review article metabotropic glutamate receptors for parkinson … · 2019. 7. 31. ·...

Hindawi Publishing CorporationParkinsonrsquos DiseaseVolume 2013 Article ID 196028 11 pageshttpdxdoiorg1011552013196028

Review ArticleMetabotropic Glutamate Receptors forParkinsonrsquos Disease Therapy

Fabrizio Gasparini1 Theacuteregravese Di Paolo23 and Baltazar Gomez-Mancilla1

1 Novartis Pharma AG Novartis Institutes for BioMedical Research Basel Forum 1 Novartis Campus 4056 Basel Switzerland2Neuroscience Research Unit Centre Hospitalier Universitaire de Quebec CHUL Quebec City QC Canada G1V 4G23 Faculty of Pharmacy Laval University Quebec City QC Canada G1K 7P4

Correspondence should be addressed to Fabrizio Gasparini fabriziogasparininovartiscom

Received 17 March 2013 Accepted 29 May 2013

Academic Editor Francisco Grandas

Copyright copy 2013 Fabrizio Gasparini et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Excessive glutamatergic signalling within the basal ganglia is implicated in the progression of Parkinsonrsquos disease (PD) and inthe emergence of dyskinesia associated with long-term treatment with L-DOPA There is considerable research focus on thediscovery and development of compounds that modulate glutamatergic signalling via glutamate receptors as treatments for PDand L-DOPA-induced dyskinesia (LID) Although initial preclinical studies with ionotropic glutamate receptor antagonists showedantiparkinsonian and antidyskinetic activity their clinical use was limited due to psychiatric adverse effects with the exception ofamantadine a weak N-methyl-d-aspartate (NMDA) antagonist currently used to reduce dyskinesia in PD patients Metabotropicreceptor (mGlu receptor) modulators were considered to have a more favourable side-effect profile and several agents have beenstudied in preclinical models of PD The most promising results have been seen clinically with selective antagonists of mGlu5receptor and preclinically with selective positive allosteric modulators of mGlu4 receptorThe growing understanding of glutamatereceptor crosstalk also raises the possibility of more precise modulation of glutamatergic transmission which may lead to thedevelopment of more effective agents for PD

1 Introduction

Parkinsonrsquos disease (PD) is a chronic progressive neurodegen-erative disorder of the central nervous system (CNS) charac-terised by a gradual loss of dopaminergic neurotransmissionCardinal symptoms of PD include tremor bradykinesia andrigidity Levodopa (L-DOPA) is considered the standard ofcare for providing symptomatic relief in PD [1] Howeverlong-term L-DOPA treatment leads to the appearance ofmotor complications in the majority of responding patientsand severely affects their quality of life [2] After 9 years of L-DOPA treatment sim90 of PD patients experience dyskinesia[3] The dyskinesia that develops is often a combinationof choreic and dystonic abnormal involuntary movementscollectively termed L-DOPA-induced dyskinesia (PD-LID)

Once PD-LID is established increasing the L-DOPAdose typically worsens dyskinesia and this may prevent theuse of L-DOPA at optimal doses required to control motor

fluctuationsThere are currently no licensed therapies for thetreatment of PD-LID although a number of clinical strategiesare employed including adding dopamine agonistsmonoam-ine oxidase inhibitors adenosine (2A) receptor antagonistscatechol-O-methyl transferase inhibitors and anticholinergicdrugs as part of a L-DOPA-sparing strategy [4ndash7] and the useof amantadine [8] see Tambasco et al 2012 for a recent review[9]

The precise mechanisms of PD-LID are not completelyunderstood but excessive glutamatergic transmission withinthe basal-ganglia is thought to play a key role in the patho-physiology of PD and PD-LID [10 11] Therefore therapeuticagents that regulate glutamate transmission are valid targetsfor drug development to alleviatemotor symptoms associatedwith PD and PD-LID (Table 1) In this paper we will reviewattempts to develop therapeutic agents capable of normalis-ing defective glutamatergic transmission via modulation ofglutamate receptors

2 Parkinsonrsquos Disease

Table 1 Glutamatergic agents cited within the text with their pharmacological profile main targets and mode of action

Target Agent Pharmacological action

AMPA receptor

GYKI-52466 Noncompetitive antagonistGYKI-53405 Noncompetitive antagonist

NBQX Competitive antagonistPerampanel Noncompetitive antagonist

AMPAkainate receptor Tezampanel (LY293558) Competitive antagonistTalampanel (LY300164) Noncompetitive antagonist

AMPANMDA receptor CPP Competitive antagonist

NMDA receptor

Amantadine Noncompetitive antagonistAPV Competitive antagonist

CGP-43487 Competitive antagonistIfenprodil Noncompetitive antagonistPAMQX Competitive antagonist

Remacemide Noncompetitive antagonistTraxoprodil Noncompetitive antagonist

mGlu1 receptor EMQMCM Noncompetitive antagonistmGlu2 receptor LY379268 Competitive agonist

mGlu4 receptorPHCCC PAMADX88178 PAMVU0155041 PAM

mGlu4mGlu5 receptor SIB-1893 PAMnoncompetitive antagonist

mGlu5 receptor

Dipraglurant (ADX48621) Noncompetitive antagonistMavoglurant (AFQ056) Noncompetitive antagonist

MPEP Noncompetitive antagonistMRZ-8676 Noncompetitive antagonistMTEP Noncompetitive antagonist

mGlu7 receptor AMN082 PAMmGlu8 receptor DCPG Competitive agonist

2 Basal Ganglia Circuitry inParkinsonrsquos Disease

A balance between inhibition and excitation of the majoroutput nuclei of the basal ganglia is important for normalmotor control This is achieved via direct and indirectinhibitory projections (GABAergic) from the striatum(caudate nucleusputamen) to the globus pallidus internal(GPi)substantia nigra pars reticulate (SNr) and excitatoryprojections (glutamatergic) from the subthalamic nucleus(STN) to the substantia nigra pars compacta (SNc) and GPiSNr Appropriate dopaminergic input from the SNc to thestriatum plays a key role in maintaining this balance [12] Inpatients with PD degeneration of dopamine nigral neuronswithin the SNc results in loss of dopaminergic modulationand increases the overall excitatory drive in the basalganglia disrupting voluntary motor control and causing thecharacteristic symptomsof PD [13]Theprogressive depletionof the endogenous dopaminergic signalling combined withthe compensatory exogenous supply of dopamine (DA)precursor L-DOPA induces profound changes in the neuro-transmitter network of the basal ganglia [14] An imbalancein the DA receptors particularly between D1 and D2receptor subtypes mainly expressed in the direct and indirect

striatal output pathways respectively has been identified indyskinetic nonhuman primates [15 16] In rodents geneticablation of the D1 receptor subtype but not the D2 subtypeabolished the L-DOPA-induced dyskinesia These resultssuggest a key role for the D1 receptor in the development ofPD-LID [16] However a role for D2 receptors in the onsetand expression of L-DOPA induced dyskinesias is also docu-mented [17] Additional changes in other dopamine receptorsubtypes such as D3 and D5 have also been identified [18]

The cellular mechanisms by which the dopaminergicneurons are lost are not fully understood although excessiveglutamatergic transmission has been implicated [19 20]Glutamate is themain excitatory neurotransmitter in theCNSand normal brain function requires balanced glutamater-gic neurotransmission As a result of striatal dopaminergicdenervation the glutamatergic projections from the STNto the basal ganglia output nuclei become overactive withreduced regulation of glutamate receptors [19] The resultantexcessive excitation by glutamate through the basal gangliacircuitry can be toxic to any remaining dopaminergic neu-rons leading to further loss of dopaminergic transmissionand progression of PD symptoms [21] Normalisation ofmotor function is initially seen with L-DOPA treatmentHowever as the severity of PD increases the substantial

Parkinsonrsquos Disease 3

dopaminergic depletion leads to further adaptive changesin the basal ganglia pathways including altered function ofnondopaminergic basal ganglia neurotransmitters such asglutamate GABA and serotonin [22] Advanced nigral celldegeneration is considered responsible for the priming ofthe basal ganglia as dyskinesia develops rapidly in monkeyswith drug-induced nigral denervation following L-DOPAtreatment [13] whereas L-DOPA treatment alone in animalmodels or healthy humans does not induce dyskinesia [2324] Further evidence for a role for excessive glutamatetransmission in PD and PD-LID comes from the clinicaluse of amantadine a weak antagonist of NMDA glutamatereceptors in the treatment of PD-LID To reduce the effects ofthe excessive glutamatergic transmission several approachesaiming to modulate the glutamate receptors are availableThese different approaches are dependent on the localisationand the function of each receptor subtype as illustrated onFigure 1 and will be described in the following sections

3 Glutamate Receptors in Parkinsonrsquos Disease

Glutamate receptors modulate glutamatergic neurotransmis-sion in the brain and play a role in memory learning andmotor control glutamatergic dysfunction is implicated in arange of neurological disorders [25ndash27] Two classes of glu-tamate receptor have been described ionotropic glutamatereceptors (iGlu receptors) [28] and metabotropic glutamatereceptors (mGlu receptors) [26]

31 Ionotropic Glutamate Receptors iGlu receptors areligand-gated ion channels composed of four large subunitsthat form a central pore within the cell membrane The iGlureceptors include theNMDA (N-methyl-d-aspartate) AMPA(120572-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)and kainate ([2S3S4S]-3-[carboxymethyl]-4-prop-1-en-2-yl-pyrrolidine-2-carboxylic acid) receptors all of which sharea similar structure but differ in their amino acid sequencessubunit combination and agonist sensitivityselectivityWithin the CNS iGlu receptors are responsible for fast exci-tatory transmission [28] Their important role in mediat-ing glutamatergic neurotransmission identifies the iGlureceptors as potential therapeutic targets for symptomaticmanagement in PD and PD-LID

311 AMPA Receptors Within the mammalian CNS themajority of fast excitatory synaptic transmission is mediatedby AMPA receptors [29] AMPA receptor function is criticalfor synaptic plasticity The potential for therapeutic AMPAmodulation for PD is yet to be conclusively proven Preclini-cal studies of AMPA receptor antagonists 6-nitro-sulfamoyl-benzo-quinoxaline-dione (NBQX) andGYKI-52466 failed toshow antiparkinsonian activity when they were administeredalone [30ndash34] NBQX has shown some antiparkinsonianactivity in another study where it reversed reserpine-inducedmuscle rigidity but not akinesia in monoamine-depletedrats and motor deficits in MPTP-lesioned Rhesus monkeys[35] In another study NBQX was combined with the com-petitive NMDA receptor antagonist 3-carboxy- piperazin-propyl phosphonic acid (CPP) and reversed the shortened

duration of L-DOPA-induced motor responses [36] Inter-estingly NBQX [31 32 34] and CPP [30 31] both potentiatethe antiparkinsonian effects of coadministered dopaminergicagents L-DOPA-sparing effects have also been shown inpreclinical models with GYKI-52466 and GYKI-53405 [3738]

Increased AMPA receptor activity has been implicatedin the development of LID [11 39] The competitive AMPAkainate receptor antagonist LY293558 (tezampanel) reversedand prevented LID in parkinsonian rats [40] and the non-competitive AMPAkainate antagonist LY300164 (talam-panel) decreased LID in MPTP-treated monkeys by up to40 [41] Another non-competitive AMPA receptor antag-onist perampanel showed promising results in preclinicalstudies reducing L-DOPA-induced motor defects 6-OHDA-primed rats [42] and dyskinesia in MPTP-treated monkeys[43] Unfortunately these results have not successfully trans-lated to the clinical setting and initial phase II and III trials ofperampanel were terminated because of lack of efficacy [44ndash46]

312 NMDA Receptors NMDA receptors mediate glutama-tergic excitation in the striatum and STN NMDA-mediatedsignalling in the brain is thought to be involved in bothneural plasticity and neurotoxicity [24] Dysfunctions inNMDA receptor trafficking in striatal neurons result in thealtered synaptic plasticity seen in animal models of PDand dyskinesia [47] Several antagonists of NMDA receptorshave shown therapeutic potential in animal models of PDneuroprotective activity by limiting the extent of nigrostriataldamage [48] or behavioural effects through the improvementofmotor symptoms of PD [49 50] and preventing or reducingLID [51ndash55] Administration of competitive NMDA receptorantagonists such as CPP CGP-43487 and APV which targetthe glutamate binding site or PAMQX which binds to theglycine site in NMDA heterodimers has also been shown topotentiate dopaminergic therapies in preclinical PD models[34 56 57] There is also evidence of synergism betweenAMPA and NMDA antagonists in animal models of PD andLID [31 58] Further evidence of crosstalk between receptorsinvolved in PD pathophysiology comes from studies showinginteractions with 5-HT (2A) receptors [59 60] and adenosine(2A) receptors in animalmodels [61] raising the possibility ofadenosine (2A) or 5-HT (2A) receptor modulation as a noveltherapeutic strategy for PDNR2B-selective non-competitiveNMDA receptor antagonists tnaxoprodil and ifenprodilhave shown therapeutic potential in animal models of PD-LID [50 52 62 63]

Despite positive results in preclinical studies clinicaldevelopment of NMDA antagonists has been hampered bythe side effects of these compounds including psychosisimpaired learning and disruption of motor function [64]which pose substantial problems with chronic use Thisobserved absence of a therapeutic window is likely due to thewide expression ofNMDAreceptors throughout theCNS andtheir key involvement in many physiological processes

The greatest success with NMDA antagonists in PDand PD-LID has been seen with amantadine a weak non-competitive NMDA receptor antagonist Amantadine is


Glu

mGluR7

mGluR2

mGluR5

mGluR5mGluR1

mGluR3

Presynaptic

Postsynaptic

Astrocyte

Ca2+

Na+

NMDAR

AMPAR

Kainate R

IP3DAG

PKC

PLC

PLD

MAPK

mGluR4 8

Figure 1 Schematic representation of ionotropic and metabotropic glutamate receptor subtypes their intracellular function and synapticlocalization AMPAR 120572-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor DAG diacylglycerol iGluR ionotropic glutamatereceptor IP

3 inositol (145)-triphosphate MAPK mitogen-activated protein kinase mGluR metabotropic glutamate receptor NMDAR

N-methyl-d-aspartate receptor PKC protein kinase C PLC phospholipase C PLD phospholipase D (reproduced with permission fromNovartis Pharma AG 2008 Novartis)

approved for the treatment of PD and is widely used totreat PD-LID (off-label indication) due to its inclusion ininternational guidelines [65 66] Antidyskinetic activity withamantadine has been reported in both 6-OHDA rodent andMPTP primate models of LID [60 67 68] Clinical benefitswith amantadine in PD-LID have been seen in an increasingnumber of clinical trials [69ndash74] and the benefits appear tobe long lasting [75 76] An extended-release formulationof amantadine amantadine ER (ADSndash5102) is currently inclinical trials for PD-LID Other non-competitive NMDAreceptor antagonists that have been investigated in the clinicalsetting include remacemide which has failed to show benefitin the symptomatic management of PD and LIDs [77ndash80] The non-competitive NMDA receptor antagonist traxo-prodil has shown clinical efficacy in two small studies [81 82]

313 Kainate Receptors The existence of kainate receptorshas been known for some time yet little is understood aboutthe contribution to the pathology of PD or the potential ofkainate receptors as therapeutic targets in PD and PD-LIDThis is primarily due to a lack of selective pharmacologicalagents to help elucidate the complex molecular mechanismsunderlying these conditions

32 Metabotropic Glutamate Receptors The limitations oftargeting iGlu receptors in PD combined with the highexpression of mGlu receptors in the basal ganglia and theirdiverse modulatory roles has raised the interest in mGlureceptors as alternative targets for modulating glutamate

hyperactivity in PD [12 27] mGlu receptors belong tothe G-protein-coupled receptor family and are membrane-bound and activated by extracellular ligands Unlike thefast excitatory glutamatergic transmission mediated by iGlureceptors mGlu receptors have a more modulatory roleresponsible for fine tuning glutamatergic transmission [26]EightmGlu receptor subtypes have been cloned and classifiedinto three groups according to sequence similarity signaltransduction mechanism and pharmacological properties[26] Group I (mGlu1 and 5) receptors are coupled toactivation of phospholipase C and mediate postsynapticexcitatory effects They are mainly located postsynapticallyand modulate glutamate transmission through negative andpositive regulation of potassium and calcium ion channelsrespectively Group II (mGlu2 and 3) and Group III (mGlu46 7 and 8) receptors are negatively coupled to adenyl cyclaseand inhibit cAMP formation Both groups are generallylocated presynaptically and inhibit neurotransmitter releaseprimarily through modulation of calcium and potassium ionchannels Of these 8 subtypes mGlu5 and mGlu4 receptorsare of particular interest as therapeutic targets in PD giventheir expression and distribution in the basal ganglia

321 Group I mGlu Receptors Group I receptors mGlu1 and5 share a high degree of sequence homology but their expres-sion patterns within the brain differ considerably (Figure 2)suggesting that they may have distinct functional roles inbrain physiology and pathophysiology


Hi SC

Th

LS IC

OT Acb

SpV

mGlu1

mGlu5

Figure 2 Immunolocalisation of mGlu 1 and 5 receptors within ratbrain parasagittal sections Acb nucleus accumbens Hi hippocam-pus IC inferior colliculus LS lateral septal nucleus OT olfactorytubercle SC superior colliculus SpV spinal trigeminal nuclei Ththalamus [84]

The role of mGlu1 receptor in PD and PD-LID was exam-ined using the selective antagonist (3-ethyl-2-methyl-quin-olin-6-yl)-(4-methoxy-cyclohexyl)-methanonemethane sul-fonate (EMQMCM) in 6-OHDA primed rats [83] Treat-ment with EMQMCM induced some improvement of dysk-inesia altered downstream molecular signalling pathwaysand attenuated L-DOPA-induced gene expression Howeverthese effects were achieved at a dose which blocked theantiakinetic (antiparkinsonian) action of L-DOPA Togetherthese data do not support the use of mGlu1 receptor antago-nists as a treatment for PD-LID

The high expression of mGlu5 receptor in the caudatenuclei putamen and basal ganglia [85 86] and its postsynap-tic localisation make the mGlu5 receptor an attractive targetto modulate the excessive glutamatergic neurotransmissioninduced by the loss of dopaminergic innervation The firstattempts to inhibit the mGlu5 receptor were made withcompetitive and nonselective antagonists These early toolcompounds had poor in vivo properties and brain penetra-tion resulting in an inability to identify a role for the mGlu5receptor The identification and use of more specific toolcompounds such as 2-methyl-6-(phenylethynyl)-pyridine(MPEP) enabled the hypothesis to be tested in variousanimal models of PD The first confirmation of the potentialto modulate excessive glutamatergic neurotransmission viainhibition of mGlu5 receptor came from the work of Spoorenet al [87]They showed that MPEP could attenuate unilateralrotating behaviour in the rat 6-hydroxydopamine (6-OHDA)lesion model Shortly after Breysse et al [88] providedfurther supportive data by showing how chronic (but notacute) treatment with MPEP could improve akinesia inthe 6-OHDA rat model However in this study no effectson haloperidol-induced catalepsy were observed followingMPEP treatment [88] In rats with nigrostriatal lesionsMPEP virtually abolished abnormal involuntary movements[89] Using 3-[(2-methyl-13-thiazol-4-yl) ethynyl]pyridine

(MTEP) which has superior specificity and bioavailabilityto MPEP a reduction of haloperidol-induced catalepsy andmuscle rigidity in rats was seen [90]

More recently mGlu5 receptor expression was shownto be enhanced within the posterior putamen and globuspallidus of parkinsonian monkeys experiencing dyskinesiafollowing chronic L-DOPA treatment [91] and in humanpostmortem brains of parkinsonian patients with dyskinesiaand wearing off [92] In addition animal models of PD-LIDshow upregulation of mGlu5 receptor genes reflecting long-term changes associated with the development of dyskinesia[93] There is also evidence of crosstalk between mGlu5receptors and NMDA receptors in the striatum and subtha-lamic nucleus [94 95] and it is possible that therapeuticmodulation of mGlu5 receptors may have beneficial effectson NMDA receptor signalling in PD Additionally mGlu5receptors and adenosine A (2A) receptors are coexpressed inD2 striatal neurons and interact to regulate the downstreameffects of mGlu5 receptor activity [96ndash99]

The first evidence for the therapeutic potential of mGlu5antagonists in PD-LID was presented by Hill et al [100]using the noncompetitive antagonist SIB-1893 to ease LIDsinMPTP-lesionedmonkeys Interestingly SIB-1893was iden-tified initially as a relatively weak mGlu5 receptor antago-nist (IC

50= 23 120583M) [101] whereas further characterisation

revealed SIB-1893 to also be a positive allosteric modulator(PAM) of the mGlu4 receptor [102]

The use of MTEP confirmed that antagonism of mGlu5receptor attenuates LID in 6-OHDA lesioned rats [103 104]andMPTP-lesioned monkeys [105] In MPTP-lesioned mon-keys MPEP showed antiparkinsonian effects and reducedthe development of LID [106] Similar results were seenwith both MPEP and MTEP in MPTP-lesioned mon-keys treated with L-DOPA [105] Other selective mGlu5receptor antagonists that have shown preclinical anti-dyskinetic effects include 66-dimethyl-2-phenylethynyl-78-dihydro-6H-quinolin-5-one (MRZ-8676) [100] dipraglu-rant (ADX48621 Addex Press Release) and mavoglurant(AFQ056) which reduced dyskinesia in L-DOPA-treatedMPTP-lesioned monkeys [100] In addition mavoglurantdid not adversely affect the response to L-DOPA in MPTP-lesioned monkeys but did potentiate the effects of low dosesof L-DOPA [107]

In contrast to other therapeutic approaches in PD thewealth of preclinical data supporting the potential of mGlu5receptor antagonists in treating PD and LID has been con-firmed clinically by two drug candidates mavoglurant [108109] and dipraglurant [110] Both have shown significant anti-dyskinetic activity in patients with moderate-to-severe PD-LID Follow-up trials with both mavoglurant and dipraglu-rant are ongoing

322 Group III mGlu Receptors Among the Group III mGlureceptors mGlu4 7 and 8 are expressed at multiple synapsesthroughout the basal ganglia and mainly localised presy-naptically [12 85] Their activation inhibits neurotransmitterrelease a mechanism implicated in the pathophysiology ofPD [111ndash113] Preclinical studies with selective Group IIImGlu receptor competitive agonists reversed akinesia and


haloperidol-induced catalepsy in rodent models of PD [114ndash116]

Similarly PAMs targeting mGlu4 receptor have shownsome antiparkinsonian activity in animal models of PDFor example N-phenyl-7-(hydroxyimino) cyclopropa[b]-chromen-1a-carboxamide (PHCCC) reversed risperidine-induced akinesia in rats [117] and reduced striatal dopamineneuron degeneration in MPTP-treated mice [118] HoweverPHCCC has low potency and poor aqueous solubility anddemonstrates antagonism at mGlu1 receptors at a similarpotency to that at mGlu4 receptors [117] Therefore agentsexhibiting greater potency and selectivity for mGlu4 recep-tors have been sought to clarify the therapeutic potentialof targeting this receptor subtype in PD One such agentVU0155041 has shown antiparkinson activity in haloperidol-induced catalepsy and 6-OHDA lesioned rats [119 120]VU0155041 also demonstrated synergy when coadministeredwith the adenosine (2A) receptor agonist preladenant as wellas L-DOPA suggesting a potential L-DOPA-sparing mech-anism [120] Similarly 5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl) thiazol-2-amine (ADX88178) a PAMwith high bioavailability and specificity for mGlu4 receptorhas antiparkinsonian activity including potentiation of L-DOPA effects without increasing LID [121]

Activation of the mGlu7 receptor using the PAMNN1015840-dibenzhydrylethane-12-diamine dihydrochloride(AMN082) has also shown antiparkinsonian and antidyski-netic activity in rodent models of PD [12 122] Currentlythere are no agonists or PAMs with appropriate oral bioavail-ability and brain permeability available for targeting themGlu8 receptor However intracerebroventricular injectionof the mGlu8 receptor agonist (S)-34-dicarboxyphenylgly-cine (DCPG) reportedly reversed parkinsonian symptomsin a rat model for PD [123]

323 Group II mGlu Receptors Activation of Group IImGlu2 and 3 receptors using competitive agonists has beenextensively characterised in animal models Based on theirpreclinical profile these group II agonists have been evaluatedin the clinic for anxiety [124] and schizophrenia [125] Incontrast preclinical data supporting a beneficial effect inPD are limited Both receptors have been located in keyareas of the basal ganglia associatedwith PDpathophysiologysuch as the SNr and their activation is known to inhibitsynaptic excitation [85 126 127] However ligand bindingautoradiography in postmortem brain tissue from MPTP-treatedmonkeys and patients with PD suggests that there areno clear changes in the expression of mGlu2 and 3 receptorsassociated with PD-LID [128 129] Systemic administrationof the competitive mGlu23 receptor agonist LY379268 failedto provide any functional benefit in the 6-OHDA lesioned ratmodel [130] Johnson et al suggested that [131] the lack of sub-type specificity and limited brain penetrability of LY379268were responsible for the absence of efficacy seen followingsystemic administration [122] PAMs selective for mGlu2receptor have an improved pharmacokinetic profile and goodbrain penetration [123] In vivo mGlu2 receptor PAMs haveshown that they are valuable alternative to the competitiveagonists in a rodent model for panic-like behaviour [132]

Future investigations of PAMs targeting mGlu2 receptorsusing appropriate animal models will be key to evaluating thepotential of this mechanism of action in PD

4 Conclusions

Nigrostriatal denervation in PD leads to increased gluta-matergic transmission in the basal ganglia which leads tofurther loss of dopaminergic neurons progression of PDand the appearance of PD-LID Pharmacological modulationof glutamatergic transmission is a key focus for researchinto novel nondopaminergic agents for PD Antagonists ofiGlu receptors have shown antiparkinsonian and antidysk-inetic effects in preclinical studies but the emergence ofadverse effects has limited the clinical value of these agentsAmantadine a weak NMDA antagonist is the exceptionshowing significant anti-dyskinetic effects in the clinicalsetting Modulators of mGlu receptors hold greater promisein PD due to their location in the basal ganglia and thedevelopment of a number of agents with high potency andselectivity for different mGlu receptor subtypes In particularpreclinical studies with mGlu5 receptor subtype selectiveantagonists and PAMs of mGlu4 receptor have shown goodefficacy in models of both PD and PD-LID and there is nowgrowing clinical evidence formGlu5 receptor antagonism as avalid therapeutic target for PD-LID Research into glutamatereceptor signalling in the basal ganglia is now revealing ahugely complex network involving cross-talk between differ-ent glutamate receptors dopamine and adenosine receptorsAs we understand more about the importance of theseinteractions we may be able to develop compounds that canfine tune dopaminergic and non-dopaminergic transmissionleading to better treatments for PD and PD-LID

Conflict of Interests

Fabrizio Gasparini and Baltazar Gomez-Mancilla are em-ployees of Novartis Pharma AG and hold shares with Novar-tis Pharma AG Fabrizio Gasparini and Baltazar Gomez-Mancilla have also received reimbursement from NovartisPharma AG for travel expenses The work of Therese DiPaolo is supported by funding from the Canadian Institutesof Health Research The Quebec Consortium for Drug Dis-covery and the Natural Sciences and Engineering ResearchCouncil of Canada Therese Di Paolo has also received com-pensation from Novartis Pharma AG for investigating newcompounds in vivo as part of a collaborative project andreimbursement for travel expenses Therese Di Paolo is alsocoauthor on patents with Novartis Pharma AG

Acknowledgments

Financial support for medical editorial assistance was pro-vided byNovartis PharmaceuticalsThe authors would like tothankKerrieOrsquoRourke PhD andGeorginaCollett PhD ofiMed Comms who provided medical writing assistance withthis paper


References

[1] N B Mercuri and G Bernardi ldquoThe ldquomagicrdquo of L-dopa whyis it the gold standard Parkinsonrsquos disease therapyrdquo Trends inPharmacological Sciences vol 26 no 7 pp 341ndash344 2005

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

[3] J E Ahlskog and M D Muenter ldquoFrequency of levodopa-related dyskinesias and motor fluctuations as estimated fromthe cumulative literaturerdquo Movement Disorders vol 16 no 3pp 448ndash458 2001

[4] S Cristina R Zangaglia F Mancini E Martignoni G NappiandC Pacchetti ldquoHigh-dose ropinirole in advancedParkinsonrsquosdisease with severe dyskinesiasrdquo Clinical Neuropharmacologyvol 26 no 3 pp 146ndash150 2003

[5] A Facca and J Sanchez-Ramos ldquoHigh-dose pergolide mono-therapy in the treatment of severe levodopa-induced dyskine-siasrdquoMovement Disorders vol 11 no 3 pp 327ndash329 1996

[6] M Mungersdorf U Sommer M Sommer and H ReichmannldquoHigh-dose therapy with ropinirole in patients with Parkinsonrsquosdiseaserdquo Journal of Neural Transmission vol 108 no 11 pp1309ndash1317 2001

[7] J Kulisevsky and M Poyurovsky ldquoAdenosine A2119886-receptor

antagonism and pathophysiology of Parkinsonrsquos disease anddrug-induced movement disordersrdquo European Neurology vol67 no 1 pp 4ndash11 2012

[8] J Brotchie ldquoAntidyskinetic actions of amantadine in Parkinsonrsquosdisease are benefits maintained in the long termrdquo ExpertReview of Neurotherapeutics vol 10 no 6 pp 871ndash873 2010

[9] N Tambasco S Simoni E Marsili et al ldquoClinical aspectsand management of levodopa-induced dyskinesiardquo ParkinsonrsquosDisease vol 2012 Article ID 745947 12 pages 2012

[10] T N Chase and J D Oh ldquoStriatal dopamine- and glutamate-mediated dysregulation in experimental parkinsonismrdquo Trendsin Neurosciences vol 23 no 10 pp S86ndashS91 2000

[11] F Calon A H Rajput O Hornykiewicz P J Bedard and T DiPaolo ldquoLevodopa-induced motor complications are associatedwith alterations of glutamate receptors in Parkinsonrsquos diseaserdquoNeurobiology of Disease vol 14 no 3 pp 404ndash416 2003

[12] K A Johnson P J Conn and C M Niswender ldquoGlutamatereceptors as therapeutic targets for Parkinsonrsquos diseaserdquo CNSand Neurological Disorders vol 8 no 6 pp 475ndash491 2009

[13] P Jenner ldquoMolecular mechanisms of L-DOPA-induced dyski-nesiardquo Nature Reviews Neuroscience vol 9 no 9 pp 665ndash6772008

[14] J Brotchie and C Fitzer-Attas ldquoMechanisms compensating fordopamine loss in early Parkinson diseaserdquo Neurology vol 72no 7 pp S32ndashS38 2009

[15] I Aubert C Guigoni K Hakansson et al ldquoIncreased D1

dopamine receptor signaling in levodopa-induced dyskinesiardquoAnnals of Neurology vol 57 no 1 pp 17ndash26 2005

[16] M M Iravani A C Mccreary and P Jenner ldquoStriatal plas-ticity in Parkinsonrsquos disease and L-DOPA induced dyskinesiardquoParkinsonism and Related Disorders vol 18 no 1 supplementpp S123ndashS125 2012

[17] M M Iravani and P Jenner ldquoMechanisms underlying the onsetand expression of levodopa-induced dyskinesia and their phar-macological manipulationrdquo Journal of Neural Transmission vol118 no 12 pp 1661ndash1690 2011

[18] A Berthet and E Bezard ldquoDopamine receptors and l-dopa-induced dyskinesiardquo Parkinsonism and Related Disorders vol15 no 4 supplement pp S8ndashS12 2010

[19] F Blandini R H P Porter and J T Greenamyre ldquoGlutamateand Parkinsonrsquos diseaserdquo Molecular Neurobiology vol 12 no 1pp 73ndash94 1996

[20] M A Cenci ldquoDopamine dysregulation of movement control inl-DOPA-induced dyskinesiardquo Trends in Neurosciences vol 30no 5 pp 236ndash243 2007

[21] E Esposito V Di Matteo and G Di Giovanni ldquoDeath in thesubstantia nigra a motor tragedyrdquo Expert Review of Neurother-apeutics vol 7 no 6 pp 677ndash697 2007

[22] M A Cenci K E Ohlin and D Rylander ldquoPlastic effects ofL-DOPA treatment in the basal ganglia and their relevanceto the development of dyskinesiardquo Parkinsonism and RelatedDisorders vol 15 supplement 3 pp S59ndashS63 2009

[23] A H Rajput M E Fenton S Birdi and R Macaulay ldquoIs lev-odopa toxic to human substantia nigrardquo Movement Disordersvol 12 no 5 pp 634ndash638 1997

[24] S Boyce N M J Rupniak M J Steventon and S D IversenldquoNigrostriatal damage is required for induction of dyskinesiasby L-DOPA in squirrel monkeysrdquo Clinical Neuropharmacologyvol 13 no 5 pp 448ndash458 1990

[25] S Nakanishi ldquoMolecular diversity of glutamate receptors andimplications for brain functionrdquo Science vol 258 no 5082 pp597ndash603 1992

[26] C M Niswender and P J Conn ldquoMetabotropic glutamatereceptors physiology pharmacology and diseaserdquo AnnualReview of Pharmacology and Toxicology vol 50 pp 295ndash3222010

[27] N Hovelsoslash F Sotty L P Montezinho P S Pinheiro K FHerrik and A Moslashrk ldquoTherapeutic potential of metabotropicglutamate receptor modulatorsrdquo Current Neuropharmacologyvol 10 no 1 pp 12ndash48 2012

[28] S F Traynelis L P Wollmuth C J McBain et al ldquoGlutamatereceptor ion channels structure regulation and functionrdquoPharmacological Reviews vol 62 no 3 pp 405ndash496 2010

[29] K Tayarani-Binazir M J Jackson S Rose A C McCreary andP Jenner ldquoThepartial dopamine agonist pardoprunox (SLV308)administered in combination with l-dopa improves efficacy anddecreases dyskinesia in MPTP treated common marmosetsrdquoExperimental Neurology vol 226 no 2 pp 320ndash327 2010

[30] B Zadow and W J Schmidt ldquoThe AMPA antagonists NBQXand GYKI 52466 do not counteract neuroleptic- inducedcatalepsyrdquo Naunyn-Schmiedebergrsquos Archives of Pharmacologyvol 349 no 1 pp 61ndash65 1994

[31] P-A Loschmann K W Lange M Kunow et al ldquoSynergism ofthe AMPA-antagonist NBQX and the NMDA-antagonist CPPwith L-Dopa inmodels of Parkinsonrsquos diseaserdquo Journal of NeuralTransmission vol 3 no 3 pp 203ndash213 1991

[32] P A Loschmann M Kunow and H Wachtel ldquoSynergism ofNBQX with dopamine agonists in the 6-OHDA rat model ofParkinsonrsquos diseaserdquo Journal of Neural Transmission Supple-ment no 38 pp 55ndash64 1992

[33] J Maj Z Rogoz G Skuza and K Kolodziejczyk ldquoSome centraleffects of GYKI 52466 a non-competitive AMPA receptorantagonistrdquo Polish Journal of Pharmacology vol 47 no 6 pp501ndash507 1995

[34] HWachtel M Kunow and P-A Loschmann ldquoNBQX (6-nitro-sulfamoyl-benzo-quinoxaline-dione) and CPP (3-carboxy-pip-erazin-propyl phosphonic acid) potentiate dopamine agonist


induced rotations in substantia nigra lesioned ratsrdquo Neuro-science Letters vol 142 no 2 pp 179ndash182 1992

[35] T Klockgether L Turski T Honore et al ldquoThe AMPA receptorantagonist NBQX has antiparkinsonian effects in monoamine-depleted rats andMPTP-treatedmonkeysrdquoAnnals of Neurologyvol 30 no 5 pp 717ndash723 1991

[36] C Marin A Jimenez M Bonastre T N Chase and E TolosaldquoNon-NMDA receptor-mediated mechanisms are involved inlevodopa-induced motor response alterations in Parkinsonianratsrdquo Synapse vol 36 no 4 pp 267ndash274 2000

[37] Z Juranyi N Sziray B Marko G Levay and L G Harsing JrldquoAMPA receptor blockade potentiates the stimulatory effect ofL-DOPA on dopamine release in dopamine-deficient corticos-triatal slice preparationrdquo Critical Reviews in Neurobiology vol16 no 1-2 pp 129ndash139 2004

[38] K Megyeri B Marko N Sziray et al ldquoEffects of 23-benzo-diazepine AMPA receptor antagonists on dopamine turnoverin the striatum of rats with experimental parkinsonismrdquo BrainResearch Bulletin vol 71 no 5 pp 501ndash507 2007

[39] J M Brotchie ldquoNondopaminergic mechanisms in levodopa-induced dyskinesiardquoMovementDisorders vol 20 no 8 pp 919ndash931 2005

[40] C Marin A Jimnez M Bonastre et al ldquoLY293558 an AMPAglutamate receptor antagonist prevents and reverses levodopa-induced motor alterations in Parkinsonian ratsrdquo Synapse vol42 no 1 pp 40ndash47 2001

[41] S Konitsiotis P J Blanchet L Verhagen E Lamers and T NChase ldquoAMPA receptor blockade improves levodopa-induceddyskinesia in MPTP monkeysrdquo Neurology vol 54 no 8 pp1589ndash1595 2000

[42] Y Hashizume M Ohgoh M Ueno T Hanada and Y Nishiz-awa ldquoEffect of perampanel a selective AMPA receptor antag-onist on L-DOPA-induced rotational behavior in L-DOPAprimed 6-OHDA hemiparkinsonian ratsrdquo in Proceedings of theAnnualMeeting of the AmericanAcademy of Neurology P061022008

[43] E Mizuta M Ueno T Hanada and S Kuno ldquoEffects of per-ampanel a selective AMPA receptor antagonist on L-DOPAinduced dyskinesia in MPTP-treated cynomolgus monkeysrdquo inProceedings of the Annual Meeting of the American Academy ofNeurology P06101 2008

[44] K Eggert D Squillacote P Barone et al ldquoSafety and efficacyof perampanel in advanced parkinsonrsquos disease a randomizedplacebo-controlled studyrdquo Movement Disorders vol 25 no 7pp 896ndash905 2010

[45] A Lees S Fahn K M Eggert et al ldquoPerampanel an AMPAantagonist found to have no benefit in reducing ldquooffrdquo time inParkinsonrsquos diseaserdquoMovementDisorders vol 27 no 2 pp 284ndash288 2012

[46] O Rascol P Barone M Behari et al ldquoPerampanel in Parkinsondisease fluctuations a double-blind randomized trial with pla-cebo and entacaponerdquo Clinical Neuropharmacology vol 35 no1 pp 15ndash20 2012

[47] B Picconi G Piccoli and P Calabresi ldquoSynaptic dysfunctionin Parkinsonrsquos diseaserdquo Advances in Experimental Medicine andBiology vol 970 pp 553ndash572 2012

[48] P K Sonsalla D S Albers and G D Zeevalk ldquoRole of glu-tamate in neurodegeneration of dopamine neurons in severalanimal models of parkinsonismrdquo Amino Acids vol 14 no 1ndash3pp 69ndash74 1998

[49] TNChase and JDOh ldquoStriatalmechanisms and pathogenesisof Parkinsonian signs and motor complicationsrdquo Annals ofNeurology vol 47 no 4 pp S122ndashS130 2000

[50] J E Nash S H Fox B Henry et al ldquoAntiparkinsonianactions of ifenprodil in the MPTP-lesioned marmoset model ofParkinsonrsquos diseaserdquo Experimental Neurology vol 165 no 1 pp136ndash142 2000

[51] B Gomez-Mancilla and P J Bedard ldquoEffect of nondopamin-ergic drugs on L-DOPA-induced dyskinesias in MPTP- treatedmonkeysrdquo Clinical Neuropharmacology vol 16 no 5 pp 418ndash427 1993

[52] P J Blanchet S Konitsiotis E R Whittemore Z L Zhou RMWoodward and T N Chase ldquoDiffering effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskine-sias in levodopa-treated 1-methyl-4-phenyl- tetrahydropyridinemonkeysrdquo Journal of Pharmacology and Experimental Thera-peutics vol 290 no 3 pp 1034ndash1040 1999

[53] AH Tahar LGregoire ADarre N Belanger LMeltzer andPJ Bedard ldquoEffect of a selective glutamate antagonist on L-dopa-induced dyskinesias in drug-naive parkinsonian monkeysrdquoNeurobiology of Disease vol 15 no 2 pp 171ndash176 2004

[54] S M Papa and T N Chase ldquoLevodopa-induced dyskinesiasimproved by a glutamate antagonist in Parkinsonian monkeysrdquoAnnals of Neurology vol 39 no 5 pp 574ndash578 1996

[55] M Morissette M Dridi F Calon et al ldquoPrevention of levodo-pa-induced dyskinesias by a selective NRA12B N-methyl-D-aspartate receptor antagonist in Parkinsonian monkeys impli-cation of preproenkephalinrdquoMovement Disorders vol 21 no 1pp 9ndash17 2006

[56] R DallrsquoOlio R Rimondini and O Gandolfi ldquoThe competitiveNMDA antagonists CGP 43487 and APV potentiate dopamin-ergic functionrdquo Psychopharmacology vol 118 no 3 pp 310ndash3151995

[57] T Klockgether and L Turski ldquoNMDA antagonists potentiateantiparkinsonian actions of L-dopa in monoamine-depletedratsrdquo Annals of Neurology vol 28 no 4 pp 539ndash546 1990

[58] F Bibbiani J D Oh A Kielaite M A Collins C Smith andT N Chase ldquoCombined blockade of AMPA and NMDA gluta-mate receptors reduces levodopa-induced motor complicationsin animal models of PDrdquo Experimental Neurology vol 196 no2 pp 422ndash429 2005

[59] G Riahi M Morissette M Parent and T Di Paolo ldquoBrain5-HT2A receptors in MPTP monkeys and levodopa-induceddyskinesiasrdquo European Journal of Neuroscience vol 33 no 10pp 1823ndash1831 2011

[60] M A Paquette A A Martinez T Macheda et al ldquoAnti-dyski-netic mechanisms of amantadine and dextromethorphan in the6-OHDA rat model of Parkinsonrsquos disease role of NMDA vs 5-HT1A receptorsrdquo European Journal of Neuroscience vol 36 no9 pp 3224ndash3234 2012

[61] M Morissette M Dridi F Calon et al ldquoPrevention of dyskine-sia by an NMDA receptor antagonist in MPTP monkeys effecton adenosineA

2119886receptorsrdquo Synapse vol 60 no 3 pp 239ndash250

2006

[62] I J Mitchell and C B Carroll ldquoReversal of parkinsoniansymptoms in primates by antagonism of excitatory amino acidtransmission potential mechanisms of actionrdquo Neuroscienceand Biobehavioral Reviews vol 21 no 4 pp 469ndash475 1997


[63] K Steece-Collier L K Chambers S S Jaw-Tsai F S Men-niti and J T Greenamyre ldquoAntiparkinsonian actions of CP-101606 an antagonist of NR2B subunit- containing N-methyl-D-aspartate receptorsrdquo Experimental Neurology vol 163 no 1pp 239ndash243 2000

[64] P Paoletti and J Neyton ldquoNMDA receptor subunits functionand pharmacologyrdquo Current Opinion in Pharmacology vol 7no 1 pp 39ndash47 2007

[65] M Horstink E Tolosa U Bonuccelli et al ldquoReview of the ther-apeutic management of Parkinsonrsquos disease Report of a jointtask force of the European Federation of Neurological Societies(EFNS) and the Movement Disorder Society-European Section(MDS-ES) Part II late (complicated) Parkinsonrsquos diseaserdquoEuropean Journal of Neurology vol 13 no 11 pp 1186ndash12022006

[66] R Pahwa S A Factor K E Lyons et al ldquoPractice parametertreatment of Parkinson disease with motor fluctuations anddyskinesia (an evidence-based review) report of the QualityStandards Subcommittee of the American Academy of Neurol-ogyrdquo Neurology vol 66 no 7 pp 983ndash995 2006

[67] P J Blanchet S Konitsiotis and T N Chase ldquoAmantadinereduces levodopa-induced dyskinesias in parkinsonian mon-keysrdquoMovement Disorders vol 13 no 5 pp 798ndash802 1998

[68] A Dekundy M Lundblad W Danysz and M A Cenci ldquoMod-ulation of l-DOPA-induced abnormal involuntary movementsby clinically tested compounds further validation of the ratdyskinesia modelrdquo Behavioural Brain Research vol 179 no 1pp 76ndash89 2007

[69] P Del Dotto N Pavese G Gambaccini et al ldquoIntravenousamantadine improves levadopa-induced dyskinesias an acutedouble-blind placebo-controlled studyrdquo Movement Disordersvol 16 no 3 pp 515ndash520 2001

[70] F P Da Silva-Junior P Braga-Neto F Sueli Monte and VMeireles Sales De Bruin ldquoAmantadine reduces the durationof levodopa-induced dyskinesia a randomized double-blindplacebo-controlled studyrdquo Parkinsonism and Related Disordersvol 11 no 7 pp 449ndash452 2005

[71] H Sawada T Oeda S Kuno et al ldquoAmantadine for dyskinesiasin parkinsonrsquos disease a randomized controlled trialrdquoPLoSOnevol 5 no 12 Article ID e15298 2010

[72] L V Metman P Del Dotto P Van Den Munckhof J FangM M Mouradian and T Chase ldquoAmantadine as treatment fordyskinesias andmotor fluctuations in Parkinsonrsquos diseaserdquoNeu-rology vol 50 no 5 pp 1323ndash1326 1998

[73] B Elahi N Phielipp and R Chen ldquoN-Methyl-D-Aspartateantagonists in levodopa induced dyskinesia a meta-analysisrdquoTheCanadian Journal of Neurological Sciences vol 39 no 4 pp465ndash472 2012

[74] C G Goetz G T Stebbins K A Chung et al ldquoWhich dysk-inesia scale best detects treatment response A double-blindplacebo controlled multicenter trial using multiple dyskinesiaoutcomesrdquo in Proceedings of the 16th International Congress ofParkinsonrsquos Disease and Movement Disorders abstract LBA 112012

[75] EWolf K Seppi R Katzenschlager et al ldquoLong-term antidysk-inetic efficacy of amantadine in Parkinsonrsquos diseaserdquoMovementDisorders vol 25 no 10 pp 1357ndash1363 2010

[76] F Ory-Magne C Thalamas M Galitsky et al ldquoLong-termeffects of amantadine in Parkinsonian (AMANDYSK)rdquo Move-ment Disorders vol 27 supplement 14 article 12 2012

[77] S R Schwid ldquoA multicenter randomized controlled trial ofremacemide hydrochloride asmonotherapy for PDrdquoNeurologyvol 54 no 8 pp 1583ndash1588 2000

[78] J A De Marcaida ldquoEvaluation of dyskinesias in a pilot ran-domized placebo-controlled trial of remacemide in advancedParkinson diseaserdquo Archives of Neurology vol 58 no 10 pp1660ndash1668 2001

[79] C E Clarke J A Cooper and T A H Holdich ldquoA randomizeddouble-blind placebo-controlled ascending-dose tolerabilityand safety study of remacemide as adjuvant therapy in Parkin-sonrsquos diseasewith response fluctuationsrdquoClinical Neuropharma-cology vol 24 no 3 pp 133ndash138 2001

[80] J L Montastruc O Rascol J M Senard and A Rascol ldquoA pilotstudy of N-Methyl-D-Aspartate (NMDA) antagonist in Parkin-sonrsquos diseaserdquo Journal of Neurology Neurosurgery and Psychiatryvol 55 no 7 pp 630ndash631 1992

[81] J G Nutt S A Gunzler T Kirchhoff et al ldquoEffects of a NR2Bselective NMDA glutamate antagonist CP-101606 on dyskine-sia and parkinsonismrdquoMovement Disorders vol 23 no 13 pp1860ndash1866 2008

[82] S R Schwid ldquoA randomized controlled trial of remacemidefor motor fluctuations in parkinsonrsquos disease parkinson studygrouprdquo Neurology vol 56 no 4 pp 455ndash462 2001

[83] D Rylander A Recchia F Mela A Dekundy W Danysz andM A Cenci Nilsson ldquoPharmacological modulation of gluta-mate transmission in a rat model of L-DOPA-induced dyski-nesia effects on motor behavior and striatal nuclear signalingrdquoJournal of Pharmacology and Experimental Therapeutics vol330 no 1 pp 227ndash235 2009

[84] R Shigemoto and N Mizuno ldquoMetabotropic glutamate recep-torsmdashimmunocytochemical and in situ hybridization analysisrdquoin Handbook of Chemical Neuroanatomy O P Ottersen and JStorm-Mathisen Eds vol 18 pp 63ndash98 Elsevier 2000

[85] P J Conn G Battaglia M J Marino and F Nicoletti ldquoMetabo-tropic glutamate receptors in the basal ganglia motor circuitrdquoNature Reviews Neuroscience vol 6 no 10 pp 787ndash798 2005

[86] C Romano M A Sesma C T McDonald K OrsquoMalley A NVan den Pol and J W Olney ldquoDistribution of metabotropicglutamate receptor mGluR5 immunoreactivity in rat brainrdquoJournal of Comparative Neurology vol 355 no 3 pp 455ndash4691995

[87] W P J M Spooren F Gasparini R Bergmann and RKuhn ldquoEffects of the prototypical mGlu

5receptor antago-

nist 2-methyl-6-(phenylethynyl)-pyridine on rotarod locomo-tor activity and rotational responses in unilateral 6-OHDA-lesioned ratsrdquo European Journal of Pharmacology vol 406 no3 pp 403ndash410 2000

[88] N Breysse C Baunez W Spooren F Gasparini and M Amal-ric ldquoChronic but not acute treatmentwith ametabotropic gluta-mate 5 receptor antagonist reverses the akinetic deficits in a ratmodel of Parkinsonismrdquo Journal of Neuroscience vol 22 no 13pp 5669ndash5678 2002

[89] G Levandis E Bazzini M-T Armentero G Nappi and FBlandini ldquoSystemic administration of an mGluR5 antagonistbut not unilateral subthalamic lesion counteracts l-DOPA-induced dyskinesias in a rodent model of Parkinsonrsquos diseaserdquoNeurobiology of Disease vol 29 no 1 pp 161ndash168 2008

[90] K Ossowska J Konieczny S Wolfarth and A Pilc ldquoMTEP anew selective antagonist of themetabotropic glutamate receptorsubtype 5 (mGluR5) produces antiparkinsonian-like effects inratsrdquo Neuropharmacology vol 49 no 4 pp 447ndash455 2005


[91] P Samadi L Gregoire M Morissette et al ldquomGluR5 metabo-tropic glutamate receptors and dyskinesias in MPTPmonkeysrdquoNeurobiology of Aging vol 29 no 7 pp 1040ndash1051 2008

[92] B Ouattara L Gregoire M Morissette et al ldquoMetabotropicglutamate receptor type 5 in levodopa-induced motor compli-cationsrdquo Neurobiology of Aging vol 32 no 7 pp 1286ndash12952011

[93] C Konradi J EWestinMCarta et al ldquoTranscriptome analysisin a rat model of L-DOPA-induced dyskinesiardquoNeurobiology ofDisease vol 17 no 2 pp 219ndash236 2004

[94] HAwadGWHubert Y Smith A I Levey andP J Conn ldquoAc-tivation of metabotropic glutamate receptor 5 has direct excita-tory effects and potentiates NMDA receptor currents in neu-rons of the subthalamic nucleusrdquo Journal of Neuroscience vol20 no 21 pp 7871ndash7879 2000

[95] A Pisani P Calabresi D Centonze andG Bernardi ldquoEnhance-ment of NMDA responses by group I metabotropic glutamatereceptor activation in striatal neuronesrdquo British Journal ofPharmacology vol 120 no 6 pp 1007ndash1014 1997

[96] M R Domenici R Pepponi A Martire M T Tebano RL Potenza and P Popoli ldquoPermissive role of adenosine A

2119886

receptors on metabotropic glutamate receptor 5 (mGluR5)-mediated effects in the striatumrdquo Journal of Neurochemistry vol90 no 5 pp 1276ndash1279 2004

[97] A Nishi F Liu S Matsuyama et al ldquoMetabotropic mGlu5

receptors regulate adenosine A2119886

receptor signalingrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 100 no 3 pp 1322ndash1327 2003

[98] P Popoli A Pezzola M Torvinen et al ldquoThe selective mGlu5

receptor agonist CHPG inhibits quinpirole-induced turning in6-hydroxydopamine-lesioned rats and modulates the bindingcharacteristics of dopamine D

2receptors in the rat striatum

interactions with adenosine A2119886

receptorsrdquo Neuropsychophar-macology vol 25 no 4 pp 505ndash513 2001

[99] Z Dıaz-Cabiale M Vivo A Del Arco et al ldquoMetabotropicglutamate mGlu

5receptor-mediated modulation of the ventral

striopallidalGABApathway in rats Interactionswith adenosineA2119886and dopamine D

2receptorsrdquo Neuroscience Letters vol 324

no 2 pp 154ndash158 2002[100] M P Hill S G McGuire A R Crossman and J M Brotchie

ldquoThe mGlu5Receptor antagonist SIB-1830 reduces L-Dopa-

induced dyskinesia in the MPTP-lesioned primate model ofParkinsonrsquos diseaserdquo in Proceedings of the Neuroscience MeetingPlanner Society for Neuroscience San Diego Calif USA 2001

[101] M A Varney N D P Cosford C Jachec et al ldquoSIB-1757 andSIB-1893 selective noncompetitive antagonists ofmetabotropicglutamate receptor type 5rdquo Journal of Pharmacology and Exper-imental Therapeutics vol 290 no 1 pp 170ndash181 1999

[102] J M Mathiesen N Svendsen H Brauner-Osborne C Thom-sen and M T Ramirez ldquoPositive allosteric modulation of thehuman metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 andMPEPrdquo British Journal of Pharmacology vol 138 no 6pp 1026ndash1030 2003

[103] A Dekundy M Pietraszek D Schaefer M A Cenci and WDanysz ldquoEffects of group I metabotropic glutamate receptorsblockade in experimental models of Parkinsonrsquos diseaserdquo BrainResearch Bulletin vol 69 no 3 pp 318ndash326 2006

[104] F Mela M Marti A Dekundy W Danysz M Morari and MA Cenci ldquoAntagonism ofmetabotropic glutamate receptor type5 attenuates L-DOPA-induced dyskinesia and its molecular andneurochemical correlates in a rat model of Parkinsonrsquos diseaserdquoJournal of Neurochemistry vol 101 no 2 pp 483ndash497 2007

[105] N Morin L Gregoire B Gomez-Mancilla F Gasparini andT Di Paolo ldquoEffect of the metabotropic glutamate receptortype 5 antagonistsMPEP andMTEP in parkinsonianmonkeysrdquoNeuropharmacology vol 58 no 7 pp 981ndash986 2010

[106] N Morin L Gregoire M Morissette et al ldquoMPEP an mGlu5

receptor antagonist reduces the development of l-DOPA-induced motor complications in de novo parkinsonian mon-keys biochemical correlatesrdquoNeuropharmacology pp 355ndash3642012

[107] L Gregoire N Morin B Ouattara et al ldquoThe acute antiparkin-sonian and antidyskinetic effect of AFQ056 a novel metabo-tropic glutamate receptor type 5 antagonist in l-Dopa-treatedparkinsonian monkeysrdquo Parkinsonism and Related Disordersvol 17 no 4 pp 270ndash276 2011

[108] D Berg J Godau C Trenkwalder et al ldquoAFQ056 treatmentof levodopa-induced dyskinesias results of 2 randomized con-trolled trialsrdquoMovement Disorders vol 26 no 7 pp 1243ndash12502011

[109] F Stocchi A Destee N Hattori et al ldquoA 13-week double-blind placebo-controlled study of AFQ056 a metabotropicglutamate receptor 5 antagonist in Parkinsonrsquos disease patientswith moderate-to-severe L-dopa-induced dyskinesiasrdquo in Pro-ceedings of the 15th International Congress of Parkinsonrsquos Diseaseand Movement Disorders vol 2011 Toronto Canada 2011

[110] F Tison F Durif J C Corvol et al ldquoSafety tolerability andanti-dyskinetic efficacy of dipaglurant a novelmGluR5negativeallosteric modulator (NAM) in Parkinsonrsquos disease patientswith levodopa-induced dyskinesia (LID)rdquo in Proceedings of the16th International Congress of Parkinsonrsquos Disease andMovementDisorders vol 2012 Dublin Ireland June2012

[111] M Amalric S Lopez C Goudet et al ldquoGroup III and subtype4 metabotropic glutamate receptor agonists discovery andpathophysiological applications in Parkinsonrsquos diseaserdquo Neuro-pharmacology vol 66 pp 53ndash64 2013

[112] C W Lindsley and C R Hopkins ldquoMetabotropic glutamatereceptor 4 (mGlu4)-positive allosteric modulators for the treat-ment of Parkinsonrsquos disease historical perspective and reviewof the patent literaturerdquo Expert Opinion onTherapeutic Patentsvol 22 no 5 pp 461ndash481 2012

[113] T Matsui and H Kita ldquoActivation of group III metabotropicglutamate receptors presynaptically reduces both GABAergicand glutamatergic transmission in the rat globus pallidusrdquoNeuroscience vol 122 no 3 pp 727ndash737 2003

[114] S Lopez N Turle-Lorenzo F Acher E De Leonibus A Meleand M Amalric ldquoTargeting group III metabotropic glutamatereceptors produces complex behavioral effects in rodentmodelsof Parkinsonrsquos diseaserdquo Journal of Neuroscience vol 27 no 25pp 6701ndash6711 2007

[115] C Beurrier S Lopez D Revy et al ldquoElectrophysiological andbehavioral evidence thatmodulation ofmetabotropic glutamatereceptor 4 with a new agonist reverses experimental parkinson-ismrdquo FASEB Journal vol 23 no 10 pp 3619ndash3628 2009

[116] OValentiM JMarinoMWittmann et al ldquoGroup IIImetabo-tropic glutamate receptor-mediated modulation of the striato-pallidal synapserdquo Journal of Neuroscience vol 23 no 18 pp7218ndash7226 2003

[117] M J Marino D L Williams Jr J A OrsquoBrien et al ldquoAllostericmodulation of group III metabotropic glutamate receptor 4 apotential approach to Parkinsonrsquos disease treatmentrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 100 no 23 pp 13668ndash13673 2003


[118] G Battaglia C L Busceti G Molinaro et al ldquoPharmacologicalactivation of mGlu4 metabotropic glutamate receptors reducesnigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1236-tetrahydropyridinerdquoThe Journal of Neurosciencevol 26 no 27 pp 7222ndash7229 2006

[119] CMNiswender K A Johnson C DWeaver et al ldquoDiscoverycharacterization and antiparkinsonian effect of novel positiveallosteric modulators of metabotropic glutamate receptor 4rdquoMolecular Pharmacology vol 74 no 5 pp 1345ndash1358 2008

[120] C K Jones M Bubser A D Thompson et al ldquoThe meta-botropic glutamate receptor 4-positive allosteric modulatorVU0364770 produces efficacy alone and in combination withL-DOPA or an adenosine 2A antagonist in preclinical rodentmodels of Parkinsonrsquos diseaserdquo Journal of Pharmacology andExperimental Therapeutics vol 340 no 2 pp 404ndash421 2012

[121] E Le Poul C Bolea F Girard et al ldquoA potent and selectivemet-abotropic glutamate receptor 4 positive allosteric modulatorimproves movement in rodent models of Parkinsonrsquos diseaserdquoJournal of Pharmacology and Experimental Therapeutics vol343 no 1 pp 167ndash177 2012

[122] B Greco S LopezHVanDer Putten P J Flor andMAmalricldquoMetabotropic glutamate 7 receptor subtype modulates motorsymptoms in rodent models of Parkinsonrsquos diseaserdquo Journal ofPharmacology and ExperimentalTherapeutics vol 332 no 3 pp1064ndash1071 2010

[123] K A Johnson C K Jones M N Tantawy et al ldquoThe meta-botropic glutamate receptor 8 agonist (S)-34-DCPG reversesmotor deficits in prolonged but not acute models of Parkinsonrsquosdiseaserdquo Neuropharmacology vol 66 pp 187ndash195 2012

[124] D D Schoepp R A Wright L R Levine B Gaydos and WZ Potter ldquoLY354740 an mGlu23 receptor agonist as a novelapproach to treat anxietystressrdquo Stress vol 6 no 3 pp 189ndash1972003

[125] B J Kinon L Zhang B A Millen et al ldquoA multicenter inpa-tient phase 2 double-blind placebo-controlled dose-rangingstudy of LY2140023 monohydrate in patients with DSM-IVschizophreniardquo Journal of Clinical Psychopharmacology vol 31no 3 pp 349ndash355 2011

[126] S R Bradley M J Marino M Wittmann et al ldquoActivationof group II metabotropic glutamate receptors inhibits synapticexcitation of the substantia nigra pars reticulatardquo Journal ofNeuroscience vol 20 no 9 pp 3085ndash3094 2000

[127] L Dawson A Chadha M Megalou and S Duty ldquoThe groupII metabotropic glutamate receptor agonist DCG-IV alleviatesakinesia following intranigral or intraventricular administra-tion in the reserpine-treated ratrdquo British Journal of Pharmacol-ogy vol 129 no 3 pp 541ndash546 2000

[128] P Samadi L Gregoire M Morissette et al ldquoBasal gangliagroup II metabotropic glutamate receptors specific binding innon-human primate model of L-Dopa-induced dyskinesiasrdquoNeuropharmacology vol 54 no 2 pp 258ndash268 2008

[129] P Samadi A Rajput F Calon et al ldquoMetabotropic glutamatereceptor II in the brains of parkinsonian patientsrdquo Journal ofNeuropathology and Experimental Neurology vol 68 no 4 pp374ndash382 2009

[130] T K Murray M J Messenger M A Ward et al ldquoEvaluationof the mGluR23 agonist LY379268 in rodent models of Parkin-sonrsquos diseaserdquo Pharmacology Biochemistry and Behavior vol 73no 2 pp 455ndash466 2002

[131] M P Johnson E S Nisenbaum T H Large R EmkeyM Baezand A E Kingston ldquoAllostericmodulators of metabotropic glu-tamate receptors lessons learnt frommGlu1 mGlu2 andmGlu

5

potentiators and antagonistsrdquo Biochemical Society Transactionsvol 32 no 5 pp 881ndash887 2004

[132] P L Johnson S D Fitz E A Engleman K A Svensson J MSchkeryantz andA Shekhar ldquoGroup IImetabotropic glutamatereceptor type 2 allosteric potentiators prevent sodium lactate-induced panic-like response in panic-vulnerable ratsrdquo Journalof Psychopharmacology vol 27 no 2 pp 152ndash161 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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of


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EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Glutamatergic agents cited within the text with their pharmacological profile main targets and mode of action

Target Agent Pharmacological action

AMPA receptor

GYKI-52466 Noncompetitive antagonistGYKI-53405 Noncompetitive antagonist

NBQX Competitive antagonistPerampanel Noncompetitive antagonist

AMPAkainate receptor Tezampanel (LY293558) Competitive antagonistTalampanel (LY300164) Noncompetitive antagonist

AMPANMDA receptor CPP Competitive antagonist

NMDA receptor

Amantadine Noncompetitive antagonistAPV Competitive antagonist

CGP-43487 Competitive antagonistIfenprodil Noncompetitive antagonistPAMQX Competitive antagonist

Remacemide Noncompetitive antagonistTraxoprodil Noncompetitive antagonist

mGlu1 receptor EMQMCM Noncompetitive antagonistmGlu2 receptor LY379268 Competitive agonist

mGlu4 receptorPHCCC PAMADX88178 PAMVU0155041 PAM

mGlu4mGlu5 receptor SIB-1893 PAMnoncompetitive antagonist

mGlu5 receptor

Dipraglurant (ADX48621) Noncompetitive antagonistMavoglurant (AFQ056) Noncompetitive antagonist

MPEP Noncompetitive antagonistMRZ-8676 Noncompetitive antagonistMTEP Noncompetitive antagonist

mGlu7 receptor AMN082 PAMmGlu8 receptor DCPG Competitive agonist

2 Basal Ganglia Circuitry inParkinsonrsquos Disease

A balance between inhibition and excitation of the majoroutput nuclei of the basal ganglia is important for normalmotor control This is achieved via direct and indirectinhibitory projections (GABAergic) from the striatum(caudate nucleusputamen) to the globus pallidus internal(GPi)substantia nigra pars reticulate (SNr) and excitatoryprojections (glutamatergic) from the subthalamic nucleus(STN) to the substantia nigra pars compacta (SNc) and GPiSNr Appropriate dopaminergic input from the SNc to thestriatum plays a key role in maintaining this balance [12] Inpatients with PD degeneration of dopamine nigral neuronswithin the SNc results in loss of dopaminergic modulationand increases the overall excitatory drive in the basalganglia disrupting voluntary motor control and causing thecharacteristic symptomsof PD [13]Theprogressive depletionof the endogenous dopaminergic signalling combined withthe compensatory exogenous supply of dopamine (DA)precursor L-DOPA induces profound changes in the neuro-transmitter network of the basal ganglia [14] An imbalancein the DA receptors particularly between D1 and D2receptor subtypes mainly expressed in the direct and indirect

striatal output pathways respectively has been identified indyskinetic nonhuman primates [15 16] In rodents geneticablation of the D1 receptor subtype but not the D2 subtypeabolished the L-DOPA-induced dyskinesia These resultssuggest a key role for the D1 receptor in the development ofPD-LID [16] However a role for D2 receptors in the onsetand expression of L-DOPA induced dyskinesias is also docu-mented [17] Additional changes in other dopamine receptorsubtypes such as D3 and D5 have also been identified [18]

The cellular mechanisms by which the dopaminergicneurons are lost are not fully understood although excessiveglutamatergic transmission has been implicated [19 20]Glutamate is themain excitatory neurotransmitter in theCNSand normal brain function requires balanced glutamater-gic neurotransmission As a result of striatal dopaminergicdenervation the glutamatergic projections from the STNto the basal ganglia output nuclei become overactive withreduced regulation of glutamate receptors [19] The resultantexcessive excitation by glutamate through the basal gangliacircuitry can be toxic to any remaining dopaminergic neu-rons leading to further loss of dopaminergic transmissionand progression of PD symptoms [21] Normalisation ofmotor function is initially seen with L-DOPA treatmentHowever as the severity of PD increases the substantial













Glu

mGluR7

mGluR2

mGluR5

mGluR5mGluR1

mGluR3

Presynaptic

Postsynaptic

Astrocyte

Ca2+

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AMPAR

Kainate R

IP3DAG

PKC

PLC

PLD

MAPK

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Hi SC

Th

LS IC

OT Acb

SpV

mGlu1

mGlu5


















4 Conclusions




Acknowledgments



References



































































2006




























5receptor antago-












2119886


















































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of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

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Glu

mGluR7

mGluR2

mGluR5

mGluR5mGluR1

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Presynaptic

Postsynaptic

Astrocyte

Ca2+

Na+

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AMPAR

Kainate R

IP3DAG

PKC

PLC

PLD

MAPK

mGluR4 8










Hi SC

Th

LS IC

OT Acb

SpV

mGlu1

mGlu5


















4 Conclusions




Acknowledgments



References



































































2006




























5receptor antago-












2119886


















































5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Hi SC

Th

LS IC

OT Acb

SpV

mGlu1

mGlu5


















4 Conclusions




Acknowledgments



References



































































2006




























5receptor antago-












2119886


















































5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















4 Conclusions




Acknowledgments



References



































































2006




























5receptor antago-












2119886


















































5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















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2006




























5receptor antago-












2119886


















































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of






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OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































2006




























5receptor antago-












2119886


















































5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































5receptor antago-












2119886


















































5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























2119886


















































5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article metabotropic glutamate receptors for parkinson … · 2019. 7. 31. ·...

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