoSt Johnrsquoswort (Hypericum perforatum L) a review of its chemistrypharmacology and clinical propertiesrdquo Journal of Pharmacy andPharmacology vol 53 no 5 pp 583ndash600 2001

[88] G Polanczyk M S de Lima B L Horta J Biederman and LA Rohde ldquoThe worldwide prevalence of ADHD a systematicreview and metaregression analysisrdquo The American Journal ofPsychiatry vol 164 no 6 pp 942ndash948 2007

[89] E G Willcutt ldquoThe prevalence of DSM-IV attention-deficithyperactivity disorder a meta-analytic reviewrdquoNeurotherapeu-tics vol 9 no 3 pp 490ndash499 2012

[90] S V Faraone P Asherson T Banaschewski et al ldquoAttention-deficithyperactivity disorderrdquo Nature Reviews Disease Primersvol 1 p 15020 2015

[91] J Prince ldquoCatecholamine dysfunction in attention-deficithyperactivity disorder an updaterdquo Journal of Clinical Psy-chopharmacology vol 28 no 3 suppl 2 pp S39ndashS45 2008

[92] A L Lopresti ldquoOxidative and nitrosative stress in ADHD pos-sible causes and the potential of antioxidant-targeted therapiesrdquoADHD Attention Deficit and Hyperactivity Disorders vol 7 no4 pp 237ndash247 2015

[93] L Briars and T Todd ldquoA review of pharmacological manage-ment of attention-deficithyperactivity disorderrdquoThe Journal ofPediatric Pharmacology andTherapeutics vol 21 no 3 pp 192ndash206 2016

[94] J Biederman T Spencer and T Wilens ldquoEvidence-basedpharmacotherapy for attention-deficit hyperactivity disorderrdquoThe International Journal of Neuropsychopharmacology vol 7no 1 pp 77ndash97 2004

[95] V A Reed J K Buitelaar E Anand et al ldquoThe safety ofatomoxetine for the treatment of children and adolescentswith attention-deficithyperactivity disorder a comprehensivereview of over a decade of researchrdquo CNS Drugs vol 30 no 7pp 603ndash628 2016

[96] J Lee N Grizenko V Bhat S Sengupta A Polotskaia andR Joober ldquoRelation between therapeutic response and sideeffects induced by methylphenidate as observed by parents andteachers of children with ADHDrdquo BMC Psychiatry vol 11 p 702011

[97] T E Wilens A Kwon S Tanguay et al ldquoCharacteristicsof adults with attention deficit hyperactivity disorder plus

substance use disorder The role of psychiatric comorbidityrdquoAmerican Journal on Addictions vol 14 no 4 pp 319ndash327 2005

[98] H R Searight K Robertson T Smith S Perkins and B KSearight ldquoComplementary and Alternative Therapies for Pedi-atric Attention Deficit Hyperactivity Disorder A DescriptiveReviewrdquo ISRN Psychiatry vol 2012 Article ID 804127 8 pages2012

[99] P L Le BarsMMKatz N Berman TM Itil AM Freedmanand A F Schatzberg ldquoA placebo-controlled double-blindrandomized trial of an extract of Ginkgo biloba for dementiaNorth American EGb Study Grouprdquo The Journal of the Ameri-can Medical Association vol 278 no 16 pp 1327ndash1332 1997

[100] A J Schmidt J-C Krieg U M Hemmeter et al ldquoImpact ofplant extracts tested in attention-deficithyperactivity disordertreatment on cell survival and energy metabolism in humanneuroblastoma SH-SY5Y cellsrdquo Phytotherapy Research vol 24no 10 pp 1549ndash1553 2010

[101] R-Y Zhou J-JWang Y You et al ldquoEffect of baicalin onATPaseand LDH and its regulatory effect on the ACcAMPPKAsignaling pathway in rats with attention deficit hyperactivitydisorderrdquo Zhongguo Dang Dai Er Ke Za Zhi vol 19 no 5 pp576ndash582 2017

[102] A A J Verlaet B Ceulemans H Verhelst et al ldquoEffect ofPycnogenol(R) on attention-deficit hyperactivity disorder(ADHD) study protocol for a randomised controlled trialrdquoTrials vol 18 no 1 p 145 2017

[103] D Benke A Barberis S Kopp et al ldquoGABAA receptors as invivo substrate for the anxiolytic action of valerenic acid amajorconstituent of valerian root extractsrdquo Neuropharmacology vol56 no 1 pp 174ndash181 2009

[104] K Appel T Rose B Fiebich T Kammler C Hoffmann and GWeiss ldquoModulation of the 120574-aminobutyric acid (GABA) systemby Passiflora incarnata Lrdquo Phytotherapy Research vol 25 no 6pp 838ndash843 2011

[105] M Miroddi G Calapai M Navarra P L Minciullo and SGangemi ldquoPassiflora incarnata L ethnopharmacology clinicalapplication safety and evaluation of clinical trialsrdquo Journal ofEthnopharmacology vol 150 no 3 pp 791ndash804 2013

[106] V Butterweck ldquoMechanism of action of St Johnrsquos wort indepression what is knownrdquo CNS Drugs vol 17 no 8 pp 539ndash562 2003

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Submit your manuscripts atwwwhindawicom


converted into dopamine producing its therapeutic effectsAnother treatment includes anticholinergic drugs that canblock striatal cholinergic receptors inhibiting the excitabilityof cholinergic nerves it has also been demonstrated thatthey can inhibit dopamine reuptake to enhance the functionof dopaminergic neurons [5] At present there are alsoother drugs in Phase III clinical trials Nevertheless thecurrent drugs used for the PD treatment have some sideeffects limiting their clinical applications [6] Drugs usedfor the PD treatment and their side effects are shown inTable 1 Thus the growing interest in alternative therapiesfor neurodegenerative disorders including PD has focusedon the neuroprotective and antioxidant effects of naturalproducts that may provide alternatives since they can havehigh efficiency and fewer side effects Natural compoundsused as alternative therapies for the management of PD areshown in Table 2

21 Ginkgo biloba Ginkgo biloba is an ancient tree native toChina and has been extensively used in traditional Chinesemedicine to manage symptoms associated with dysfunctionsof the heart and lungs G biloba usually contains three ingre-dients which include flavonoids terpenoids and ginkgolicacid [81] Ginkgolides well-known plant extracts obtainedfrom leaves from G biloba especially in the preparationEGb761 which contains ginkgolide B and bilobalide haveemerged as natural therapeutic compounds in part due totheir antioxidant activity These effects have been observed inthe 1-methyl-4-phenyl-1236-tetrahydropyridine- (MPTP-)treated mouse model of PD where chronic ingestion ofEGb761 preventedMPTP-induced reduction in the dopamin-ergic nerve endings [9] In addition EGb761 administeredbefore or after MPTP treatment protected against MPTP-induced dopaminergic neurotoxicity [10] Moreover EGb761attenuated the neurotoxic effect of levodopa in the 6-hydroxydopamine (6-OHDA) model of PD indicated thatlevodopa is neurotoxic and that EGb761 may decrease thistoxicity [11] The neuroprotective effects of EGb761 weredemonstrated in the 6-OHDA rat model as indicated by thereduction in the behavioural deficit in the rat [12] Paraquat isa pesticide that has been linked to PD and it has been demon-strated that EGb761 protects against paraquat-induced apop-tosis of PC12 cells by increasing bcl-2 activation maintainingofmitochondrial membrane potential ( Ψm) and decreasingcaspase-3 activation through the mitochondria-dependentpathway [13] The neuroprotective effect of EGb761 againstMPTP neurotoxicity is associated with the blockade of lipidperoxidation reduction of oxidative stress and attenuation ofMPTP-induced neurodegeneration of the nigrostriatal path-way [14] Also it was demonstrated in an extensive review thatEGb761 may exert therapeutic actions in an animal modelof PD via the antioxidant effects [82] Ginkgetin a naturalbiflavonoid isolated from leaves of G biloba protectedagainst 1-methyl-4-phenylpyridinium ion- (MPP+-) inducedcell damage in vitro by decreasing the levels of intracellularreactive oxygen species (ROS) and by maintaining Ψmand also improved the sensorimotor coordination in amousePD model induced by MPTP suggesting that the neuro-protective mechanism of ginkgetin occurs via regulating

iron homeostasis [16] In low-dose whole-body 120574-irradiationin the reserpine model of PD EGb761 was protective byameliorating the reserpine-induced state of oxidative stressmitochondrial dysfunction and apoptosis in the brain [15]The pretreatment with ginkgolide B or bilobalide protectedSH-SY5Y cells against 120572-synuclein-induced cell injury andapoptosis [17] Ultimately the G biloba extract treatmentimproved locomotor activity decreased oxidative damagemaintained the dopamine homeostasis and inhibited thedevelopment of PD inA53T120572-synuclein transgenicmice [18]

22 Ginseng Ginseng is a traditional Chinese herb con-taining more than 30 ginsenosides the active ingredientsof ginseng Ginsenosides Rb1 and Rg1 are regarded as themain compounds responsible for the therapeutic actionsof ginseng Previous studies have shown that in SN-K-SHcells both ginsenosides Rb1 and Rg1 reversedMPTP-inducedcell death [19] The protective effect of Rg1 against MPTP-induced apoptosis was attributed to enhancing Bcl-2 andBcl-xl expression reducing Bax and iNOS expression andinhibiting activation of caspase-3 [20] The ginseng extractG115 significantly blocked tyrosine hydroxylase- (TH-)positive cell loss in the SN and reduced the appearance oflocomotor dysfunction in two rodent models of PD [21]Pretreatments of Rg1 or N-acetylcysteine were found toprotect against MPTP-induced SN neuron loss by preventingglutathione (GSH) reduction attenuate the phosphorylationsof JNK and c-Jun and activate superoxide dismutase (SOD)[22] MPP+-induced cytotoxicity in SH-SY5Y was inhibitedbywater extract of ginseng as demonstrated by the inhibitoryeffect on cell death overproduction of ROS elevated BaxBcl-2 ratio release of cytochrome c and activation of caspase-3 expression [23] It was demonstrated that ginsenosidesprotect by reducing intracellular ROS levels enhancingantioxidant activity preserving the activity of complex I sta-bilising the Ψm and increasing intracellular ATP levels Rg1treatment restored motor functions in MPTP-treated miceand these behavioural ameliorations were accompanied byrestoration of dopaminergic neurons in the SN and striatum[24] Additionally the ginsenoside Rb1 exhibited a strongability to disaggregate fibrils and to inhibit the polymerisationof 120572-synuclein [25] Rg1 treatment inhibited the activation ofmicroglia and reduced the infiltration of CD3+ and T cellsand also protected TH-positive cells in the SN and reducedthe serum concentrations of proinflammatory cytokinesTNF120572 IFN120574 IL-1120573 and IL-6 in MPTP mouse models [26]Also using in vivo and in vitro models of PD it was demon-strated that ginsenoside Rg1 may exert therapeutic effects onPD via the Wnt120573-catenin signalling pathway [27] In theMPTP-probenecidmousemodel the oral treatment with Rg1significantly attenuated MPTP-induced mortality behaviourdefects and loss of dopaminergic neurons The protectiveeffect of Rg1 may be mediated by reducing aberrant 120572-synuclein-mediated neuroinflammation [28]Theneurotoxinrotenone is an inhibitor of complex I and has been widelyused in vivo and in vitro tomodel PDThus cotreatment withginsenosides Rd and Re inhibited the increased intracellularROS production and lipid peroxidation accumulation causedby rotenone Besides the major ginsenosides Rd and Re


Table1Drugs

used

inPD


ffects

Drugs

forP

D[7]

Mecha

nism

Side

effects

L-DOPA

and

Carbido

paAprecursortodo

paminecombinedwith

carbidop

awhich

blocks

arom

aticam

inoacid

decarboxylase

Nauseavomiting

insom

niapsycho

sishallucinatio

nshypotensio

narrhythm

iasom

nolencenigh

tmares

Selegilin

eRa

sagilin

eSafin

amide

Mon

oamineo

xidase

Binhibitors(M

AO-B)increase

thes

ynaptic

availabilityof

dopaminesafin

amidea

lsoinhibitsglutam

aterelease

Abno

rmalmovem

ents

dizzinessnauseavom

iting

dry

mou

th

persistentd

iarrho

eacon

stipatio

nwe

ight

loss

Entacapo

neand

Tolcapon

eCatecho

l-O-m

ethyltransfe

raseinhibitors(C

OMT)IncreaseC

NS

L-DOPA

bioavailabilityby

decreasin

gperip

heralL

-DOPA

metabolism

Dyskinesia

nauseasle

epdistu

rbancesarteria

lhypotensio

nliver

toxicityvom

iting

dizziness

Pram

ipexole

Ropinirole

Rotig

otine

Apom

orph

ine

Dop

aminea

gonists

stim

ulatethe

actio

nof

dopaminea

tpostsy

naptic

receptors

Nauseadyskinesiah

allucinatio

nssleepinesssle

epattacksconfusion

ankleo

edem

aorthostatic

hypo

tension

constip

ation

Trihexyphenidyl

and

Benztro

pine

Anticho

linergicsblock

acetylcholineinthes

triatum

Dry

mou

thu

riner

etentio

nhallu

cinatio

nsdry

eyescon

stipatio

nblurredvisio

nlossof

mem

oryandconfusion

somno

lencedizziness

Amantadine

Isan

antagonistof

theN

MDAtype

glutam

atereceptora

ndalso

stimulates

dopaminer

elease

Oedem

ahallu

cinatio

nsinsom

niaconfusion

Drugs

ForA

DHD

[8]

Mecha

nism

Side

effects

Methylphenidate

Inhibitsreup

take

ofdo

paminea

ndno

repineph

rine

Anx

ietyagitatio

ninsomniadecrease

appetitewe

ight

lossirritability

hypertensio


umbn

ess

Amph

etam

ines

Inhibitreuptakeo

fdop

aminea

ndno

repineph

rine

Decreasea

ppetitew

eigh

tlossirr


nanxiety

agitatio

nnervou

snessdepressio

n

Atom

oxetine

Selectiven

orepinephriner

euptakeinh

ibito

rDry

mou

thsedation

fatig

ueincreased

sweatin

ghypertensio

ndecrease



impo

tence

unusually

fastor

irregular


Imipramine

Nortriptylin

eAmitriptylin

eDesipramine

Tricyclic

antid

epressants

Inhibitreuptakeo

fdop

aminea

ndno

repineph

rine

Dry

mou

thswe

atingabno

rmalitiesdrowsin

esssedatio

nincreased

suicidality

Clon

idinea

ndGuanfacine

Agonists

ofthe120572


refro

ntal

cortex

Dry

mou


dwith

draw

aleffects


Table2Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forP

D

Source

Com

poun

dAc

tionmecha

nism

Refs

Ginkgobiloba

EGb761

Antioxidantinh

ibitedtoxice

ffectof

levodo

painh

ibitedMAO

activ

itydarrbehaviou

raldeficit

anti-apop

totic



idperoxidatio

ndarroxidatives

tress

[9ndash15]

Ginkgobiloba

Ginkgetin

darrRO

SmaintainΔΨm

[16]

Ginkgobiloba

GinkgolideBand

Bilobalid


poptotic

[17]

Ginkgobiloba

Ginkgobiloba

extract

uarrSO

DuarrGHSdarrmalon

dialdehyde

[18]

Ginseng

Ginseno

sides

Rb1a

ndRg

1Antioxidantanti-a

poptoticuarrbcl-2

darrBa

xdarriN



fibrilsdarrTN


-3120573m

aintainΔΨm

darrcytochromec

release

[19ndash28]

Ginseng

Ginseno

sides

RdandRe

Antioxidantanti-a

poptoticimproved

mito

chon

drialfun

ction

[2930]

Flavon

oid

Baicalein

darrlip

idperoxidatio




aggregation


KdarrJN

K[31ndash40

]

Flavon

oid

Luteolin


Sdarroxidatives

tress

[41ndash43]

Flavon

oid

Quercetin

AntioxidantuarrSO

DuarrGPx

darroxidatives

tressuarrAT


IactivityuarrPK

D1

uarrAktuarrCR

EBuarrBD

NF

[44ndash

47]

Flavon

oid

Kaem

pferol

uarrSO

DuarrGHSdarrlip

idperoxidatio

nuarrautoph

agy

[4849]

Flavon

oid

Rutin

darroxidatives

tressuarrSO

DuarrGPx

darroxidatives

tressdarrlip

idperoxidatio

nuarrcatalase

[5051]

Flavon

oid

Isoq

uercitrin

darroxidatives

tress

[52]

Flavon

oid

Apigenin


S[4353]

Flavon

oid

Troxerutin

darrlip

idperoxidatio

ndarrRO


n[54]

Flavon

oid

Hesperid

inAntioxidant

[5556]

Valeria

naoffi

cinalis

Extracto

fvalerian

Normalise

dSO

Dandcatalase

mRN

As

[57]

Valeria

nawallichii

Valeria

nawallichii

darrRO


idperoxidatio

n[58]

Passifloraincarnata

Extracto

fpassio

nflo

wer

Antioxidant

[59]

Passiflorac

incinn

ata

Passiflorac

incinn

ata

Antioxidant

[60]

Hypericum

perfo

ratum

Extracto

fStJohn

rsquoswo

rtAntioxidantanti-a



n[6162]















Table3Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forA

DHD

Com

poun

dOutcome

Refs

Ginkgobiloba


sinchild

renandhasm

inor

sidee

ffects

[63]

Ginkgobiloba

Dou

bleb

lindrand

omise

dtrialwas

lesseffectiv

ethanMPH

inchild

renwith

ADHD

[64]

Ginkgobiloba

Improved

behaviou

ralratings

ofADHDsymptom

sand

thee

lectric

albrainactiv

ityin

child

ren

[65]

Ginkgobiloba

Rand

omise


espo

nser

atew

ashigh

er[66]

Ginseng

Opentrialim

proved

theinatte


pulsive

scoreinchild

renwith

ADHD

[67]

Ginseng

Observatio

nalclin

icalstu

dyimproved


renwith

ADHD

[68]

Ginseng

Dou

ble-blindrand

omise


scores

inchild

renwith

ADHD

[69]

Ginseno

sideR

g3and

Ginkgobiloba

darrRO

SuarrBD

NFlevelsuarrp-TrkB

uarrBD

NFuarrdo

paminetranspo

rteruarrno

repineph

rinetranspo

rter

[70]

Flavon

oid



otor

coordinatio

nandconcentrationof

child

renwith

ADHD

[71]

Flavon

oid

Rand

omise

ddo

uble-blin


dyn

ormalise

dtotalantioxidant


amagetoDNAand

improved

attentionin

child

renwith

ADHD

[72]

Flavon

oid

Rand

omise

ddo

uble-blin

dcontrolleddesig


dcatecholam

inec

oncentratio

nsanddarroxidatives

tress

inchild

renwith

ADHD

[73]

Flavon

oid

uarrdo

paminergicn

eurotransm

ission

improved

synaptosom

alAT

Paseregulated

motor


ory


ntionandim

pulsivity

intheS

HRmod

el[74ndash

76]

Valeria

naoffi

cinalis

doub

le-blin


ADHDsymptom

s[77]

Passifloraincarnata

Rand

omise

dstu

dyalleviated

ADHDsymptom

sand

hastolerablesid

eeffect

[78]

Hypericum

perfo

ratum

Rand

omise


timproves

ymptom

sinchild

renwith

ADHD

[79]

Hypericum

perfo

ratum

Aprelim

inarystu

dyimproved

somes

ymptom

sinADHDpatie

nts

[80]









4 Conclusions






Acknowledgments


References






















































































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of



Table1Drugs

used

inPD


ffects

Drugs

forP

D[7]

Mecha

nism

Side

effects

L-DOPA

and

Carbido

paAprecursortodo

paminecombinedwith

carbidop

awhich

blocks

arom

aticam

inoacid

decarboxylase

Nauseavomiting

insom

niapsycho

sishallucinatio

nshypotensio

narrhythm

iasom

nolencenigh

tmares

Selegilin

eRa

sagilin

eSafin

amide

Mon

oamineo

xidase

Binhibitors(M

AO-B)increase

thes

ynaptic

availabilityof

dopaminesafin

amidea

lsoinhibitsglutam

aterelease

Abno

rmalmovem

ents

dizzinessnauseavom

iting

dry

mou

th

persistentd

iarrho

eacon

stipatio

nwe

ight

loss

Entacapo

neand

Tolcapon

eCatecho

l-O-m

ethyltransfe

raseinhibitors(C

OMT)IncreaseC

NS

L-DOPA

bioavailabilityby

decreasin

gperip

heralL

-DOPA

metabolism

Dyskinesia

nauseasle

epdistu

rbancesarteria

lhypotensio

nliver

toxicityvom

iting

dizziness

Pram

ipexole

Ropinirole

Rotig

otine

Apom

orph

ine

Dop

aminea

gonists

stim

ulatethe

actio

nof

dopaminea

tpostsy

naptic

receptors

Nauseadyskinesiah

allucinatio

nssleepinesssle

epattacksconfusion

ankleo

edem

aorthostatic

hypo

tension

constip

ation

Trihexyphenidyl

and

Benztro

pine

Anticho

linergicsblock

acetylcholineinthes

triatum

Dry

mou

thu

riner

etentio

nhallu

cinatio

nsdry

eyescon

stipatio

nblurredvisio

nlossof

mem

oryandconfusion

somno

lencedizziness

Amantadine

Isan

antagonistof

theN

MDAtype

glutam

atereceptora

ndalso

stimulates

dopaminer

elease

Oedem

ahallu

cinatio

nsinsom

niaconfusion

Drugs

ForA

DHD

[8]

Mecha

nism

Side

effects

Methylphenidate

Inhibitsreup

take

ofdo

paminea

ndno

repineph

rine

Anx

ietyagitatio

ninsomniadecrease

appetitewe

ight

lossirritability

hypertensio


umbn

ess

Amph

etam

ines

Inhibitreuptakeo

fdop

aminea

ndno

repineph

rine

Decreasea

ppetitew

eigh

tlossirr


nanxiety

agitatio

nnervou

snessdepressio

n

Atom

oxetine

Selectiven

orepinephriner

euptakeinh

ibito

rDry

mou

thsedation

fatig

ueincreased

sweatin

ghypertensio

ndecrease



impo

tence

unusually

fastor

irregular


Imipramine

Nortriptylin

eAmitriptylin

eDesipramine

Tricyclic

antid

epressants

Inhibitreuptakeo

fdop

aminea

ndno

repineph

rine

Dry

mou

thswe

atingabno

rmalitiesdrowsin

esssedatio

nincreased

suicidality

Clon

idinea

ndGuanfacine

Agonists

ofthe120572


refro

ntal

cortex

Dry

mou


dwith

draw

aleffects


Table2Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forP

D

Source

Com

poun

dAc

tionmecha

nism

Refs

Ginkgobiloba

EGb761

Antioxidantinh

ibitedtoxice

ffectof

levodo

painh

ibitedMAO

activ

itydarrbehaviou

raldeficit

anti-apop

totic



idperoxidatio

ndarroxidatives

tress

[9ndash15]

Ginkgobiloba

Ginkgetin

darrRO

SmaintainΔΨm

[16]

Ginkgobiloba

GinkgolideBand

Bilobalid


poptotic

[17]

Ginkgobiloba

Ginkgobiloba

extract

uarrSO

DuarrGHSdarrmalon

dialdehyde

[18]

Ginseng

Ginseno

sides

Rb1a

ndRg

1Antioxidantanti-a

poptoticuarrbcl-2

darrBa

xdarriN



fibrilsdarrTN


-3120573m

aintainΔΨm

darrcytochromec

release

[19ndash28]

Ginseng

Ginseno

sides

RdandRe

Antioxidantanti-a

poptoticimproved

mito

chon

drialfun

ction

[2930]

Flavon

oid

Baicalein

darrlip

idperoxidatio




aggregation


KdarrJN

K[31ndash40

]

Flavon

oid

Luteolin


Sdarroxidatives

tress

[41ndash43]

Flavon

oid

Quercetin

AntioxidantuarrSO

DuarrGPx

darroxidatives

tressuarrAT


IactivityuarrPK

D1

uarrAktuarrCR

EBuarrBD

NF

[44ndash

47]

Flavon

oid

Kaem

pferol

uarrSO

DuarrGHSdarrlip

idperoxidatio

nuarrautoph

agy

[4849]

Flavon

oid

Rutin

darroxidatives

tressuarrSO

DuarrGPx

darroxidatives

tressdarrlip

idperoxidatio

nuarrcatalase

[5051]

Flavon

oid

Isoq

uercitrin

darroxidatives

tress

[52]

Flavon

oid

Apigenin


S[4353]

Flavon

oid

Troxerutin

darrlip

idperoxidatio

ndarrRO


n[54]

Flavon

oid

Hesperid

inAntioxidant

[5556]

Valeria

naoffi

cinalis

Extracto

fvalerian

Normalise

dSO

Dandcatalase

mRN

As

[57]

Valeria

nawallichii

Valeria

nawallichii

darrRO


idperoxidatio

n[58]

Passifloraincarnata

Extracto

fpassio

nflo

wer

Antioxidant

[59]

Passiflorac

incinn

ata

Passiflorac

incinn

ata

Antioxidant

[60]

Hypericum

perfo

ratum

Extracto

fStJohn

rsquoswo

rtAntioxidantanti-a



n[6162]















Table3Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forA

DHD

Com

poun

dOutcome

Refs

Ginkgobiloba


sinchild

renandhasm

inor

sidee

ffects

[63]

Ginkgobiloba

Dou

bleb

lindrand

omise

dtrialwas

lesseffectiv

ethanMPH

inchild

renwith

ADHD

[64]

Ginkgobiloba

Improved

behaviou

ralratings

ofADHDsymptom

sand

thee

lectric

albrainactiv

ityin

child

ren

[65]

Ginkgobiloba

Rand

omise


espo

nser

atew

ashigh

er[66]

Ginseng

Opentrialim

proved

theinatte


pulsive

scoreinchild

renwith

ADHD

[67]

Ginseng

Observatio

nalclin

icalstu

dyimproved


renwith

ADHD

[68]

Ginseng

Dou

ble-blindrand

omise


scores

inchild

renwith

ADHD

[69]

Ginseno

sideR

g3and

Ginkgobiloba

darrRO

SuarrBD

NFlevelsuarrp-TrkB

uarrBD

NFuarrdo

paminetranspo

rteruarrno

repineph

rinetranspo

rter

[70]

Flavon

oid



otor

coordinatio

nandconcentrationof

child

renwith

ADHD

[71]

Flavon

oid

Rand

omise

ddo

uble-blin


dyn

ormalise

dtotalantioxidant


amagetoDNAand

improved

attentionin

child

renwith

ADHD

[72]

Flavon

oid

Rand

omise

ddo

uble-blin

dcontrolleddesig


dcatecholam

inec

oncentratio

nsanddarroxidatives

tress

inchild

renwith

ADHD

[73]

Flavon

oid

uarrdo

paminergicn

eurotransm

ission

improved

synaptosom

alAT

Paseregulated

motor


ory


ntionandim

pulsivity

intheS

HRmod

el[74ndash

76]

Valeria

naoffi

cinalis

doub

le-blin


ADHDsymptom

s[77]

Passifloraincarnata

Rand

omise

dstu

dyalleviated

ADHDsymptom

sand

hastolerablesid

eeffect

[78]

Hypericum

perfo

ratum

Rand

omise


timproves

ymptom

sinchild

renwith

ADHD

[79]

Hypericum

perfo

ratum

Aprelim

inarystu

dyimproved

somes

ymptom

sinADHDpatie

nts

[80]









4 Conclusions






Acknowledgments


References






















































































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of



Table2Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forP

D

Source

Com

poun

dAc

tionmecha

nism

Refs

Ginkgobiloba

EGb761

Antioxidantinh

ibitedtoxice

ffectof

levodo

painh

ibitedMAO

activ

itydarrbehaviou

raldeficit

anti-apop

totic



idperoxidatio

ndarroxidatives

tress

[9ndash15]

Ginkgobiloba

Ginkgetin

darrRO

SmaintainΔΨm

[16]

Ginkgobiloba

GinkgolideBand

Bilobalid


poptotic

[17]

Ginkgobiloba

Ginkgobiloba

extract

uarrSO

DuarrGHSdarrmalon

dialdehyde

[18]

Ginseng

Ginseno

sides

Rb1a

ndRg

1Antioxidantanti-a

poptoticuarrbcl-2

darrBa

xdarriN



fibrilsdarrTN


-3120573m

aintainΔΨm

darrcytochromec

release

[19ndash28]

Ginseng

Ginseno

sides

RdandRe

Antioxidantanti-a

poptoticimproved

mito

chon

drialfun

ction

[2930]

Flavon

oid

Baicalein

darrlip

idperoxidatio




aggregation


KdarrJN

K[31ndash40

]

Flavon

oid

Luteolin


Sdarroxidatives

tress

[41ndash43]

Flavon

oid

Quercetin

AntioxidantuarrSO

DuarrGPx

darroxidatives

tressuarrAT


IactivityuarrPK

D1

uarrAktuarrCR

EBuarrBD

NF

[44ndash

47]

Flavon

oid

Kaem

pferol

uarrSO

DuarrGHSdarrlip

idperoxidatio

nuarrautoph

agy

[4849]

Flavon

oid

Rutin

darroxidatives

tressuarrSO

DuarrGPx

darroxidatives

tressdarrlip

idperoxidatio

nuarrcatalase

[5051]

Flavon

oid

Isoq

uercitrin

darroxidatives

tress

[52]

Flavon

oid

Apigenin


S[4353]

Flavon

oid

Troxerutin

darrlip

idperoxidatio

ndarrRO


n[54]

Flavon

oid

Hesperid

inAntioxidant

[5556]

Valeria

naoffi

cinalis

Extracto

fvalerian

Normalise

dSO

Dandcatalase

mRN

As

[57]

Valeria

nawallichii

Valeria

nawallichii

darrRO


idperoxidatio

n[58]

Passifloraincarnata

Extracto

fpassio

nflo

wer

Antioxidant

[59]

Passiflorac

incinn

ata

Passiflorac

incinn

ata

Antioxidant

[60]

Hypericum

perfo

ratum

Extracto

fStJohn

rsquoswo

rtAntioxidantanti-a



n[6162]















Table3Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forA

DHD

Com

poun

dOutcome

Refs

Ginkgobiloba


sinchild

renandhasm

inor

sidee

ffects

[63]

Ginkgobiloba

Dou

bleb

lindrand

omise

dtrialwas

lesseffectiv

ethanMPH

inchild

renwith

ADHD

[64]

Ginkgobiloba

Improved

behaviou

ralratings

ofADHDsymptom

sand

thee

lectric

albrainactiv

ityin

child

ren

[65]

Ginkgobiloba

Rand

omise


espo

nser

atew

ashigh

er[66]

Ginseng

Opentrialim

proved

theinatte


pulsive

scoreinchild

renwith

ADHD

[67]

Ginseng

Observatio

nalclin

icalstu

dyimproved


renwith

ADHD

[68]

Ginseng

Dou

ble-blindrand

omise


scores

inchild

renwith

ADHD

[69]

Ginseno

sideR

g3and

Ginkgobiloba

darrRO

SuarrBD

NFlevelsuarrp-TrkB

uarrBD

NFuarrdo

paminetranspo

rteruarrno

repineph

rinetranspo

rter

[70]

Flavon

oid



otor

coordinatio

nandconcentrationof

child

renwith

ADHD

[71]

Flavon

oid

Rand

omise

ddo

uble-blin


dyn

ormalise

dtotalantioxidant


amagetoDNAand

improved

attentionin

child

renwith

ADHD

[72]

Flavon

oid

Rand

omise

ddo

uble-blin

dcontrolleddesig


dcatecholam

inec

oncentratio

nsanddarroxidatives

tress

inchild

renwith

ADHD

[73]

Flavon

oid

uarrdo

paminergicn

eurotransm

ission

improved

synaptosom

alAT

Paseregulated

motor


ory


ntionandim

pulsivity

intheS

HRmod

el[74ndash

76]

Valeria

naoffi

cinalis

doub

le-blin


ADHDsymptom

s[77]

Passifloraincarnata

Rand

omise

dstu

dyalleviated

ADHDsymptom

sand

hastolerablesid

eeffect

[78]

Hypericum

perfo

ratum

Rand

omise


timproves

ymptom

sinchild

renwith

ADHD

[79]

Hypericum

perfo

ratum

Aprelim

inarystu

dyimproved

somes

ymptom

sinADHDpatie

nts

[80]









4 Conclusions






Acknowledgments


References






















































































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of
















Table3Eff

ectsof

naturalcom

poun

dsused

asan

alternativetherapy

forA

DHD

Com

poun

dOutcome

Refs

Ginkgobiloba


sinchild

renandhasm

inor

sidee

ffects

[63]

Ginkgobiloba

Dou

bleb

lindrand

omise

dtrialwas

lesseffectiv

ethanMPH

inchild

renwith

ADHD

[64]

Ginkgobiloba

Improved

behaviou

ralratings

ofADHDsymptom

sand

thee

lectric

albrainactiv

ityin

child

ren

[65]

Ginkgobiloba

Rand

omise


espo

nser

atew

ashigh

er[66]

Ginseng

Opentrialim

proved

theinatte


pulsive

scoreinchild

renwith

ADHD

[67]

Ginseng

Observatio

nalclin

icalstu

dyimproved


renwith

ADHD

[68]

Ginseng

Dou

ble-blindrand

omise


scores

inchild

renwith

ADHD

[69]

Ginseno

sideR

g3and

Ginkgobiloba

darrRO

SuarrBD

NFlevelsuarrp-TrkB

uarrBD

NFuarrdo

paminetranspo

rteruarrno

repineph

rinetranspo

rter

[70]

Flavon

oid



otor

coordinatio

nandconcentrationof

child

renwith

ADHD

[71]

Flavon

oid

Rand

omise

ddo

uble-blin


dyn

ormalise

dtotalantioxidant


amagetoDNAand

improved

attentionin

child

renwith

ADHD

[72]

Flavon

oid

Rand

omise

ddo

uble-blin

dcontrolleddesig


dcatecholam

inec

oncentratio

nsanddarroxidatives

tress

inchild

renwith

ADHD

[73]

Flavon

oid

uarrdo

paminergicn

eurotransm

ission

improved

synaptosom

alAT

Paseregulated

motor


ory


ntionandim

pulsivity

intheS

HRmod

el[74ndash

76]

Valeria

naoffi

cinalis

doub

le-blin


ADHDsymptom

s[77]

Passifloraincarnata

Rand

omise

dstu

dyalleviated

ADHDsymptom

sand

hastolerablesid

eeffect

[78]

Hypericum

perfo

ratum

Rand

omise


timproves

ymptom

sinchild

renwith

ADHD

[79]

Hypericum

perfo

ratum

Aprelim

inarystu

dyimproved

somes

ymptom

sinADHDpatie

nts

[80]









4 Conclusions






Acknowledgments


References






















































































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of










4 Conclusions






Acknowledgments


References






















































































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of






Acknowledgments


References






















































































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of





























































































Arthritis










AddictionJournal of







Journal of


Pharmaceutics



Volume 2018



Canadian Journal of






of


Natural Compounds for the Management of Parkinson’s...

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Transcript of Natural Compounds for the Management of Parkinson’s...