Monoamine oxidase and α-synuclein as targets in Parkinson’s disease therapy

Monoamine oxidase anda-synuclein as targets inParkinsonrsquos disease therapyExpert Rev Neurother 14(6) 703ndash716 (2014)

Cristian FollmerDepartment of Physical Chemistry

Institute of Chemistry Federal University

of Rio de Janeiro Av Athos Silveira

Ramos 149 CT A407 Cidade

Universitaria Rio de Janeiro 21941-909

Brazil

Tel +55 212 562 7752

Fax +55 212 562 7265

follmeriqufrjbr

The degeneration of dopaminergic neurons in Parkinsonrsquos disease (PD) is suggested to beassociated with the generation of cytotoxic products from dopamine (DA) metabolism andthe formation of fibrillar inclusions of the protein a-synuclein (AS) Despite of the role of ASin the pathogenesis of PD is not completely understood the stabilization of nontoxicaggregates could represent a potential therapeutic route In respect to the DA metabolism awell-established strategy is the inhibition of the enzyme monoamine oxidase which isresponsible to catalyze the major route of inactivation of neurotransmitters Althoughpharmacological strategies to treat different aspects of the parkinsonian condition are underinvestigation the development of multifunctional molecules that act simultaneously ondifferent targets associated to PD has gained attention only recently In this work we examinethe biochemical properties of synthetic and natural molecules that are capable of interferingon both DA system (via monoamine oxidase inhibition) and AS fibrillation

KEYWORDS a-synuclein bull dopamine bull fibrils bull monoamine oxidase bull oxidative stress bull Parkinsonrsquos disease

bull protofibrils

Parkinsonrsquos disease (PD) the second mostcommon age-related disorder after Alzheimerrsquosdisease (AD) is a progressive movement disor-der that affects approximately 1ndash2 of thepopulation over 65 years of age [1] The clini-cal symptoms (resting tremor bradykinesiarigidity and postural dysfunction etc) resultfrom the loss of dopaminergic neurons in thesubstantia nigra pars compacta and dopamine(DA) deficiency in the striatum [1ndash3] Althoughthe etiology of PD remains unclear the neuro-degeneration is thought to result from tightlyinterconnected phenomena associated with DAmetabolism oxidative stress and the formationof intracellular protein aggregates of the pro-tein a-synuclein (AS) [4ndash7]

The main purpose of the current medicaltreatment of PD is to stimulate the dopaminer-gic neurons mainly through the administrationof 34-dihydroxy-L-phenylalanin (L-dopa) aprecursor of DA that is capable of crossingthe bloodndashbrain barrier whereas DA itselfcannot [8] Another strategy is the administra-tion of inhibitors of the enzyme monoamineoxidase (MAO) which catalyzes the oxidativedeamination of endogenous and exogenous

monoamines [9] Two MAO isoforms havebeen identified MAO-A and MAO-B whichhave a sequence identity of approximately 72and differ from each other in relation to sub-strate and inhibitor specificity [1011] MAO iso-forms are located in the outer mitochondrialmembrane of most cell types including neu-rons and astroglia (MAO-A and MAO-B)liver gastrointestinal tract and placenta (MAO-A) and blood platelets (MAO-B) Among thesubstrates are endogenous monoamines such asthe neurotransmitters DA 5-hydroxytrypta-mine norepinephrine and epinephrine andexogenous amines such as the neurotoxin1-methyl-4-phenyl-1236-tetrahydropyridine(MPTP) [1213] MAO-A acts preferentially on5-hydroxytryptamine whereas MAO-B is moreactive on arylalkylamines such as benzylaminepreventing exogenous amines from acting asfalse neurotransmitters [14] Interestingly PETexperiments indicate a slight increase of MAO-B level with aging in neuronal tissue in normalhealthy human subjects [15] Increased MAO-Blevels have also been observed in platelet-associated astrocytes of brains from ADpatients [16]

informahealthcarecom 101586147371752014920235 2014 Informa UK Ltd ISSN 1473-7175 703

Review

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

Certain inhibitors of MAO (IMAO) used in PD therapy dis-play a broad spectrum of neuroprotective activities includinganti-apoptotic and antioxidant actions [17ndash19] Strikingly theIMAO-B selegiline was suggested to inhibit the formation oftoxic aggregates AS [20] Although the role of AS in the patho-genesis of PD is not completely elucidated the stabilization ofnon-toxic aggregates of the protein might represent an impor-tant strategy in the development of new therapies for PDBesides PD AS is involved in other neurodegenerative disordersthat include dementia with Lewy bodies and multiple systematrophy [21ndash24] AD is actually the condition that is most com-monly associated with secondary AS aggregation [25] and one-half of the patients with familial forms of AD exhibits numerousfibrillar AS aggregates in the form of Lewy bodies in their amyg-dala [26] Thus AS might be considered a potential target in thedevelopment of therapies not only for PD but also for AD

Understanding the molecular basis of different targets associ-ated with PD might provide new perspectives in the developmentof therapies capable of interfering not only with symptoms butalso with the progression of the neurodegenerative processHerein we revisit some important pathways associated with theneuropathogenesis of PD including the non-enzymatic andMAO-mediated oxidation of DA as well as the AS fibrillationConsidering these pathways we discuss the biochemical proper-ties of molecules that are capable of acting on both dopaminergicsystem and AS fibrillation focusing on MAO inhibitors thatinterfere with the formation of neurotoxic aggregates of AS

Catecholamine metabolism amp oxidative stressThe characteristic symptoms of PD are associated primarilywith the loss of DA and norepinephrine neurons in the sub-stantia nigra and locus coeruleus [1ndash3] DA epinephrine andnorepinephrine the major catecholamines in human tissueshave widespread projection to the cortex basal ganglia and lim-bic areas and play important roles in the regulation of diversebrain functions such as mood memory behavior and move-ment which are lost in PD and AD [314] This high selectivityof neuronal degeneration reinforces the hypothesis that

catecholamine neurons produce specific neurotoxins whoseaccumulation might trigger neuronal death Among these toxicspecies are reactive oxygen species (ROS) and toxic metabolitesgenerated from DA metabolism [527]

An increase of oxidative stress mediated by mitochondrialdysfunction decreased concentrations of antioxidants andincreased iron levels have been associated with neurodegenera-tion in PD [4ndash6] Although low concentrations of ROS stimu-late several cellular processes and regulate certain physiologicalfunctions [28] excessive ROS production can result in lipid per-oxidation and chemical modifications of proteins and nucleicacids which might trigger cellular degeneration [29] Oxidativestress can be generated in dopaminergic neurons through DAdegradation via both non-enzymatic and enzymatic pathwaysDA undergoes non-enzymatic oxidation (erroneously namedauto-oxidation) to generate semiquinone radical and ortho-quinone that are potentially toxic to cells [30] These species inturn undergo polymerization to form neuromelamin with theconcomitant generation of ROS as shown in FIGURE 1 Alterna-tively ROS might be generated from the conversion ofprostaglandin-G2 to prostaglandin-H2 catalyzed by peroxidaseactivity of cyclooxygenase (COX) In this process DA can actas a co-substrate during donation of electrons to COX leadingto the formation of DA-quinone Interestingly an upregulationof COX-2 has been reported in nigrostriatal dopaminergic neu-rons in both MPTP mice model and human PD samples [31]Therefore toxic metabolites and ROS are continuously gener-ated from DA oxidation which could explain at least in partthe selectivity of degeneration of dopaminergic neurons In thiscontext it has been proposed that the administration of antiox-idants could slow the rate of progression of PD even thoughevidences to support this therapeutic strategy are still limited

The enzymatic oxidation of DA by the enzymes MAO-Aand MAO-B produces the aldehyde 34-dihydroxyphenylacetal-dehyde (DOPAL) and hydrogen peroxide Indeed withindopaminergic nerve terminals the oxidative deamination ofDA by MAO action is the main catabolic pathway for DA [14]MAO-induced oxidative stress occurs as a result of an increase

NH2NH2

HO

HO

O

O

NH2

O-

O

NH

HO

HO NH

-1 e-

2 e-

Oxidation

Dopamine Dopamine ortho-quinone Dopaminechrome Leucodopaminechrome

Dopaminesemiquinone radical

Neuromelanin

ROS

-1 e-

ROS

O

O

Figure 1 Potential neurotoxic quinones and reactive oxygen species are produced in the non-enzymatic oxidation ofdopamineROS Reactive oxygen species

Review Follmer

704 Expert Rev Neurother 14(6) (2014)

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

of hydrogen peroxide production Although hydrogen peroxideis poorly reactive it can be converted into highly reactivehydroxyl radicals in the presence of iron via Fenton reaction [32]as shown in FIGURE 2 The high levels of iron in the substantianigra provide the favorable conditions for generation ofROS [33] Thereby an increase in MAO activity will result notonly in a decrease in the levels of certain neurotransmitters butalso in an increase of the oxidative stress associated with thegeneration of hydrogen peroxide

The idea that MAO plays a central role in the neuropatho-genesis of PD was reinforced by data that demonstrated thatthe aldehydes generated from catecholamine oxidation byMAO action might promote oxidative stress and neuron deathDOPAL is capable of reacting with proteins via the formationof Schiff base and displays toxicity in vivo and in vitro that is100 to 1000-times greater than that observed for DA [34] Thegeneration of ROS notably superoxide during the oxidation ofDOPAL to its quinone derivative might in part explain thehigh toxicity of DOPAL and its connection with PD

Aldehyde dehydrogenase (ALDH) isoenzymes namelyALDH-1A1 (cytosolic) and ALDH-2 (inner mitochondrial mem-brane) have a possible protective effect in dopaminergic neuronsthrough the conversion of DOPAL to its non-toxic metabolite34-dihydroxyphenylacetic acid [3536] A reduction of ALDH-1expression in surviving neurons in PD substantia nigra pars com-pacta was observed in post-mortem studies [35] while ALDH-2activity was significantly increased in the putamen of PDpatients [36] The inhibition of mitochondrial complex I whichsynthesizes nicotinamide adenine dinucleotide a cofactor forALDH results in an elevation of DOPAL concentration and deathof dopaminergic neurons in vitro and in vivo [273738] InterestinglyPD patients have a deficit in mitochondrial complex I [37]

Another neurotoxic aldehyde associated with catecholaminemetabolism is 34-dihydroxyphenylglycolaldehyde (DOPE-GAL) which is generated by MAO-A action on norepineph-rine Strikingly increased DOPEGAL and MAO-A levels havebeen found in locus coeruleus of post-mortem AD [39] In con-trast with DA and norepinephrine DOPAL and DOPEGALinduce cellular death via apoptosis by activating pore formationon the inner mitochondrial membrane (permeability transitionpore) which results in the release of Ca2+ and cytochrome c[27] These data suggest that the aldehyde metabolites DOPALand DOPEGAL may be associated with PD and AD neuropa-thogenesis respectively

MAO inhibitionMany investigations have indicated that MAO activity is tightlyassociated with neurological disorders such as depressionanxi-ety PD and AD [9] For instance MAO-B activity in plateletswas found to be elevated in AD and demented PD patients(but not in non-demented PD patients) [40] Additionally theinvolvement of MAO-B in PD is strongly evidenced by thefact that this enzyme converts the neurotoxin MPTP to1-methyl-4-phenylpyridinium (MPP+) which triggers Parkin-sonism in humans and non-human primates [13]

Several reversible and irreversible MAO-A and MAO-Binhibitors have been developed to treat neurological disordersincluding depression PD and AD [94142] Although DA ismetabolized by both MAO isoforms only IMAO-B is clinicallyeffective in PD therapy [43] In PD IMAO-B exerts a symp-tomatic effect by diminishing DA degradation and a protectiveeffect by preventing the formation of neurotoxic DA metabo-lites and ROS Considering that many of the IMAO that areused in the clinic have a broad spectrum of activities their neu-roprotective properties may be due to effects other than justMAO-B inhibition [43]

The inhibition of MAO-A has been applied primarily in thetreatment of depressive and anxiety illnesses [9] In this casespecial attention must be given to the administration of irre-versible IMAO-A An important side effect associated with theirreversible inhibition of MAO-A is the hypertensive crisis dueto a potentialization of sympathetic cardiovascular activity viathe release of norepinephrine [44] This side effect occurs whentyramine which is effectively metabolized by intestinal MAO-A enters the circulation promoting in norepinephrine releasefrom sympathetic nerve endings and epinephrine release fromthe adrenal gland Tyramine and other sympathomimeticamines are found in fermented foods and drinks for examplecheese and beer which made this side effect be known aslsquocheese-reactionrsquo Since the intestine contains low levels ofMAO-B the administration of any IMAO-B especially selec-tive inhibitors does not promote the cheese reaction even inmost cases where the inhibitor is administered in a dose highenough to inhibit MAO-A On the other hand hypertensivecrisis can be avoided by using tissue-specific inhibitors such asladostigil which inhibits specifically MAO-A in the brain [45]However the molecular basis of tissue-specific IMAO is notwell understood

Inhibition of MAO by synthetic amp natural compoundsOne of the most important classes of IMAO is that of propar-gylamines which exhibit therapeutic effects on different neuro-logical disorders including PD and depressionanxiety [9]Selegiline (R-Deprenyl) is a selective non-competitive and irre-versible IMAO-B that exhibits neuroprotective activity against

ONH2

HO

HO

HO

HO

H2O + FAD FADH2 + NH3

Dopamine DOPAL

MAO

Fe2+ + H2O2 rarr Fe3+ + OH- + bullOH

Figure 2 Conversion of dopamine to DOPAL by MAOaction The side product hydrogen peroxide might generatehydroxyl radicals via Fenton reactionDOPAL Dihydroxyphenylacetaldehyde MAO Monoamine oxidase

MAO amp AS as targets in PD therapy Review

informahealthcarecom 705

Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

MPTP [46] and is thought to delay the progression of PDthrough diverse mechanisms [43] Selegiline administration leadsto an increase of DA levels in the striatum and substantia nigraof squirrel monkeys following L-dopa therapy [47] Similarlyanalysis of post-mortem brains from selegilineL-dopa-treatedPD patients indicated that the selective inhibition of MAO-Bby selegiline results in an increase of DA in caudate nucleusglobus pallidus putamen and substantia nigra While MAO-Bwas fully inhibited by the therapeutic doses of selegiline sub-stantial MAO-A activity was still observed suggesting thatselective inhibition of MAO-B by selegiline is capable of pro-moting an increased brain levels of DA from L-dopa [48]

In addition to inhibiting the enzymatic oxidation of MAOpropargylamines such as selegiline and clorgyline exhibit antiox-idant and anti-apoptotic activities Selegiline protects neuroblas-toma cells SY-SH5Y against the DNA damage and apoptosisinduced by nitric oxide and peroxynitrite [19] and exhibits anti-oxidant effects against free radicals generated during the non-enzymatic oxidation of DA [49] These neuroprotective activitiesmake selegiline useful not only in the treatment of PD butalso in the treatment of AD in which it displays beneficialeffects on cognitive performance [50]

Based on the results of ethnopharmacological and epidemio-logical investigations several natural products have been identi-fied as potent IMAO For instance epidemiological data havesuggested that cigarette smoking is associated with a decreasedrisk of PD [51] which could be explained by the reduction ofMAO-B levels (~40) in brains of living smokers in compari-son with non-smokers [52] Considering that low levels ofMAO-B in platelets have been associated with personality traitslinked to substance abuse vulnerability [53] it remains unclearwhether people are predisposed to become smokers as a resultof a low MAO-B activity or the reduction in MAO-B activityis a result of exposure to tobacco substances

The presence of the b-carboline alkaloids norharman andharman in cigarette smoke might explain at least in part thereduction of MAO levels in the brains of smokers [54] Norhar-man and harman occur endogenously in mammalian tissuessuch as the brain blood plasma heart kidney and liver whereit might serve as natural inhibitors of MAO [55] These mole-cules exhibit a broad spectrum of neuropharmacological prop-erties including MAO inhibition and interaction withbenzodiazepine receptors which results in sedative anxiolyticand hypnotic effects [56] In addition norharman and harmanisolated from smoke and coffee exhibit protective action againstMPTP toxicity [57] Interestingly epidemiological data indicatean apparently lower incidence of PD associated with coffeedrinking which could be associated with the presence of har-man and norharman in coffee [5859]

In addition to the b-carboline alkaloids 236-trimethyl-14-naphthoquinone isolated from flue-cured tobacco leavesand smoke exhibits MAO inhibitory activity [60] 236-Tri-methyl-14-naphthoquinone is a competitive and non-selectiveIMAO exhibiting protective properties against MPTP toxicityin mice [61] These data suggest that naphthoquinones

especially 14-naphthoquinone may be important pharmaco-phores for reversible MAO inhibition [62] Naphthoquinonesare widespread in nature and have been found in higher plantsfungi and actinomycetes In particular the 14-naphthoquinonescaffold is often found in bioactive molecules including certainanti-tumoral drugs and multiforms of vitamin K [63] Menadi-one (vitamin K3) behaves as a reversible inhibitor of MAO-Bwith 60-fold selectivity for human MAO-B than for MAO-Amaking it as selective as rasagiline (50-fold selectivity for thehuman MAO-B) but less selective than selegiline (250-foldselectivity for human or mouse MAO-B) [62] Interestinglymenadione reduces the formation of the toxic pyridinium1-methyl-4-phenyl-23-dihydropyridinium (MPDP+) and MPP+

from MPTP suggesting an eventual neuroprotective activityagainst MPTP toxicity [57]

Polyphenols (flavonoids and non-flavonoids) capable ofinhibiting MAO have been isolated from vegetables fruits andspices and their effects on PD and AD have gained particularattention [64] For more information on the levels of dietaryMAO inhibitors in foods the pharmacokinetics of the absorp-tion and distribution and tissue levels see reference [65] Amongthese polyphenols are quercetin and curcumin Quercetin a fla-vonoid widely distributed in plant foods was reported toexhibit antidepressant-like effects in mice likely via the modula-tion of the serotonergic activity associated with MAO-A inhibi-tion in the brain [66] Although bioavailability was variabledepending on the source it has been suggested that a healthydiet may contain sufficient amounts of quercetin to affectMAO-A activity in the brain Indeed dietary presence andpharmacokinetics of quercetin norharman and harman areconsistent with significant levels reaching neuronal MAO-Afrom the diet or smoking [65]

Curcumin a yellow spice that is extracted from rhizomes ofthe plant Curcuma longa exhibits potential therapeutic effectson learning and memory disturbances induced by chronicstress [67] In mice curcumin and tetrahydrocurcumin one ofthe major metabolites of curcumin inhibit MAO-B and pro-tect against MPTP neurotoxicity suggesting that the neuropro-tective and antidepressant effects of these compounds areassociated with MAO-B inhibition properties [68] Additionallysome reports have suggested that curcumin might be useful inAD therapy notably due to its wide range of pharmacologicalactivities such as anti-fibrillogenic action on the amyloid-b pep-tide anti-inflammation properties as well as inhibition ofb-secretase and acetylcholinesterase activities [69] Besides curcu-min and quercetin the flavones kaempferol apigenin andchrysin which have been isolated from Ginkgo biloba leavesexhibit potent MAO-A inhibitory activity in vitro Howeverkaempferol or Ginkgo biloba leaf extract were found to haveno effect ex-vivo on MAO from rat or mouse brain or on thelevels of DA norepinephrine or 5-hydroxytryptamine [70]

It should be kept in mind that the effective concentrationreached by dietary MAO inhibitors in the brain might varyenormously depending on their bioavailabilities [65] Examplesof that are curcumin and quercetin which display low

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

bioavailability because of poor aqueoussolubility and low intestinal absorptionTherefore the ingestion of large amountsof dietary MAO inhibitors will not neces-sarily result in effective levels of thesecompounds in the brain The develop-ment of derivatives or new formulationsmight be required to improve the bio-availability of dietary MAO inhibitors

Role of AS in PDIn PD the loss of dopaminergic neuronsin the substantia nigra is accompanied bythe presence of intracellular protein depos-its (Lewy bodies and Lewy neurites) thatare composed primarily of fibrillarAS [72171] Missense mutations and geno-mic multiplications of the AS gene havebeen linked to autosomal dominant famil-ial PD For instance mutations of AS(A53T A30P and E46K) are found infamilial early-onset PD [7273] AS is amonomeric 14 kDa presynaptic proteinthat belongs to the class of the intrinsicallydisordered proteins which are character-ized by lack of stable tertiary structureunder physiological conditions [74] Recentdata suggested that AS isolated from neu-ronal and non-neuronal cell lines existspredominantly as a putative tetramer thatis rich in a-helices [75] These apparentlycontradictory data on the native structureof AS in different cell lines might arisefrom the time-dependent multimerizationaggregation of the pro-tein post-translational modifications as well as the influence ofthe purification protocols on the dynamic equilibrium betweenthe disordered monomer and oligomeric forms of AS [7677]

In Lewy bodies AS was found to be ubiquitinated and phos-phorylated at Ser129 [78] An elevation in the levels of AS-Ser129 phosphorylation was observed in the synaptic-enrichedfractions of the frontal cortex in PD and in advanced stages ofAD [79] Besides PD the aggregation of AS occurs in severalother neurological disorders such as multiple system atrophyHallervordenndashSpatz disease and the Lewy body variant ofAD [21ndash24] Thereby AS is an important target in the develop-ment of therapies not only for PD but also for several otherneurodegenerative diseases

Recently new insights into the mechanism by which AStriggers neurodegeneration in PD have arisen from the discov-ery that AS acts as a non-classical chaperone in the formationof a soluble N-ethylmaleimide-sensitive factor attachment pro-tein receptor (SNARE)-complex assembly in a presynapticterminal [80] In this process AS directly binds to the SNARE-protein synaptobrevin-2 and promotes SNARE-complex assem-bly This finding suggests that the loss of functional AS rather

than the toxicity of the AS aggregates could be associated withthe PD pathogenesis

FIGURE 3 displays two main current hypotheses for the AS aggre-gation triggering neurodegeneration in PD In the first hypothe-sis (model I) the soluble AS monomer aggregates under certainconditions (high protein concentration PD-linked protein muta-tions or the presence of specific ligands) resulting in the forma-tion toxic aggregates of the protein (toxic gain function)According to some experimental evidences the intermediate olig-omeric species (protofibrils) rather than mature fibrils would bethe toxic entity generated from the fibrillation process Forinstance certain oligomeric species generated during the fibrilla-tion process notably annular protofibrils might be toxic to theneurons by acting similarly to pore-forming toxins [81] Corrobo-rating to this hypothesis mutation in the AS that stabilizeoligomers resulted in a more severe loss of dopaminergic neuronsin the substantia nigra of rats than did mutations that stabilizefibrils [82] It is worth mentioning that in several models of PDsuch as the overexpression of human AS in mice Drosophila orin the substantia nigra of rats and primates parkinsonian pheno-type was not accompanied by the formation of AS fibrillaraggregates [83ndash87]

Model I

Presynaptic vesicles

Model II

SNARE complex

Fibrillization

Functional ASNeurodegeneration

Disordered monomer

Neurotoxic protofibrils

Nontoxic oligomers

Fibrils

Amorphous aggregates

SNARE

Figure 3 Current hypotheses for the involvement of a-synuclein in Parkinsonrsquosdisease pathogenesis In the model I AS disordered monomer aggregates into eitheramorphous or fibrillar structures During the fibrillation process neurotoxic intermediates(protofibrils) rather than non-toxic oligomers are populated in PD In the model II thefibrillation process results in loss of functional AS accompanied by destabilization of solu-ble N-ethylmaleimide-sensitive factor attachment protein receptor complex whichtriggers neurodegenerationAS a-synuclein PD Parkinsonrsquos disease



Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

In the second hypothesis (model II) AS aggregation wouldresult in loss of the protein function that in turn will compro-mise the synaptic functionality for example by destabilizingthe SNARE complex (loss of function) Interestingly exoge-nous AS aggregates (fibrils or protofibrils) can be internalizedinto neurons where they might work as an lsquoinfective agentrsquo byrecruiting the soluble AS to fibrillate like typical Lewy bodyand Lewy neurites found in PD The sequestering of solublefunctional AS resulted in damage to the synapse functionalityand neuronal death [88] It is worth noting that mature fibrilsunless submitted to a fragmentation process do not work asefficient nuclei (seeds) for the growth of fibrils this could bethe reason why protofibrils are more toxic than fibrils Surpris-ingly fragments are shed from A30P fibrils (but not fromwild-type fibrils) and these fragments can act as efficient seedsfor recruiting soluble AS monomers [89] Similar results wereobserved for other amyloidogenic proteins In the case of theprion protein fragmentation of amyloid fibrils can acceleratethe protein fibrillation and increase the prion infectivity [90]

Although both models for AS triggering neurodegenerationin PD are possible the hypothesis of gain of toxic functiondue to the protein aggregation seems to be most widelyaccepted In a recent study systematic mutagenesis in AS wasapplied to compare the sequences requirements for both theSNARE-related physiological function and pathological func-tion of AS [91] Using in vitro ex vivo and in vivo models itwas demonstrated that there is no correlation between thephysiological and pathological functions of AS Importantlythe aggregation and neurotoxicity of AS seem to correlate pre-cisely suggesting that the toxicity of AS is associated with itsaggregation rather than loss of physiological function Thesedata reinforce the idea of inhibition of AS aggregation as apromising therapeutic strategy for PD

DA oxidative stress amp AS fibrillationConsidering that protofibrils are the putative toxic species gener-ated by AS fibrillation the stabilization of these intermediatesmight represent a harmful event associated with PD In this con-text AS and DA metabolism could work synergistically to triggerneurodegeneration [92] Dopaminechrome generated during DAoxidation (FIGURE 1) inhibits AS fibrillation stabilizes the protofibrilsspecies and promotes the breakdown of pre-existing fibrils [93]Notably oxidative stress DA metabolism and AS aggregation arethree tightly interconnected events in PD neuropathogenesis

Lansbury and collaborators demonstrated for the first time apossible synergy between DA and the formation of toxic aggre-gates of AS [93] In this study the incubation of AS with DAresulted in the stabilization of AS protofibrils via formation of aDA-AS adduct Interestingly ROS produced by DA oxidationmight promote the oxidation of four methionine residues at theC- and N-terminal domains of AS inhibiting the formation ofthe b-sheet conformation and stabilizing oligomeric speciesIndeed methionine oxidation is pointed out as the dominantmechanism by which DA generates soluble AS oligomers whichare toxic to dopaminergic neurons [9495] In this case the

substitution of all four methionines to alanine significantlyreduced the formation of DA-mediated soluble oligomers [94]

A connection between DA oxidative stress and PD-linked ASmutations was proposed by Follmer et al [96] It was demon-strated that DA under oxidative conditions interacts with ASand distinguishably modulates the stability of the protein aggre-gates generated from wild-type or mutant forms of the proteinIn the presence of DA protofibrils generated from AS mutants(A30P and A53T) exhibited a significant enhancement in theirstabilities compared with protofibrils generated from the wild-type protein Thereby DA would have a stabilizing effect on theintermediate species of AS fibrillation (presumably more toxicthan the fibrils) only when they are generated from PD-linkedAS mutants Note that this effect depends on the DA oxidationMoreover the neurotoxicity of DA protofibrils from A30P-AS inprimary neurons was remarkably reduced by breaking the proto-fibrils into smaller aggregates suggesting that strategies aimed atbreaking andor clearing these toxic aggregates might be promis-ing in the development of new therapies for PD These data sug-gest a link between familial PD-linked missense mutations of ASDA oxidation and the formation of toxic protofibrils

In addition to the compounds generated from the non-enzy-matic oxidation of DA those generated from the enzymatic oxi-dation by MAO action were capable of stabilizing oligomers ofAS DOPAL stabilizes potentially toxic oligomers of AS in vitroinduces large intracellular AS oligomers in the cell bodies andaxons of SHSY-5Y cells overexpressing wild-type AS and pro-motes loss of dopaminergic neurons accompanied by an accumu-lation of high molecular weight oligomers of AS when injectedinto the substantia nigra of rat brains [97] Collectively these dataindicate that the interaction of AS with oxidized derivatives ofDA such as dopaminochrome or DOPAL could lead to anincrease in the levels of potentially toxic protein aggregates

Targeting AS fibrillationSeveral anti-parkinsonian agents inhibit or retard AS andoramyloid-b peptide fibrillation this latter involved in AD patho-genesis DA L-dopa selegiline pergolide and bromocriptineinhibit AS and amyloid-b aggregation and were capable ofdestabilizing pre-existing fibrils [9899] Additionally manypotential neuroprotective molecules have been described tomodulate AS fibrillation antioxidants such as nordihydroguaia-retic acid curcumin rosmarinic acid ferulic acid and wine-related polyphenols remarkably inhibit the formation of ASfibrils in vitro as well as reduce the cytotoxicity associated withAS fibrillation [100] melatonin blocks AS fibrillation destabil-izes preformed AS fibrils and reduces the cytotoxicity inducedby AS [101] sex hormones especially estriol exert significantanti-fibrillogenic and fibril-destabilizing activities on AS [102]multiforms of vitamin A (retinol retinal and retinoic acid) [103]

and vitamin K [104] were capable of inhibiting AS fibrillationPolyphenols have been shown to exhibit anti-fibrillogenic

activity on AS which might be in part associated with the abil-ity of these compounds to be spontaneously oxidized to hydro-quinones and quinones [105] The interaction of quinones with

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

AS likely occurs via the formation ofimino bonds in which the amino groupsof AS undergo nucleophilic attack on thequinone group For instance baicalein aflavonoid originally isolated from theroots of Scutellaria baicalensis is a verypotent inhibitor of AS fibrillation thatcovalently binds to the protein via inter-action between the quinone moiety andthe Lys side chain resulting in a Schiffbase (carbon-nitrogen double bond withthe nitrogen atom connected to an arylor alkyl group (R) not hydrogen ieR1R2C=NR3) [106] In addition to qui-nones catechols and hydroquinones havebeen described as inhibitors of the fibril-lation of AS [105107] Entacapone andtolcapone are two inhibitors of catechol-O-methyl transferase that are co-administered with L-dopa to improve thebioavailability of this drug in PD ther-apy [108] Interestingly entacapone andtolcapone are also capable of inhibitingAS and amyloid-b fibrillation which isattributed to the presence of a catecholscaffold Entacapone and tolcapone canalso protect against the toxicity inducedby AS and amyloid-b aggregates in vitro[105] Thus entacapone and tolcaponemight be potential lead molecules in the development of multi-target drugs for PD even though the effectiveness of thesecompounds on PD progression is still unknown Anti-fibrillogenic properties are also displayed by the catechols caf-feic acid gallic acid and pyrogallol [105]

Molecules targeting on both AS amp MAOIn light of the complexity of the biochemical events associatedwith the neurodegeneration in PD significant efforts have beendone to develop multitarget drugs for this disorder that isdrugs capable of inhibiting different pathways associated withneuropathogenesis FIGURE 4 depicts important pathways that arepresumably associated with the pathogenesis of PD where anoverlap between DA metabolism and AS aggregation can beobserved To develop multitarget drugs for PD certain impor-tant properties of the compounds should be considered antiox-idant activity by reducing the levels of both ROS and toxicmetabolites generated during DA oxidation inhibition ofMAO activity that will increase neurotransmitter levels (withreduction of their aldehyde derivatives) and decrease hydrogenperoxide-induced oxidative stress inhibition of the formationof toxic aggregates of AS by stabilizing either functional AS ornon-toxic protein aggregates brain bioavailability Taken thesebiochemical properties into account several molecules havebeen pointed out as inhibitors of both MAO activity and ASfibrillation including selegiline certain 14-naphthoquinone

derivatives the polyphenols curcumin quercetin catechin epi-catechin and kaempferol (TABLE 1) Most of these compounds arealso potent antioxidants

The interaction between selegiline and AS results in the for-mation of amorphous aggregates and large annular oligomerswhich are innocuous to primary neuron culture Structurallyselegiline appears to prevent the random-coil-to-b-sheet transi-tion that occurs during the fibrillation process Interestinglyalthough selegiline prolongs the lifetime of the spherical aggre-gates fibril formation is enhanced in the long term [20] Con-sidering that selegiline prevents the oxidation of DA (via non-enzymatic and enzymatic pathways) and the administration ofDA (from L-dopa) and selegiline is widely applied in the clinicfor PD therapy an important question is how selegiline affectsthe system consisting of AS plus DA The answer to this ques-tion is essential because a rational approach to treating PDmust consider the combined action of these drugs on the dis-ease progression It was demonstrated that in the combinationof selegiline plus DA selegiline counteracted the inhibitory effectof DA on AS fibrillation which resulted in the formation ofmature fibrils in vitro Importantly selegiline prevented the for-mation of DA-induced toxic protofibrils of AS presumably byinhibiting (or delaying) the oxidation of DA into its quinonederivatives [2049] Collectively these data suggest that selegilinebehaves as multifunctional drug for PD by inhibiting both MAOactivity and the formation of toxic aggregates of AS

DA DA-quinones + ROS

DOPAL

MAO

H2O2 + Fe2+ ----gt Fe3+ + OH + OH-

H2O2 + Fe3+ ----gt Fe2+ + OOH + H+

Fenton reaction

Toxicprotofibrils

No toxicoligomers

Fibrils

Unfolded monomerA

B

C

Figure 4 Potential pharmacological targets in PD therapy (A) Multitarget drugsmight interfere in the generation of ROS and toxic metabolites associated with DAmetabolism (B) in the enzymatic oxidation of DA by MAO action that results in thetoxic aldehyde DOPAL and hydrogen peroxide and (C) in formation of toxic aggregatesfrom AS fibrillizationAS a-synuclein DA Dopamine DOPAL 34-dihydroxyphenylacetaldehydeMAO Monoamine oxidase PD Parkinsonrsquos disease ROS Reactive oxygen species



Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

Among the polyphenols curcumin is able to inhibit the fibril-lation of AS and amyloid-b peptides (IC50 of 022 mM) as wellas disaggregate pre-existing fibrils of these proteins [100] Theinhibitory action of curcumin on AS has been attributed to itsstrong binding to the highly hydrophobic NAC domain a por-tion of AS that is directly involved in the protein fibrillogene-sis [109] Curcumin also inhibits the formation of high molecularweight aggregates of AS induced by Fe3+ [110] In addition cur-cumin can protect against AS-induced cytotoxicity in both SH-SY5Y neuroblastoma cells and PC12 inducible cell model forParkinsonism by reducing intracellular ROS levels and apopto-sis [111112] Regarding the wide-spectrum biochemical propertiesof curcumin and the fact this molecule can cross the bloodndashbrain barrier curcumin might be considered a potential multi-functional neuroprotective agent for PD and possibly for otherneurodegenerative disorders

Similar to curcumin the polyphenols quercetin catechinand epicatechin are able to inhibit both MAO activity and thefibrillation of AS and amyloid-b Catechin and epicatechinpotentially inhibit AS aggregation in vitro with IC50 values of08 mM [100] For amyloid-b peptides IC50 values in the rangeof 024ndash07 mM were found for these compounds [113] How-ever these compounds are weak MAO-B inhibitors with Kivalues of 74 and 21 mM respectively [114] Although the mech-anism underlying the effect of these compounds on AS ispoorly understood these compounds contain a catechol moietysimilarly to other anti-fibrillogenic agents Catechol can be oxi-dized to its quinone form which might interact with theamino groups of AS residues In contrast with catechin orepicatechin which are poor IMAO kaempferol has been iden-tified as a potent MAO-A inhibitor that displays in vitro anti-fibrillogenic properties on AS and amyloid-b peptides [100]However the lack of effects of kaempferol on the levels of DAnorepinephrine or 5-hydroxytryptamine makes the pharmaco-logical potential of this compound as IMAO unclear

ConclusionEmerging pharmacological treatments for PD have focusedmainly on inhibitors of DA reuptake inhibitors of MAO andderivatives of L-dopa (for revision see [115]) Examples of thesedrugs are melevodopa a methyl-esterified form of L-dopa andrasagiline (MAO-B inhibitor) which have both been launchedPromising therapeutic strategies such as neuroimmunophilinsmodulators of mitochondrial function growth factors estrogensand inhibitors of AS aggregation remain in developmentRecently multitarget drugs for PD and AD have beenproposed [116ndash119] including some compounds that exhibit bothcholinesterase and brain selective MAO inhibitory activitiesand iron chelators with potent MAO inhibitory activity [118119]Nevertheless the development of compounds inhibiting bothMAO activity and the formation neurotoxic aggregates of ASvia direct interaction with the protein still remains poorlyexplored MAO activity and AS fibrillation are two importantpharmacological targets for PD therapy MAO action is respon-sible for the metabolism of catecholamine neurotransmitters in

which toxic metabolites such as DOPAL and DOPEGAL aswell as hydrogen peroxide are produced These compoundstogether with DA-quinones generated from the non-enzymaticoxidation of DA were capable of stabilizing toxic AS aggre-gates Thereby DA oxidative stress and AS might worksynergically to trigger neurodegeneration The discovery ofpharmacophores acting on different targets associated with PDin addition to the elucidation of the role of AS in PD consti-tutes the main challenges to the successful development of mul-titarget drugs for PD and other neurodegenerative disorders

Expert commentaryAlthough the etiology of PD is not completely elucidated MAOactivity and AS fibrillation seem to be two important pharmaco-logical targets for the therapy of this disease While the use ofMAO inhibitors has been well established in the clinic currentlyavailable therapeutic strategies for PD do not include any drugtargeting on AS fibrillation The inexistence of AS-based therapiesmight be attributed to the fact that the role of AS aggregation inPD remains inconclusive even though several studies have dem-onstrated that the formation of AS neurotoxic oligomers ratherthan the loss of functional AS is a causative of neurodegeneration

The development of anti-parkinsonian drugs that act simulta-neously on more than one target for example MAO activityand the formation neurotoxic aggregates of AS is a newapproach that has been poorly explored On the other hand thediscovery that certain MAO inhibitors (synthetic or naturallyoccurring compounds) might interfere on AS fibrillation hasopened new perspectives in the development of multifunctionaldrugs not only for PD but also for AD and other neurodegen-erative disorders in which MAO and AS are involved In thiscontext selegiline and certain polyphenols (curcumin quercetincatechin epicatechin and kaempferol) have a broad spectrum ofbiochemical properties which include MAO inhibitory activityinhibition of AS fibrillation as well as antioxidant propertieswhich make them promising multifunctional drugs for PD

Five-year viewFrom the point of view of basic research important advanceswill occur in the development of therapeutic strategies for PDbased on neuroimmunophilins modulators of mitochondrialfunction growth factors estrogens and inhibitors of AS aggre-gation The role of the catecholamines DOPAL and DOPE-GAL produced by MAO action in PD and AD will beclarified notably in relation to the effect of these compoundson AS fibrillation in vivo and in vitro

In clinical fields the evaluation of anti-parkinsonian drugsbased on AS aggregation will be still difficult in the next yearsNew multifunctional drugs exhibiting a combination of differentactivities in a single molecule (eg inhibition of cholinesterasebrain selective MAO inhibition iron chelation etc) will bedeveloped and some of them will be evaluated in clinical trialsUnfortunately the development of compounds inhibiting bothMAO activity and the formation neurotoxic aggregates of AS willremain poorly explored for a couple years

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

Table 1 Examples of molecules that act as both monoamine oxidase inhibitors and modulatorsof a-synuclein fibrillation

Compound MAO inhibition AS fibrillation

Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]

Stabilization of non-toxic oligomers [20]

MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]

Anti-fibrillogenic action and disaggregation of

preformed fibrils [104]

CurcuminO O

H3CO

OHHO

OCH3

ND Anti-fibrillogenic action (IC50 = 022 mM) and

disaggregation of preformed fibrils [100]

Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]

Anti-fibrillogenic action [105]

CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]

Anti-fibrillogenic action (IC50 = 08 mM) and


Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]



AS a-synuclein MAO Monoamine oxidase ND Not determined



Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

Financial amp competing interests disclosure

C Follmer has received grants from the International Foundation for Science

(IFS) Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro

(FAPERJ) and Conselho Nacional de Desenvolvimento Cientıfico e Tecnolo-

gico (CNPq) The author has no other relevant affiliations or financial

involvement with any organization or entity with a financial interest in or

financial conflict with the subject matter or materials discussed in the manu-

script This includes employment consultancies honoraria stock ownership or

options expert testimony grants or patents received or pending or royalties

No writing assistance was utilized in the production of this manuscript

Key issues

bull The high selectivity of neuronal degeneration in Parkinsonrsquos disease (PD) reinforces the hypothesis that catecholamine neurons produce

specific neurotoxins whose accumulation might trigger neuronal death

bull The idea that monoamine oxidase (MAO) plays a central role in neuropathogenesis of PD was reinforced by data that demonstrated

that the aldehydes generated from catecholamine oxidation by MAO action might promote oxidative stress and neuron death

bull The stabilization of non-toxic aggregates of a-synuclein (AS) might represent an important strategy in the development of new

therapies for PD

bull The aggregation and neurotoxicity of AS seem to correlate precisely suggesting that the role of in PD AS is likely associated with its

aggregation rather than loss of physiological function

bull The interaction of AS with either oxidized derivatives of dopamine (eg dopaminochrome) or 34-dihydroxyphenylacetaldehyde could

lead to an increase in the levels of potentially toxic protein aggregates

bull In addition to MAO inhibitory activity certain bioactive polyphenols (flavonoids and non-flavonoids) exhibit anti-fibrillogenic activity on AS

which might be in part associated with the ability of these compounds to be spontaneously oxidized to hydroquinones and quinones

bull Selegiline might behave as multifunctional drug for PD by inhibiting both MAO activity and the formation of toxic aggregates of AS

bull Regarding the wide-spectrum biochemical properties of curcumin and the fact this molecule can cross the bloodndashbrain barrier curcumin

might considered a potential multifunctional neuroprotective agent for PD and possibly for other neurodegenerative disorders

References

1 Langston JW The Parkinsonrsquos complex

parkinsonism is just the tip of the iceberg

Ann Neurol 200659591-6

2 Langston JW Ballard P Tetrud JW et al

Chronic parkinsonism in humans due to a

product of meperidine-analog synthesis

Science 1983219979-80

3 Sulzer D Multiple hit hypotheses for

dopamine neuron loss in Parkinsonrsquosdisease Trends Neurosci 200730244-50

4 Sian J Dexter DT Lees AJ et al

Alterations in glutathione levels in

Parkinsonrsquos disease and other

neurodegenerative disorders affecting basal

ganglia Ann Neurol 199436348-55

5 Martignoni E Blandini F Godi L et al

Peripheral markers of oxidative stress in

Parkinsonrsquos disease The role of L-DOPA

Free Radic Biol Med 199927428-37

6 Buhmann C Arlt S Kontush A et al

Plasma and CSF markers of oxidative stress

are increased in Parkinsonrsquos disease andinfluenced by antiparkinsonian medication

Neurobiol Dis 200415160-70

7 Spillantini MG Crowther RA Jakes R

et al Alpha-Synuclein in filamentous

inclusions of Lewy bodies from Parkinsonrsquos

disease and dementia with Lewy bodies

Proc Natl Acad Sci USA 1998956469-73

8 Androulidakis AG Kuhn AA Chen CC

et al Dopaminergic therapy promotes

lateralized motor activity in the subthalamic

area in Parkinsonrsquos disease Brain 2007130

457-68

9 Youdim MB Edmondson D Tipton KF

The therapeutic potential of monoamine

oxidase inhibitors Nat Rev Neurosci

20067295-309

10 Bach AW Lan NC Johnson DL et al

cDNA cloning of human liver monoamine

oxidase A and B molecular basis of

Table 1 Examples of molecules that act as both monoamine oxidase inhibitors and modulatorsof a-synuclein fibrillation (cont)


Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

differences in enzymatic properties Proc

Natl Acad Sci USA 1988854934-8

11 Johnston JP Some observations upon a new

inhibitor of monoamine oxidase in brain

tissue Biochem Pharmacol 196817

1285-97

12 Binda C Newton-Vinson P Hubalek F

et al Structure of human monoamine

oxidase B a drug target for the treatment of

neurological disorders Nat Struct Biol

2002922-6

13 Javitch JA DrsquoAmato RJ Strittmatter SM

et al Parkinsonism-inducing neurotoxin N-

methyl-4-phenyl-1236-tetrahydropyri-dine

uptake of the metabolite N-methyl-4-

phenylpyridine by dopamine neurons

explains selective toxicity Proc Natl Acad

Sci USA 1985822173-7

14 Youdim MBH Finberg JPM Tipton KF

In Trendelenburg U Weiner N editors

Catecholamines II handbook of

experimental pharmacology Springer

Berlin 1998 p 127-99

15 Fowler JS Volkow ND Wang GJ et al

Age-related increases in brain MAO B in

healthy human subjects Neurobiol Aging

199718431-5

16 Saura J Luque JM Cesura AM et al

Increased monoamine oxidase B activity in

plaque-associated astrocytes of Alzheimer

brains revealed by quantitative enzyme

radioautography Neuroscience 199462

15-30

17 Palhagen S Heinonen E Hagglund J et al

Swedish Parkinson Study Group Selegiline

slows the progression of the symptoms of

Parkinson disease Neurology 200666

1200-6

18 Olanow CW Hauser RA Gauger L et al

The effect of deprenyl and levodopa on the

progression of Parkinsonrsquos disease AnnNeurol 199538771-7

19 Maruyama W Takahashi T Naoi M (-)-

Deprenyl protects human dopaminergic

neuroblastoma SH-SY5Y cells from

apoptosis induced by peroxynitrite and

nitric oxide J Neurochem 1998702510-15

20 Braga CA Follmer C Palhano FL et al

The anti-parkinsonian drug selegiline delays

the nucleation phase of a-synucleinaggregation leading to the formation of

nontoxic species J Mol Biol 2011405

254-73

21 Spillantini MG Schmidt ML Lee VM

et al Alpha-synuclein in Lewy bodies

Nature 1997388839-40

22 Wakabayashi K Yoshimoto M

Fukushima T et al Widespread occurrence

of alpha-synucleinNACP-immunoreactive

neuronal inclusions in juvenile and

adult-onset Hallervorden-Spatz disease with

Lewy bodies Neuropathol Appl Neurobiol

1999225363-8

23 Wakabayashi K Yoshimoto M Tsuji S

et al Alpha-synuclein immunoreactivity in

glial cytoplasmic inclusions in multiple

system atrophy Neuroscience 1998249

180-2

24 Baba M Nakajo S Tu PH et al

Aggregation of alpha-synuclein in Lewy

bodies of sporadic Parkinsonrsquos disease anddementia with Lewy bodies Am J Pathol

1998152879-84

25 Lippa SM Lippa CF Mori H

Alpha-synuclein aggregation in pathological

aging and Alzheimerrsquos disease the impact of

beta-amyloid plaque level Am J Alzheimers

Dis Other Demen 200520315-18

26 Lippa CF Fujiwara H Mann DM et al

Lewy bodies contain altered alpha-synuclein

in brains of many familial Alzheimeracutes

disease patients with mutations in preselin

and amyloid precursor protein genes Am J

Pathol 19981531365-70

27 Burke WJ Li SW Williams EA et al

34-Dihydroxyphenylacetaldehyde is the

toxic dopamine metabolite in vivo

implications for Parkinsonrsquos diseasepathogenesis Brain Res 2003989205-13

28 Shen HM Liu ZG JNK signaling pathway

is a key modulator in cell death mediated

by reactive oxygen and nitrogen species


29 Ray PD Huang BW Tsuji Y Reactive

oxygen species (ROS) homeostasis and

redox regulation in cellular signaling Cell

Signal 201224981-90

30 Sulzer D Zecca L Intraneuronal

dopamine-quinone synthesis a review

Neurotox Res 2000181-195

31 Teismann P Tieu K Choi DK et al

Cyclooxygenase-2 is instrumental in

Parkinsonrsquos disease neurodegeneration ProcNatl Acad Sci USA 20031005473-8

32 Zigler JS Jr Jernigan HM Jr Garland D

et al The effects of oxygen radicals

generated in the medium on lenses in organ

culture inhibition of damage by chelated

iron Arch Biochem Biophys 1985241

163-72

33 Jellinger K Paulus W Grundke-Iqbal I

et al Brain iron and ferritin in Parkinsonrsquosand Alzheimerrsquos diseases J Neural Transm

Park Dis Dement Sect 19902327-40

34 Anderson DG Mariappan SV

Buettner GR et al Oxidation of 34-

dihydroxyphenylacetaldehyde a toxic

dopaminergic metabolite to a semiquinone

radical and an ortho-quinone J Biol Chem

201128626978-86

35 Galter D Buervenich S Carmine A et al

ALDH1 mRNA presence in human

dopamine neurons and decreases in

substantia nigra in Parkinsonrsquos disease andin the ventral tegmental area in

schizophrenia Neurobiol Dis 200314

637-47

36 Michel TM Kasbauer L Gsell W et al

Aldehyde dehydrogenase 2 in sporadic

Parkinsonrsquos disease Parkinsonism Relat

Disord 20142068-72

37 Mizuno Y Ohta S Tanaka M et al

Deficiencies in complex I subunits of the

respiratory chain in Parkinsonrsquos diseaseBiochem Biophys Res Commun 1989163

1450-5

38 Lamensdorf I Eisenhofer G

Harvey-White J et al Metabolic stress in

PC12 cells induces the formation of the

endogenous dopaminergic neurotoxin 34-

dihydroxyphenylacetaldehyde J Neurosci

Res 200060552-8

39 Burke WJ Li SW Schmitt CA et al

Accumulation of 34-

dihydroxyphenylglycolaldehyde the

neurotoxic monoamine oxidase A metabolite

of norepinephrine in locus coeruleus cell

bodies in Alzheimerrsquos disease mechanism of

neuron death Brain Res 1999816633-7

40 Zellner M Baureder M Rappold E et al

Comparative platelet proteome analysis

reveals an increase of monoamine oxidase-B

protein expression in Alzheimerrsquos disease butnot in non-demented Parkinsonrsquos diseasepatients J Proteomics 2012752080-92

41 Guay DR Rasagiline (TVP-1012) a new

selective monoamine oxidase inhibitor for

Parkinsonrsquos disease Am J Geriatr

Pharmacother 20064330-46

42 Youdim MB Weinstock M Therapeutic

applications of selective and non-selective

inhibitors of monoamine oxidase A and B

that do not cause significant tyramine

potentiation Neurotoxicology 200425

243-50

43 Nagatsu T Sawada M Molecular

mechanism of the relation of monoamine

oxidase B and its inhibitors to Parkinsonrsquosdisease possible implications of glial cells J

Neural Transm Suppl 20067153-65

44 Lippman SB Nash K Monoamine oxidase

inhibitor update Potential adverse food and

drug interactions Drug Saf 19905195-204

45 Weinstock M Gorodetsky E Wang RH

et al Limited potentiation of blood pressure

response to oral tyramine by brain-selective

monoamine oxidase A-B inhibitor



Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

TV-3326 in conscious rabbits

Neuropharmacology 200243999-1005

46 Cohen G Pasik P Cohen B et al

Pargyline and deprenyl prevent the

neurotoxicity of 1-methyl-4-phenyl-

1236-tetrahydropyridine (MPTP) in

monkeys Eur J Pharmacol 1984106

209-10

47 Di Monte DA DeLanney LE Irwin I et al

Monoamine oxidase-dependent metabolism

of dopamine in the striatum and substantia

nigra of L-DOPA-treated monkeys Brain

Res 199673853-9

48 Riederer P Youdim MB Monoamine

oxidase activity and monoamine metabolism

in brains of parkinsonian patients treated

with l-deprenyl J Neurochem 198646

1359-65

49 Chiueh CC Huang SJ Murphy DL

Suppression of hydroxyl radical formation

by MAO inhibitors a novel possible

neuroprotective mechanism in dopaminergic

neurotoxicity J Neural Transm Suppl

199441189-96

50 Tolbert SR Fuller MA Selegiline in

treatment of behavioral and cognitive

symptoms of Alzheimer disease Ann


51 Grandinetti A Morens DM Reed D et al

Prospective study of cigarette smoking and

the risk of developing idiopathic Parkinsonrsquosdisease Am J Epidemiol 19941391129-38


Inhibition of monoamine oxidase B in the

brains of smokers Nature 1996379733-6

53 Palomo T Kostrzewa RM Beninger RJ

et al Gene-environment interplay in

alcoholism and other substance abuse

disorders expressions of heritability and

factors influencing vulnerability Neurotox

Res 20046343-61

54 Herraiz T Chaparro C Human

monoamine oxidase is inhibited by tobacco

smoke beta-carboline alkaloids act as potent

and reversible inhibitors Biochem Biophys

Res Commun 2005326378-86

55 Rommelspacher H The beta-carbolines

(harmanes) - a new class of endogenous

compounds their relevance for the

pathogenesis and treatment of psychiatric

and neurological diseases

Pharmacopsychiatria 198114117-25

56 Cao R Peng W Wang Z et al

Beta-Carboline alkaloids biochemical and

pharmacological functions Curr Med Chem

200714479-500

57 Herraiz T Evaluation of the oxidation of 1-

methyl-4-phenyl-1236-tetrahydropyridine

(MPTP) to toxic pyridinium cations by

monoamine oxidase (MAO) enzymes and its

use to search for new MAO inhibitors and

protective agents J Enzyme Inhib Med

Chem 201227810-17


monoamine oxidase enzyme inhibition by

coffee and beta-carbolines norharman and

harman isolated from coffee Life Sci

200678795-802

59 Ross GW Abbott RD Petrovitch H et al

Association of coffee and caffeine intake

with the risk of Parkinson disease JAMA

20002832674-9

60 Khalil AA Steyn S Castagnoli N Isolation

and characterization of a monoamine

oxidase inhibitor from tobacco leaves Chem

Res Toxicol 20001331-5

61 Castagnoli KP Steyn SJ Petzer JP et al

Neuroprotection in the MPTP Parkinsonian

C57BL6 mouse model by a compound

isolated from tobacco Chem Res Toxicol

200114523-7

62 Coelho-Cerqueira E Netz PA Diniz C

et al Molecular insights into human

monoamine oxidase (MAO) inhibition by

14-naphthoquinone evidences for

menadione (vitamin K3) acting as a

competitive and reversible inhibitor of

MAO Bioorg Med Chem 2011197416-24

63 Thomson RH Naturally occurring

quinones Springer London 1996

64 Jager AK Saaby L Flavonoids and the

CNS Molecules 2011161471-85

65 Dixon Clarke SE Ramsay RR Dietary

inhibitors of monoamine oxidase A J

Neural Transm 20111181031-41

66 Yoshino S Hara A Sakakibara H et al

Effect of quercetin and glucuronide

metabolites on the monoamine

oxidase-A reaction in mouse brain

mitochondria Nutrition 201127847-52

67 Xu Y Lin D Li S et al Curcumin reverses

impaired cognition and neuronal plasticity

induced by chronic stress


68 Rajeswari A Sabesan M Inhibition of

monoamine oxidase-B by the polyphenolic

compound curcumin and its metabolite

tetrahydrocurcumin in a model of

Parkinsonrsquos disease induced by MPTP

neurodegeneration in mice

Inflammopharmacology 20081696-9

69 Hamaguchi T Ono K Yamada M

REVIEW curcumin and Alzheimerrsquosdisease CNS Neurosci Therap 201016

285-97

70 Sloley BD Urichuk LJ Morley P et al

Identification of kaempferol as a

monoamine oxidase inhibitor and potential

Neuroprotectant in extracts of Ginkgo

biloba leaves J Pharm Pharmacol 200052

451-9

71 Fink AL The aggregation and fibrillation of

alpha-synuclein Acc Chem Res 200639

628-34

72 Polymeropoulos MH Lavedan C Leroy E

et al Mutation in the a-synuclein gene

identified in families with Parkinsonrsquosdisease Science 19972762045-7

73 Zarranz JJ Alegre J Gomez-Esteban JC

et al The new mutation E46K of

alpha-synuclein causes Parkinson and Lewy

body dementia Ann Neurol 200455

164-73

74 Fauvet B Mbefo MK Fares MB et al

Alpha-synuclein in the central nervous

system and from erythrocytes mammalian

cells and E coli exists predominantly as a

disordered monomer J Biol Chem

201228715345-64

75 Bartels T Choi JG Selkoe DJ a-Synucleinoccurs physiologically as a helically folded

tetramer that resists aggregation Nature

2011477107-10

76 Coelho-Cerqueira E Carmo-Goncalves P

Pinheiro A et al a-Synuclein as an

intrinsically disordered monomer - fact or

artefact FEBS J 20132804915-27

77 Burre J Vivona S Diao J et al Properties

of native brain a-synuclein Nature

2013498E4-6

78 Hasegawa M Fujiwara H Nonaka T et al

Phosphorylated alpha-synuclein is

ubiquitinated in alpha-synucleinopathy

lesions J Biol Chem 200227749071-6

79 Muntane G Dalfo E Martinez A Ferrer I

Phosphorylation of tau and alpha-synuclein

in synaptic-enriched fractions of the frontal

cortex in Alzheimerrsquos disease and in

Parkinsonrsquos disease and related

alpha-synucleinopathies Neuroscience

2008152913-23

80 Burre J Sharma M Tsetsenis T et al

Alpha-synuclein promotes SNARE-complex

assembly in vivo and in vitro Science

20103291663-7

81 Lashuel HA Hartley D Petre BM et al

Neurodegenerative disease amyloid pores

from pathogenic mutations Nature

2002418291

82 Winner B Jappelli R Maji SK et al In

vivo demonstration that alpha-synuclein

oligomers are toxic Proc Natl Acad Sci

USA 20111084194-9

83 Masliah E Rockenstein E Veinbergs I

et al Dopaminergic loss and inclusion body

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

formation in alpha-synuclein mice

implications for neurodegenerative disorders

Science 20002871265-9

84 Karpinar DP Balija MB Kugler S et al

Pre-fibrillar alpha-synuclein variants with

impaired beta-structure increase

neurotoxicity in Parkinsonrsquos disease models

EMBO J 2009283256-68

85 Feany MB Bender WW A Drosophila

model of Parkinsonrsquos disease Nature

2000404394-8

86 Kirik D Rosenblad C Burger C et al

Parkinson-like neurodegeneration induced

by targeted overexpression of

alpha-synuclein in the nigrostriatal system J

Neurosci 2002222780-91

87 Kirik D Annett LE Burger C et al

Nigrostriatal alpha-synucleinopathy induced

by viral vector-mediated overexpression of

human alpha-synuclein a new primate

model of Parkinsonrsquos disease Proc Natl

Acad Sci USA 20031002884-9

88 Volpicelli-Daley LA Luk KC Patel TP

et al Exogenous a-synuclein fibrils induce

Lewy body pathology leading to synaptic

dysfunction and neuron death Neuron

20117257-71

89 Yonetani M Nonaka T Masuda M et al

Conversion of wild-type alpha-synuclein

into mutant-type fibrils and its propagation

in the presence of A30P mutant J Biol

Chem 20092847940-50

90 Tanaka M Collins SR Toyama BH

Weissman JS The physical basis of how

prion conformations determine strain

phenotypes Nature 2006442585-9

91 Burre J Sharma M Sudhof TC Systematic

mutagenesis of a-synuclein reveals distinct

sequence requirements for physiological and

pathological activities J Neurosci 201232

15227-42

92 Hasegawa T Matsuzaki-Kobayashi M

Takeda A et al Alpha-synuclein facilitates

the toxicity of oxidized catechol metabolites

implications for selective neurodegeneration

in Parkinsonrsquos disease FEBS Lett 2006580

2147-52

93 Conway KA Rochet JC Bieganski RM

Lansbury PT Jr Kinetic stabilization of the

alpha-synuclein protofibril by a

dopamine-alpha-synuclein adduct Science

20012941346-9

94 Leong SL Pham CL Galatis D et al

Formation of dopamine-mediated

alpha-synuclein-soluble oligomers requires

methionine oxidation Free Radic Biol Med

2009461328-37

95 Nakaso K Tajima N Ito S et al

Dopamine-mediated oxidation of

methionine 127 in a-synuclein causes

cytotoxicity and oligomerization of

a-synuclein PLoS One 20038e55068

96 Follmer C Romao L Einsiedler CM et al

Dopamine affects the stability hydration

and packing of protofibrils and fibrils of

wild-type and variants of a-synucleinBiochemistry 200746472-82

97 Burke WJ Kumar VB Pandey N et al

Aggregation of alpha-synuclein by DOPAL

the monoamine oxidase metabolite of

dopamine Acta Neuropathol 2008115

193-203

98 Ono K Hasegawa K Naiki H Yamada M

Anti-parkinsonian agents have

anti-amyloidogenic activity for Alzheimeracutes

b-amyloid fibrils in vitro Neurochem Int

200648275-85

99 Ono K Hirohata M Yamada M

Anti-fibrillogenic and fibril-destabilizing

activities of anti-Parkinsonian agents for

alpha-synuclein fibrils in vitro J Neurosci

Res 2007851547-57

100 Ono K Yamada M Antioxidant

compounds have potent anti-fibrillogenic

and fibril-destabilizing effects for

alpha-synuclein fibrils in vitro J Neurochem

200697105-15

101 Ono K Mochizuki H Ikeda T et al Effect

of melatonin on a-synuclein self-assembly

and cytotoxicity Neurobiol Aging 201233

2172-85

102 Hirohata M Ono K Morinaga A et al

Anti-aggregation and fibril-destabilizing

effects of sex hormones on alpha-synuclein

fibrils in vitro 2009217434-9

103 Ono K Yamada M Vitamin A potently

destabilizes preformed alpha-synuclein fibrils

in vitro implications for Lewy body

diseases Neurobiol Dis 200725446-54

104 Silva FL Coelho-Cerqueira E Freitas MS

et al Vitamins K interact with N-terminus

a-synuclein and modulate the protein

fibrillization in vitro Exploring the

interaction between quinones and

a-synuclein Neurochem Int 201362

103-12

105 Di Giovanni S Eleuteri S Paleologou KE

et al Entacapone and tolcapone two

catechol O-methyltransferase inhibitors

block fibril formation of alpha-synuclein

and beta-amyloid and protect against

amyloid-induced toxicity J Biol Chem

201028514941-54

106 Zhu M Rajamani S Kaylor J et al The

flavonoid baicalein inhibits fibrillation of

alpha-synuclein and disaggregates existing

fibrils J Biol Chem 200427926846-57

107 Li HT Lin DH Luo XY et al Inhibition

of alpha-synuclein fibrillation by dopamine

analogs via reaction with the amino groups

of alpha-synuclein Implication for

dopaminergic neurodegeneration FEBS J

20052723661-72

108 Mannisto PT Tuomainen P

Tuominen RK Different in vivo properties

of three new inhibitors of catechol

O-methyltransferase in the rat Br J

Pharmacol 1992105569-74

109 Ahmad B Lapidus LJ Curcumin prevents

aggregation in a-synuclein by increasing

reconfiguration rate J Biol Chem 2012287

9193-9

110 Pandey N Strider J Nolan WC et al

Curcumin inhibits aggregation of

alpha-synuclein Acta Neuropathol

2008115479-89

111 Wang MS Boddapati S Emadi S

Sierks MR Curcumin reduces

alpha-synuclein induced cytotoxicity in

Parkinsonrsquos disease cell model BMC

Neurosci 20101157

112 Liu Z Yu Y Li X et al Curcumin protects

against A53T alpha-synuclein-induced

toxicity in a PC12 inducible cell model for

Parkinsonism Pharmacol Res 201163

439-44

113 Ono K Yoshiike Y Takashima A et al

Potent anti-amyloidogenic and

fibril-destabilizing effects of polyphenols in

vitro implications for the prevention and

therapeutics of Alzheimerrsquos disease JNeurochem 200387172-81

114 Hou WC Lin RD et al Monoamine

oxidase B (MAO-B) inhibition by active

principles from Uncaria rhynchophylla J

Ethnopharmacol 2005100216-20

115 Johnston TH Brotchie JM Drugs in

development for Parkinsonrsquos diseasean update Curr Opin Investig Drugs

2006725-32

116 Dalpiaz A Cacciari B Vicentini CB et al

A novel conjugated agent between

dopamine and an A2A adenosine receptor

antagonist as a potential anti-Parkinson

multitarget approach Mol Pharm 2012

9(3)591-604

117 Gal S Zheng H Fridkin M Youdim MB

Restoration of nigrostriatal dopamine

neurons in post-MPTP treatment by the

novel multifunctional brain-permeable

iron chelator-monoamine oxidase

inhibitor drug M30 Neurotox Res

20101715-27

118 Youdim MB Fridkin M Zheng H

Bifunctional drug derivatives of MAO-B

inhibitor rasagiline and iron chelator



Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

VK-28 as a more effective approach to

treatment of brain ageing and ageing

neurodegenerative diseases Mech Ageing

Dev 2005126317-26

119 Youdim MB Multi target neuroprotective

and neurorestorative anti-Parkinson and

anti-Alzheimer drugs ladostigil and

m30 derived from rasagiline Exp Neurobiol

2013221-10

120 Geha RM Rebrin I Chen K Shih JC

Substrate and inhibitor specificities for

human monoamine oxidase A and B are

influenced by a single amino acid J Biol

Chem 20012769877-82

121 Han XH Hong SS Hwang JS et al

Monoamine oxidase inhibitory components

from Cayratia japonica Arch Pharm Res

20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y

Catecholamine metabolism amp oxidative stress

MAO inhibition

Inhibition of MAO by synthetic amp natural compounds

Role of AS in PD

DA oxidative stress amp AS fibrillation

Targeting AS fibrillation

Molecules targeting on both AS amp MAO

Conclusion

Expert commentary

Five-year view


Certain inhibitors of MAO (IMAO) used in PD therapy dis-play a broad spectrum of neuroprotective activities includinganti-apoptotic and antioxidant actions [17ndash19] Strikingly theIMAO-B selegiline was suggested to inhibit the formation oftoxic aggregates AS [20] Although the role of AS in the patho-genesis of PD is not completely elucidated the stabilization ofnon-toxic aggregates of the protein might represent an impor-tant strategy in the development of new therapies for PDBesides PD AS is involved in other neurodegenerative disordersthat include dementia with Lewy bodies and multiple systematrophy [21ndash24] AD is actually the condition that is most com-monly associated with secondary AS aggregation [25] and one-half of the patients with familial forms of AD exhibits numerousfibrillar AS aggregates in the form of Lewy bodies in their amyg-dala [26] Thus AS might be considered a potential target in thedevelopment of therapies not only for PD but also for AD

Understanding the molecular basis of different targets associ-ated with PD might provide new perspectives in the developmentof therapies capable of interfering not only with symptoms butalso with the progression of the neurodegenerative processHerein we revisit some important pathways associated with theneuropathogenesis of PD including the non-enzymatic andMAO-mediated oxidation of DA as well as the AS fibrillationConsidering these pathways we discuss the biochemical proper-ties of molecules that are capable of acting on both dopaminergicsystem and AS fibrillation focusing on MAO inhibitors thatinterfere with the formation of neurotoxic aggregates of AS

Catecholamine metabolism amp oxidative stressThe characteristic symptoms of PD are associated primarilywith the loss of DA and norepinephrine neurons in the sub-stantia nigra and locus coeruleus [1ndash3] DA epinephrine andnorepinephrine the major catecholamines in human tissueshave widespread projection to the cortex basal ganglia and lim-bic areas and play important roles in the regulation of diversebrain functions such as mood memory behavior and move-ment which are lost in PD and AD [314] This high selectivityof neuronal degeneration reinforces the hypothesis that

catecholamine neurons produce specific neurotoxins whoseaccumulation might trigger neuronal death Among these toxicspecies are reactive oxygen species (ROS) and toxic metabolitesgenerated from DA metabolism [527]

An increase of oxidative stress mediated by mitochondrialdysfunction decreased concentrations of antioxidants andincreased iron levels have been associated with neurodegenera-tion in PD [4ndash6] Although low concentrations of ROS stimu-late several cellular processes and regulate certain physiologicalfunctions [28] excessive ROS production can result in lipid per-oxidation and chemical modifications of proteins and nucleicacids which might trigger cellular degeneration [29] Oxidativestress can be generated in dopaminergic neurons through DAdegradation via both non-enzymatic and enzymatic pathwaysDA undergoes non-enzymatic oxidation (erroneously namedauto-oxidation) to generate semiquinone radical and ortho-quinone that are potentially toxic to cells [30] These species inturn undergo polymerization to form neuromelamin with theconcomitant generation of ROS as shown in FIGURE 1 Alterna-tively ROS might be generated from the conversion ofprostaglandin-G2 to prostaglandin-H2 catalyzed by peroxidaseactivity of cyclooxygenase (COX) In this process DA can actas a co-substrate during donation of electrons to COX leadingto the formation of DA-quinone Interestingly an upregulationof COX-2 has been reported in nigrostriatal dopaminergic neu-rons in both MPTP mice model and human PD samples [31]Therefore toxic metabolites and ROS are continuously gener-ated from DA oxidation which could explain at least in partthe selectivity of degeneration of dopaminergic neurons In thiscontext it has been proposed that the administration of antiox-idants could slow the rate of progression of PD even thoughevidences to support this therapeutic strategy are still limited

The enzymatic oxidation of DA by the enzymes MAO-Aand MAO-B produces the aldehyde 34-dihydroxyphenylacetal-dehyde (DOPAL) and hydrogen peroxide Indeed withindopaminergic nerve terminals the oxidative deamination ofDA by MAO action is the main catabolic pathway for DA [14]MAO-induced oxidative stress occurs as a result of an increase

NH2NH2

HO

HO

O

O

NH2

O-

O

NH

HO

HO NH

-1 e-

2 e-

Oxidation

Dopamine Dopamine ortho-quinone Dopaminechrome Leucodopaminechrome

Dopaminesemiquinone radical

Neuromelanin

ROS

-1 e-

ROS

O

O

Figure 1 Potential neurotoxic quinones and reactive oxygen species are produced in the non-enzymatic oxidation ofdopamineROS Reactive oxygen species

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y









ONH2

HO

HO

HO

HO


Dopamine DOPAL

MAO





Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y







Model I


Model II

SNARE complex

Fibrillization


Disordered monomer


Nontoxic oligomers

Fibrils


SNARE




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






DOPAL

MAO

H2O2 + Fe2+ ----gt Fe3+ + OH + OH-

H2O2 + Fe3+ ----gt Fe2+ + OOH + H+

Fenton reaction

Toxicprotofibrils

No toxicoligomers

Fibrils

Unfolded monomerA

B

C




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y









Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]


MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]



CurcuminO O

H3CO

OHHO

OCH3



Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]


CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]



Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view










ONH2

HO

HO

HO

HO


Dopamine DOPAL

MAO





Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y







Model I


Model II

SNARE complex

Fibrillization


Disordered monomer


Nontoxic oligomers

Fibrils


SNARE




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






DOPAL

MAO

H2O2 + Fe2+ ----gt Fe3+ + OH + OH-

H2O2 + Fe3+ ----gt Fe2+ + OOH + H+

Fenton reaction

Toxicprotofibrils

No toxicoligomers

Fibrils

Unfolded monomerA

B

C




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y









Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]


MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]



CurcuminO O

H3CO

OHHO

OCH3



Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]


CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]



Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view












Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y







Model I


Model II

SNARE complex

Fibrillization


Disordered monomer


Nontoxic oligomers

Fibrils


SNARE




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






DOPAL

MAO

H2O2 + Fe2+ ----gt Fe3+ + OH + OH-

H2O2 + Fe3+ ----gt Fe2+ + OOH + H+

Fenton reaction

Toxicprotofibrils

No toxicoligomers

Fibrils

Unfolded monomerA

B

C




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y









Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]


MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]



CurcuminO O

H3CO

OHHO

OCH3



Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]


CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]



Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view








Model I


Model II

SNARE complex

Fibrillization


Disordered monomer


Nontoxic oligomers

Fibrils


SNARE




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






DOPAL

MAO

H2O2 + Fe2+ ----gt Fe3+ + OH + OH-

H2O2 + Fe3+ ----gt Fe2+ + OOH + H+

Fenton reaction

Toxicprotofibrils

No toxicoligomers

Fibrils

Unfolded monomerA

B

C




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y









Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]


MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]



CurcuminO O

H3CO

OHHO

OCH3



Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]


CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]



Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view












Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






DOPAL

MAO

H2O2 + Fe2+ ----gt Fe3+ + OH + OH-

H2O2 + Fe3+ ----gt Fe2+ + OOH + H+

Fenton reaction

Toxicprotofibrils

No toxicoligomers

Fibrils

Unfolded monomerA

B

C




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y









Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]


MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]



CurcuminO O

H3CO

OHHO

OCH3



Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]


CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]



Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view







DOPAL

MAO

H2O2 + Fe2+ ----gt Fe3+ + OH + OH-

H2O2 + Fe3+ ----gt Fe2+ + OOH + H+

Fenton reaction

Toxicprotofibrils

No toxicoligomers

Fibrils

Unfolded monomerA

B

C




Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y









Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]


MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]



CurcuminO O

H3CO

OHHO

OCH3



Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]


CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]



Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view










Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]


MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]



CurcuminO O

H3CO

OHHO

OCH3



Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]


CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]



Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view




Selegiline

N

H3C

CH3

CH

MAO-B

IC50 = 4 nM [120]


MenadioneO

O

CH3

MAO-B

Ki = 04 mM [62]



CurcuminO O

H3CO

OHHO

OCH3



Quercetin

O

OH

OOH

OH

OH

HO

MAO-A

IC50 = 28 mMMAO-B

Ki = 90 mM [121]


CatechinOH

O

OH

OH

HO

OH

MAO-B

Ki = 74 mM [114]



Epicatechin

HO

OH

O

OH

OH

OH

MAO-B

Ki = 21 mM [114]






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y











Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view












Key issues






therapies for PD










References







Science 1983219979-80

























457-68




20067295-309






Kaempferol

O

OH

OOH

OH

HO

MAO-A

IC50 = 07 mM [70]




Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y






1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view







1285-97





2002922-6







Sci USA 1985822173-7





Berlin 1998 p 127-99




199718431-5






15-30





1200-6













254-73



Nature 1997388839-40







1999225363-8





180-2




1998152879-84











Pathol 19981531365-70












Signal 201224981-90












163-72









201128626978-86






637-47




Disord 20142068-72




1450-5






Res 200060552-8


Accumulation of 34-



















243-50














Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y








209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view









209-10





Res 199673853-9





1359-65






199441189-96
















Res 20046343-61





Res Commun 2005326378-86










200714479-500







Chem 201227810-17





200678795-802




20002832674-9









200114523-7

































285-97






451-9



628-34








164-73






201228715345-64



2011477107-10







2013498E4-6











2008152913-23




20103291663-7




2002418291




USA 20111084194-9



Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y



Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view




Science 20002871265-9





EMBO J 2009283256-68



2000404394-8





Neurosci 2002222780-91






Acad Sci USA 20031002884-9





20117257-71





Chem 20092847940-50









15227-42






2147-52





20012941346-9





2009461328-37














193-203





200648275-85





Res 2007851547-57





200697105-15




2172-85















103-12







201028514941-54










20052723661-72





Pharmacol 1992105569-74




9193-9




2008115479-89





Neurosci 20101157





439-44












2006725-32






9(3)591-604







20101715-27






Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y




Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view





Dev 2005126317-26





2013221-10





Chem 20012769877-82




20073013-17

Review Follmer


Exp

ert R

evie

w o

f N

euro

ther

apeu

tics

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Nat

iona

l Uni

vers

ity o

f Si

ngap

ore

on 0

524

14

For

pers

onal

use

onl

y


MAO inhibition


Role of AS in PD




Conclusion

Expert commentary

Five-year view


Monoamine oxidase and α-synuclein as targets in Parkinson’s disease therapy

Documents

Transcript of Monoamine oxidase and α-synuclein as targets in Parkinson’s disease therapy