Mavoglurant as a treatment for Parkinson's disease.

Drug Evaluation

Mavoglurant as a treatment for Parkinson’s disease 1.

Introduction

2.

Current treatments of PD

3.

PD-LID: molecular basis and treatment strategies

Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by University of Newcastle on 08/25/14 For personal use only.

4.

Alterations in BG glutamatergic neurotransmission in PD

5.

Potential role of mGluR5 in brain disorders

6.

Therapeutic potential of mGluR5 NAM in PD: preclinical studies

7.

Therapeutic potential of mGluR5 NAM and mavoglurant for PD: clinical studies

8.

Conclusion

9.

Expert opinion

Dmitry Petrov, Ignacio Pedros, Maria Luisa de Lemos, Merce` Palla`s, Anna Maria Canudas, Alberto Lazarowski, Carlos Beas-Zarate, Carme Auladell, Jaume Folch & Antoni Camins† †

Universitat de Barcelona, Institut de Biomedicina (IBUB), Centros de Investigacioń Biome´dica en Red de Enfermedades Neurodegenerativas (CIBERNED), Unitat de Farmacologia I Farmacogno`sia, Facultat de Farma`cia, Barcelona, Spain

Introduction: A major unresolved issue in the Parkinson’s disease (PD) treatment is the development of L-DOPA-induced dyskinesias (LIDs) as a side effect of chronic L-DOPA administration. Currently, LIDs are managed in part by reducing the L-DOPA dose or by the administration of amantadine. However, this treatment is only partially effective. A potential strategy, currently under investigation, is the coadministration of metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) and L-DOPA; a treatment that results in the improvement of dyskinesia symptoms and that permits reductions in L-DOPA dosage frequency. Areas covered: The authors examine the role of mGluR5 in the pathophysiology of PD and the potential use of mGluR5 NAM as an adjuvant therapy together with a primary treatment with L-DOPA. Specifically, the authors look at the mavoglurant therapy and the evidence presented through preclinical and clinical trials. Expert opinion: Interaction between mGluR5 NAM and L-DOPA is an area of interest in PD research as concomitant treatment results in the improvement of LID symptoms in humans, thus enhancing the patient’s quality of life. However, few months ago, Novartis decided to discontinue clinical trials of mavoglurant for the treatment of LID, due to the lack of efficacy demonstrated in trials NCT01385592 and NCT01491529, although no safety concerns were involved in this decision. Nevertheless, the potential application of mGluR5 antagonists as neuroprotective agents must be considered and further studies are warranted to better investigate their potential. Keywords: L-DOPA, mavoglurant, mlgu5, Parkinson’s disease Expert Opin. Investig. Drugs (2014) 23(8):1165-1179

1.

Introduction

Currently, one of the biggest problems in the therapeutic area that needs to be addressed is the lack of effective drugs that can either cure neurodegenerative conditions or are at least capable of delaying the progression of these diseases [1,2]. As a consequence of improved medical care, better living standards, and resulting higher life expectancy in developed countries, the number of people affected with dementias is due to increase exponentially in the coming years. Existing medical treatments for Parkinson’s disease (PD) are not particularly effective and are frequently only palliative [1-3]. PD is the second most frequent chronic and progressive neurodegenerative disorder of the CNS worldwide and affects ~ 1% of the global population over 65 years of age [1]. The main characteristic of the disease is the development of alterations in motor activity that is related to the loss of dopamine release from nerve 10.1517/13543784.2014.931370 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure

Mavoglurant Discontinued Parkinson’s disease Glutamate 5 receptor antagonist Oral H3C

O O


N

OH

H3C

Pivotal trial(s)

[99,101,102]

terminals in the substantia nigra pars compacta (SNc) on the striatum (nigrostriatal tract), leading to dopamine neurotransmission dysfunction [4-9]. The basal ganglia (BG) are subcortical nuclear complexes that are implicated in the coordination and integration of motor activity. The main complexes forming the BG are: i) the caudate nucleus; ii) lenticular nucleus, formed by the putamen; (i and ii forming the striatum); iii) the medial or internal globus pallidus (GPi) and lateral or external globus pallidus (GPe); iv) subthalamic nucleus (STN); and v) substantia nigra [4]. Thus, the BG are an interconnected core interposed between the cerebral cortex, thalamus and the premotor areas of the brainstem. The striatum constitutes the primary input nucleus of the BG receiving excitatory glutamatergic inputs from the cerebral cortex [7]. Striatum also receives a number of primarily inhibitory dopaminergic fibers originating in the SNc, which sends axons both to the caudate nucleus and the putamen [7-9]. Besides, the striatum receives projections from the dorsal raphe (5HT containing) and locus coeruleus (noradrenergic). The efferent structures of the striatum within the BG are the substantia nigra pars reticulata (SNr) and the GPi, which send inhibitory GABA containing projections to communicate with the frontal cortex through the motor nuclei of the thalamus. In this way, GABA containing neurons maintain a high level of tonic inhibition in the thalamus and the brainstem. The striatal efferent pathways are classically divided into two: the direct and the indirect pathways. Dopamine receptor type 1 (D1) is responsible for the activation of the direct pathway. Inhibitory striatal GABA containing neurons project to GPi and the SNr resulting in an inhibition of the thalamic 1166

neurons, which have an excitatory function in the frontal cortex [5-9]. Striatum, which receives inhibitory dopaminergic projections from the SNc, favors the activation of a direct pathway causing an increased firing of neurons in the motor cortex (because the inhibitory projections of GPi to the thalamus are themselves inhibited). The indirect pathway is normally inactive due to the inhibition of dopaminergic SNr projections via D2 dopamine receptors. Thus, GPi/SNr activities are monitored by the striatum and the STN. The activities of STN are controlled both by the cerebral cortex through excitatory glutamatergic neurons and by the substantia nigra via dopaminergic axons. Moreover, the GPe, through inhibitory neurons, is strongly interconnected with the STN [4]. Therefore, the loss of dopaminergic neurons in the SNc results in an over activation of the GABA containing output nuclei that project to the thalamus, causing an excessive glutamatergic input from the cortex to the BG [5-8]. Thereby, the loss of dopaminergic modulation promotes an increase in the overall excitatory drive in the BG, disrupting voluntary motor control and causing the characteristic motor symptoms of PD: bradykinesia (slowness and difficulty initiating movement), hypokinesia (decreased range of motion) and resting tremor. However, in the presence of dopamine, critical afferent neurotransmitter in the BG, the direct pathway is preferentially activated and the indirect pathway is turned off, resulting in a decrease in excessive excitatory neurotransmission within the BG. Therefore, one of the key reasons for the effectiveness of dopamine replacement therapy in PD is that the treatment with L-DOPA promotes the preferential activation of the direct pathway. Unfortunately, one of the side effects of L-DOPA administration is the development of L-DOPAinduced dyskinesias (LIDs) [4-9]. Earlier studies indicated that dyskinesias may be caused by the excessive dopamine release; however, it is the synergic synaptic transmission via dopamine and NMDA receptors (NMDAr) that underlies the occurrence of dyskinesias [10-15]. Thus, amantadine, an NMDAr antagonist, was introduced as a pharmacological treatment for PD-LID; however, this treatment is unsatisfactory [12]. In recent years, it was suggested that metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator (NAM) could be useful adjuncts to dopamine replacement therapy. Drugs in this class are capable of increasing the L-DOPA therapeutic window, thereby alleviating dyskinesia and perhaps allowing for the reduction of L-DOPA dosing frequency [16]. Apart from possible uses in PD, mGluR5 NAM may also have potential to treat a wide range of diseases such as fragile X syndrome, depression and schizophrenia [17,18]. The purpose of this review is to examine current approaches to improve PD treatment, with a particular focus on how to alleviate the occurrence of side effects of the most frequently prescribed anti-parkinsonian drug: L-DOPA. Suitability of mGluR5 modulation via the use of mGluR5 antagonists as a potential treatment strategy is assessed.

Expert Opin. Investig. Drugs (2014) 23(8)

Mavoglurant


2.

Current treatments of PD

The neuropathological hallmarks of PD include the appearance of cytoplasmic protein aggregates (Lewy bodies) inside the neurons and the progressive loss of the dopaminergic neurons in the SNc, which cause a series of neurochemical, anatomical and metabolic changes that alter BG outputs [4,6-8]. The aggregates are composed of a-synuclein that was recently proposed to be involved in the process of neuronal cell death [5]. As a consequence of striatal dopamine loss, the principle goal of PD treatment is to restore dopamine neurotransmission in the brain, as well as to increase dopamine availability [1-5]. One of the main obstacles to the development of effective anti-PD drugs is that these compounds have to be sufficiently lipophilic, in order to be able to diffuse across the blood--brain barrier (BBB) into the CNS. Currently available dopamine replacement therapy is based on the oral administration of dopamine precursor L-DOPA + carbidopa (which inhibits peripheral metabolism of L-DOPA) and dopamine agonists (DAs) [1-3,5]. This treatment strategy is not capable of slowing down or stopping neuronal loss, so it is necessary to develop drugs that are able to modify disease progression. Both L-DOPA and DAs improve motor performance in PD patients; however; long-term L-DOPA administration (3 years or longer) produces severe undesirable motor side effects such as LIDs, which usually present as dystonic abnormal involuntary movements [5,9,12-16]. In an attempt to reduce side effects profile of anti-PD drugs, monoamine oxidase inhibitors are frequently added to the treatment regimen [3]. DAs, such as bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine and apomorphine, directly stimulate postsynaptic dopamine receptors in the striatum, resulting in receptor activation [1-4,17-20]. Five dopamine receptor subtypes are divided into two families: D1-like family, which includes D1 and D5 subtypes, and D2-like family, consisting of D2, D3 and D4 receptor subtypes. Each agonist has a differential affinity for these subtypes, but the majority of available drugs mainly target D2 and D3 [2,3]. However, all these compounds are known to produce severe side effects, including confusion, hallucinations, psychosis and excessive sleepiness [4,5]. In order to block peripheral conversion of L-DOPA to 3-omethyldopa, thereby increasing the synaptic availability of L-DOPA, inhibitors of catechol-o-methyltransferase (COMT) are employed [1]. Two COMT inhibitors have successfully passed clinical trials and are currently in use: tolcapone and entacapone. The major difference between these two substances is the ability of tolcapone to easily cross the BBB, whereas entacapone passes the BBB at a much slower rate. COMT inhibitors are indicated for the treatment of motor disturbances in PD [2-5]. Monoamine oxidase (MAO) is an enzyme implicated in oxidative metabolism, specifically in deamination of monoamine neurotransmitters (e.g., dopamine, norepinephrine and

5-hydroxytryptamine [5-HT]) and biogenic amines such as tyramine. Two distinct isoforms of MAO are described, known as MAO types A and B [21-30]. MAO-B is the predominant isoform involved in the dopamine breakdown in the human brain. Rasagiline and selegiline, both selective irreversible MAO-B inhibitors with a much lesser affinity for MAO-A, are two anti-PD drugs that have been specifically developed with the goal of increasing L-DOPA half-life, while simultaneously reducing some of the side effects of earlier compounds [21-26]. Oral administration of rasagiline as a monotherapy or in combination with L-DOPA is generally well tolerated in patients with PD [23]. Interestingly, preclinical experimental studies suggest that rasagiline may have neuroprotective properties and, therefore, potential for modifying the course of PD [24-31]. Possible neuroprotective effect of rasagiline is independent of its action as an MAO-B inhibitor and appears to be related to its metabolite aminoindan, which induces a blockade of a mitochondrial permeability transition pore opening, thereby inhibiting nuclear translocation of GAPDH [24]. In addition, MAO-A inhibition by rasagiline may also increase the expression of anti-apoptotic genes such as Bcl-2 (prosurvival effects) and brain-derived neurotrophic factor in human PD patients [25]. In a double-blind delayed-start clinical trial of rasagiline in PD (ADAGIO), in which daily rasagiline was administered over the course of 36 weeks, the authors demonstrated significantly less functional deterioration in the early-onset group, compared to the delayed-start group (according to Unified Parkinson’s Disease Rating Scale [UPDRS] score) [30-32]. Thus, it was concluded that rasagiline is probably the only drug that has shown an effect modifier on the clinical course of PD, suggesting a neuroprotective role of this drug. In line with the desire to discover disease-modifying compounds, the development of pharmaceuticals that can change the course of PD became a priority [29]. As oxidative stress and reactive oxygen species generation in the SNc of the parkinsonian brain is considered a potential pathogenic mechanism, the development of antioxidant drugs could be a suitable strategy in PD treatment. The neuroprotective properties of a number of antioxidant drugs were evaluated, among them a coenzyme Q10, and a DA Pramipexole [19,20,30]. In the case of coenzyme Q10, despite some indications of its neuroprotective role in in vitro and in experimental animal models, very few results were reproducible in humans [32]. For a D2-receptor agonist pramipexole, which is widely used for PD treatment, preclinical data indicate that it can protect neurons by acting on mitochondria, an action independent of its DA effects [17-20]. Over the last decade, new data have extended our understanding of the pathophysiology of LID, suggesting the involvement of non-dopaminergic pathways including glutamate, 5-HT and adenosine signaling [4]. Glutamatergic neurotransmission, in particular, has received a lot of attention in the PD field. As mentioned earlier, amantadine is the only noncompetitive NMDAr antagonist currently in


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use to treat PD in humans and it is only moderately effective [12,13]. A number of other ionotropic glutamate receptor inhibitors had been investigated for their potential role in PD-LID treatment, including MK-801 and CP-101,606 [14]. Unfortunately, MK-801, a noncompetitive NMDAr antagonist, does not exhibit any anti-diskynetic activity [12,13]. The actions of CP-101,606, which is a selective inhibitor of NR2B subunit of NMDAr, are much more interesting. In preclinical studies, the drug has shown neuroprotective and antidyskinetic effects in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-lesioned monkeys [14]. Moreover, the safety and the efficacy of CP-101,606 have been evaluated in patients with idiopathic PD [14]. Despite the potentially beneficial roles of ionotropic glutamate inhibitors, the side effects profile of this group of drugs limit their clinical usefulness for PD treatment. Metabotropic glutamate receptors have also been targeted, with the mGluR5 receiving the most attention [4]. 3. PD-LID: molecular basis and treatment strategies

The pathophysiology of LIDs is complex, and multiple factors are likely involved, such as the inability of conventional L-DOPA regimens to provide continuous drug delivery, neurotransmitter and cell signaling alterations and other mechanisms [5,33-45]. There is evidence suggesting that overactivation of dopamine receptors D1 and D2 contribute to LIDs. Both D1 and D2 agonists can induce dyskinesia in experimental animal models of PD [35,36]. As disease progresses, there is a gradual loss of dopaminergic terminals in the striatum causing alterations in dopamine equilibrium by reducing the numbers of dopamine autoreceptors, which are responsible for the negative inhibition of further presynaptic dopamine release. This, in turn, results in an increase in extracellular dopamine following L-DOPA administration, which may be one of the precursors of LID. Therefore, these presynaptic-related abnormalities will induce oscillations (with oral L-DOPA administration) in synaptic dopamine levels, thus affecting synaptic transmission [5]. This hypothesis is supported by experimental evidence in humans, where it was demonstrated that continuous duodenal infusion of levodopa-carbidopa intestinal gel provides persistent dopaminergic stimulation and decreases the risk of development of motor fluctuations and improves LID symptoms, when compared to oral administration [38]. With regard to dopamine signaling pathways at the molecular level, LIDs have been linked to the persistent activation of the transcription factors DFosB in the striatum of dopamine-denervated L-DOPA-treated animal models [40-43] and in humans [43]. In addition, elevated extracellular dopamine, as a result of L-DOPA administration, causes an increase in intracellular cAMP levels and D1-receptor-mediated protein kinase A (PKA) activation. PKA activation further leads to a sequential phosphorylation of DARPP-32 (dopamine and 1168

cAMP-regulated phosphoprotein of 32 kDa) at Thr-34, extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase 1 (MSK-1) and histone 3 (H3) at Ser10 [40-42]. It is noteworthy that both of the above-mentioned modifications (increased levels of FosB/DFosB and H3 phosphorylation) are relatively stable, result in the altered transcription of genes thought to be responsible for dyskinesia symptoms, and will persist in the brain for an extended period after the last L-DOPA treatment, thus contributing to chronic LIDs. Apart from targeting dopamine signaling pathways directly, various other treatment strategies have been employed with varying degrees of success. Subthalamic deep brain stimulation is an effective surgical treatment in the advanced stages of PD, which consists of the stereotactic clinical intervention in the BG. Even though this procedure is considered surgically safe, it is nevertheless associated with adverse events, which include cognitive decline, speech difficulties and instability [5]. Nicotinic acetylcholine receptors have also been pharmacologically targeted based on preclinical research suggesting the role of nicotinic neurotransmission in PD-LID. In fact, a 14-day treatment with TC-8831, an experimental nicotinic receptor agonist, resulted in a significant reduction in dyskinesia in MPTP-lesioned L-DOPA-treated monkeys, with the apparently superior anti-dyskinetic profile when compared to the amantadine and L-DOPA dual therapy [39]. Preclinical data in rodents indicate that 5HT containing neurons from the midbrain raphe nuclei are involved in LID [41]. 5-HT neurons express amino acid decarboxylase that converts L-DOPA into dopamine, and these neurons are also capable of releasing dopamine. Initial results with sarizotan, a 5-HT1A receptor agonist with an additional affinity to dopamine D3 and D4 receptors (developed by Merck KGaA), have shown considerable promise for the reduction in PD-LID symptoms [44,45]; however, Phase III clinical trials were terminated due to lack of efficacy. Likewise, another 5-HT1A agonist tandospirone was not effective [46]. Eltoprazine is another agonist of both 5-HT1A and 5-HT1B receptors, which demonstrated an antidyskinetic profile in preclinical studies; unfortunately, it also reduces the antiparkinsonian effects of L-DOPA in animal models [47]. As can be seen from the above overview, the onset of LID is not solely dependent on dopamine signaling and may involve interplay between various neurotransmitters including 5-HT, acetylcholine, adenosine and glutamate.

Alterations in BG glutamatergic neurotransmission in PD

4.

In PD, the loss of dopaminergic signaling in the striatum causes excessive glutamatergic neurotransmission in the BG. Both physiological and neurotoxic effects of glutamate in the CNS are mediated through the interactions with ionotropic and metabotropic (G-protein-coupled) receptors. The ionotropic glutamate receptors are categorized in three groups



Mavoglurant

which include NMDA, AMPA receptors and kainate receptors. All these receptors are ligand-gated ion channels [12,13]. The activation of NMDAr channels by glutamate plays a prominent physiological role in the excitatory synaptic transmission and neuroplasticity. However, if an excess of glutamate is present in the synapses, CNS excitotoxicity may occur. It has been demonstrated that the activation of NMDAr induces the intracellular (cytosolic) calcium increase, which is required for long-term potentiation and long-term depression [11-13]. In addition, an overly dramatic increase in cytoplasmic calcium levels favors the activation of proinflammatory enzymes, mitochondrial alterations, and leads to oxidative stress, whereby initiating the processes of neuronal loss by necrosis or apoptosis [11-13]. In PD, the net effect of glutamate overstimulation of the BG circuitry is glutamate excitotoxicity, which may produce further loss of dopaminergic transmission, leading to disease progression [12]. Ionotropic NMDAr are widely expressed in the BG and their overactivation in the SNc contributes to excitotoxicity component and neurodegeneration [12]. In fact, glutamate release inhibitors riluzole and naftazone improve dyskinesia symptoms in experimental parkinsonian models [5]. While ionotropic glutamate receptors mediate fast excitatory synaptic transmission, metabotropic receptors also play a prominent role in the functional control of CNS excitability, modulating either presynaptic neurotransmitter release or postsynaptic excitatory neurotransmission. Eight metabotropic glutamate receptors have been characterized (mGluR1-8), all of which are G-protein-coupled receptors expressed in both neuronal and glial cells of the CNS [12,48-61]. Structurally, mGluRs have a large extracellular amino-terminal domain, with agonists binding at the seven-transmembrane helix that forms a binding pocket for compounds acting as allosteric modulators [48]. mGluRs are classified into three major groups, separated according to sequence homology, pharmacological properties and downstream second-messenger systems activation. Receptors belonging to Group 1 (mGluR1 and 5), which are coupled primarily to Gq/G11, stimulate phospholipase C and participate in phosphoinositide exchange [48-53]. Group 2 (mGluR2 and 3) and Group 3 (mGluR4, 6, 7 and 8) are coupled to Gi/o and associated signaling pathways, and act to inhibit cAMP production, via the inhibition of adenylyl cyclase [48]. Moreover, neuronal Group I mGlu receptors are typically expressed postsynaptically along the BG. Accordingly, mGluR1 is localized on dopaminergic neurons within the SNc and dopaminergic fibers within the striatum. In the striatum, mGluR1 is also expressed on medium spiny neurons and GABA containing interneurons [48-53]. On the other hand, Group 2 and Group 3 receptors are predominantly presynaptic, localized in axonal domains and axon terminals in corticostriatal fibers, and on SNc dopaminergic neurons, where they regulate neurotransmitter release [53]. For example, mGluRs 4, 7 and 8 are localized presynaptically within the

BG. In addition, mGluRs 4 and 7 are found on terminals of the striatum, striatonigral pathways and on terminals projecting from the STN to the SNc and SNr [48,51-53,62]. Cellular localization and modulatory role of mGluRs makes them suitable targets for pharmacological intervention within the indirect pathway of the BG [62]. 5.

Potential role of mGluR5 in brain disorders

Functional characterization of glutamatergic pathways constitutes an intensive area of preclinical research because glutamate is involved in a multitude of neurochemical processes within the brain, such as the mechanisms of drug addiction, behavior alterations, pathogenesis of schizophrenia, fragile X syndrome, PD, Huntington’s disease and Alzheimer’s disease [48,51-53]. Within the CNS, mGluR5 is widely expressed in multiple brain regions, such as the cerebral cortex, hippocampus, nucleus accumbens, lateral septum, striatum, hypothalamus, some parts of the amygdala, as well as on non-neuronal cells such as astrocytes, oligodendrocytes and microglia [62-66]. Three mGluR5 splice variants have been described to date: mGluR5a, which has a possible role in rat brain development; mGluR5b, which is abundant in the adult brain; and mGluR5d, which is mainly localized to human cerebellum and hippocampus [63]. Given the expression and distribution profile of mGluRs in the BG, these receptors are of particular interest as potential therapeutic targets for PD treatment [66]. Membrane-bound mGluR5 is a disulfide-linked dimer coupled via Gq to phospholipase C, which regulates neuronal excitability and currents through ionotropic GluRs [45,54-56]. Many physiological effects of mGluR5 activation/inactivation depend on interactions with other receptors. In this respect, modulation of mGluR5 attracts considerable scientific interest due to the involvement of mGluR5 in memory processes, through the interaction with the ionotropic NMDAr that play a critical role in synaptic plasticity [48,58-60]. In fact, electrophysiological studies suggest a synergistic relationship between mGluR5 and NMDAr [58,59]. It has been demonstrated that the activation of mGluR5 enhances NMDA currents, thus regulating NMDAr-evoked responses. A reciprocal relationship between mGluR5 and NMDAr exists, whereby mGluR5 agonists enhance, and antagonists attenuate NMDA currents, while the activation of NMDAr also affects mGluR5-mediated responses [58-60]. mGluR5 multimer formation with adenosine A2A receptors, as well as with opioid receptors, had also been reported [48,56,57]. The interactions between mGluR5 and adenosine A2A receptors have garnered a lot of attention because these receptors can form functional striatal heterodimers in vivo, and synergistic coactivation of both receptors could modulate dopaminergic signaling and the second messenger cascades of interest in PD treatment. Thus, both adenosine A2A and mGlu5 receptor agonists could synergistically reduce binding affinity of the D2 agonist binding sites in striatal membranes and thus modulate physiological functions


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of D2 receptors [53,57]. Interestingly, co-immunoprecipitation experiments in brain striatal tissue demonstrated the existence of an oligomeric complex with the presence of mGluR5, D2 and A2A receptors, localized to the dendritic spines [48,51-53,65]. Likewise, mGluR5-antagonist-induced motor activation requires A2A and probably D2 receptors, suggesting a possible role of the interactions of these two/three receptors in modulating motor function [51]. Presynaptic heterodimers in the glutamatergic terminals could modulate glutamate release, which is relevant to PD treatment, where antagonist administration improves some characteristics of motor deficits of the disease, as well as alleviates some of the side effects of L-DOPA treatment. Besides, there is now evidence for the existence and functional relevance of mGluR5/ m-opioid receptor heteromers and mGluR5/ calcium-sensing receptor heterodimers [51-53]. It is becoming increasingly clear that modulating mGluR5 function will likely affect multiple systems. As mentioned earlier, drugs that target mGluR5 can act as allosteric modulators, in other words exert their effects on a receptor through a binding site that is topographically distinct from the binding site of the endogenous ligand. The multitude of potential interactions between these receptors opens up new avenues for future drug development [53,66]. The first compounds targeting mGluR5 used in preclinical studies were 1, 2-diarylalkynes: 2-methyl-6- (phenylethynyl) pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine (MTEP). These were successful in reducing pain, anxiety and PD-LID in animal models [48]. Interestingly, Fenobam, an atypical anxiolytic compound with unknown molecular targets discovered in the 1970s, had recently been shown to be a potent and selective mGluR5 inhibitor and is currently under investigation for the treatment of PD-LID [18]. Possible neuroprotective role of mGluR5 inhibition is supported by recent studies suggesting that MTEP exerts beneficial effects in excitotoxic animal models, such as Kainic acid (KA) -induced damage in the hippocampus. In this model, MTEP decreases, but does not block completely, glutamate release mediated by KA, which may contribute, in part, to the neuroprotective properties of MTEP [67]. Likewise, MPEP was found to protect the neurons against quinolinic acid-induced striatal toxicity in rats, an experimental neurodegenerative model associated with striatal toxicity and Huntington’s disease [68,69]. It is of additional interest that MPEP also acts as a neuroprotector in a rat model of methamphetamineinduced toxicity [70-74]. Therefore, mGluR5 antagonists may find their place as neuroprotective agents, because they appear to attenuate excitotoxic process without the complete inhibition of glutamate neurotransmission. 6. Therapeutic potential of mGluR5 NAM in PD: preclinical studies

One of the major goals in PD treatment is the development of new compounds that improve motor deficits without the risk 1170

of chronic adverse events of standard dopaminergic drugs. As mentioned earlier, selective modulation of glutamatergic transmission through mGlu5 receptors can be used as a potential pharmacological strategy for the treatment of brain disorders that involve alterations in glutamatergic signaling, as is the case with PD. In this context, Samadi et al. performed binding studies in monkeys utilizing [3H] MPEP radioligand. Authors provide evidence that the specific activation of mGluR5 in the BG may contribute to the pathogenesis of dyskinesias in PD [75]. In addition, Ismayilova et al. demonstrated altered expression of mGluR5 mRNA in rat striatum after treatment with reserpine, which causes a reduction in brain dopamine levels [54]. It has been hypothesized that in animals treated with parkinsonian neurotoxins, the activation of mGluR5 results in nigrostriatal damage. In line with this hypothesis, a number of studies demonstrated the benefits of blockade of mGluR5, leading to an improvement in parkinsonian symptoms (Table 1) [75-92]. Several toxins are widely used to study PD in experimental animal models (rodents and monkeys): these include 6-hydroxydopamine (6-OHDA), mitochondrial neurotoxins MPTP and rotenone (both are mitochondrial complex I inhibitors) [75-83]. Coccurello et al. has shown that chronic inhibition of mGluR5 by MPEP was effective at reversing negative motor symptoms induced by 6-OHDA [80]. Likewise, in another study, chronic administration of MPEP produced robust antiparkinsonian effects in hemiparkinsonian 6-OHDA-lesioned rats, although these effects were not seen when the drug was administered acutely [76,80]. Bashkatova and Sudakov demonstrated that long-term treatment with rotenone results in enhanced nitric oxide (NO) generation in the striatum, mediated by the inducible NO synthase [82]. Rotenone-induced neurotoxicity and catalepsy was partially prevented by the administration of MPEP. Similarly, experimental motor deficits and dyskinesia induced in animals following chronic L-DOPA treatment were attenuated following the blockade of mGluR5 receptor with MPEP [82,93]. Moreover, chronic administration of MPEP, as well as of MTEP (which has superior specificity and bioavailability) in rats, improved adverse motor side effects such as catalepsy and muscle rigidity caused by haloperidol, a dopamine D2 receptor antagonist [73,84]. Additional evidence for mGluR5 involvement in experimentally induced PD comes from the research in mice lacking the mGluR5 gene, in which nigrostriatal dopamine neurons were protected from neurotoxicity mediated by 6-OHDA and MPTP neurotoxins [87]. An interesting observation is the demonstration that the coadministration of MPEP and NMDAr antagonist MK-801 at low doses, prevented akinesia in 6-OHDA-lesioned rats, an effect not seen if these compounds were administered individually [81]. These results suggest that the combined blockade of mGluR5 and NMDAr is more effective in reversing movement disorders in preclinical models of PD, when compared to the blockade of individual receptors at a time [81]. Taken together, various studies indicate that mGluR5 antagonists


Mavoglurant

Table 1. Preclinical studies testing drugs acting on mGlu5 receptor. Study/ref.


Breysse et al. [76]

Animal

PD model

Treatment/dosing

ROA Treatment length

6-OHDA

MPEP (1.5, 3 and 6 mg/kg)

i.p.

3 weeks

Coccurello et al. [80]

Male Wistar rats Male Wistar rats

6-OHDA

CSC (0.625, 1.25 mg/kg) ; MPEP (0. 375, 1.5 mg/kg); CSC (0.625 mg/kg) + MPEP (0.375 mg/kg)

i.p.

3 weeks

Turle-Lorenzo et al. [81]

Male Wistar rats

6-OHDA

MPEP (0.375, 0.75 mg/kg); MPEP (0,375, 0,75 mg/ kg) + MK-801 (0.02 mg/kg)

i.p.

3 weeks

Morin et al. [79]

Female monkeys

MPTP

p.o.

1 month

Black et al. [87]

mGluR5 KO mice

6-OHDA

L-DOPA/bensezaride (100/25 mg); L-DOPA/bensezaride (100/25 mg) + MPEP (10 mg/kg) N/A

N/A

N/A

Johnston et al. [85]

Monkeys

MPTP

L-DOPA (33 mg/kg); MTEP (4.5 -- 36 mg/kg); L-DOPA (33 mg/kg) + MTEP (4.5 -- 36 mg/kg)

p.o

6h

Lopez et al. [84]

Male Wistar rats

Haloperidol

MPEP (1.5 mg/kg) + CSC (0.625, 1.25 mg/kg)

i.p.

2 h; 3 weeks

Ossowska et al. [73] Male Wistar rats

Haloperidol

MTEP (1, 3, 5 mg/kg)

i.p.

30 and 60 min

MPEP (3 mg/kg)

i.p.

60 days

L-DOPA/bensezaride (5 -- 15 mg/kg/ 25 mg) + mavoglurant (25 mg/kg); L-DOPA/bensezaride (15 -- 35 mg/kg/ 50 mg) + Mavoglurant (5 -- 250 mg/kg)

p.o.

24 h

MPEP (2 -- 10 nM)

i.c.v. 24 h

Bashkatova and Sudakov [82] Gre´goire et al. [92]

Vernon et al. [77]

Male Sprague Rotenone Dawley rats (1.5 mg/kg) 60 days Female MPTP monkeys

Sprague Dawley rats

6-OHDA

Results

Full reversal of akinesia at all doses tested Full reversal of akinesia with coadministration of lower doses, or individual administration of higher doses/no effect with individual administration of lower doses Reversal of akinesia with coadministration of lower MPEP dose/individual MPEP administration only effective at higher dose Improvement in PD-LID symptoms with coadministration

Reduced dopamine loss and improved motor functions in 6-OHDA-lesioned knockout mice, compared to wild-type animals MTEP monotherapy does not have antiparkinsonian effects/acute coadministration reduces peak dose LID by 96% Acute coadministration has no effect on haloperidolinduced catalepsy/chronic coadministration inhibits catalepsy only with higher CSC dose Inhibition of catalepsy only with 3 and 5 mg/kg MTEP doses, both 30 and 60 min after MTEP injection Reduction of rotenoneinduced catalepsy/reduction in NO content in rat striatum Antiparkinsonian activity of LDOPA is increased with coadministration of low doses of both compounds, with the incidence of dyskinesias remaining low/ with the coadministration of high doses of L-DOPA and mavoglurant, LID is significantly reduced Neuroprotection

6-OHDA: 6-Hydroxydopamine; CSC: 8-(3-chlorostyryl)caffeine; ip: Intraperitoneal; LID: L-DOPA-induced dyskinesia; mGluR5: metabotropic glutamate receptor 5; MPEP: 2-Methyl-6-(phenylethynyl)pyridine; MPTP: 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine; MTEP: 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine; NO: Nitric oxide; PD: Parkinson’s disease.


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Table 2. A summary of the published mavoglurant clinical trials conducted in the USA.


ClinicalTrials.gov Disease/ ID# (USA) condition

NCT00718341

FXS

NCT00888004

PD-LID

NCT01491529

PD-LID

Study/(title)

Efficacy, safety and tolerability of AFQ056 in fragile X patients Efficacy and safety of AFQ056 in reducing PD-LID

Primary outcomes/(under investigation) Evaluations of the Aberrant-Behavior Checklist score

Treatment/ Year measured concluded length (reported) *estimated 28 days

Number and severity 20 days of dyskinesias and the safety and tolerability of coadministering AFQ056 and L-DOPA Evaluation of Comprehensive 13 weeks the efficacy and evaluation of both safety of modified safety and efficacy release AFQ056 in of AFQ056 in Parkinson’s patients PD-LID patients with PD-LID

Ref.

Results

2009 [99]

Gomez-Mancilla Inconclusive et al. [99]

2009 [101]

Berg et al. [101] Improvement in PD-LID symptoms

2013 [102]

Stocchi et al. [102]

Safe, limited improvement in PD-LID symptoms

LID: L-DOPA-induced dyskinesia; PD: Parkinson’s disease.

have antiparkinsonian effects in 6-OHDA-lesioned rats, and reduce MPTP-induced toxicity in midbrain dopaminergic neurons in rodents. [86]. Recent studies in non-human primates show that mGluR5 expression was enhanced in the BG of parkinsonian monkeys that developed dyskinesias following chronic L-DOPA treatment, as well as in postmortem brains of PD patients with motor disturbances [90-92]. When MPTP-lesioned monkeys were treated with L-DOPA, they developed motor dysfunctions, which were associated with an increase in the specific binding to mGluR5 in the posterior putamen and pallidum [89]. Interestingly, when dyskinesias were prevented by the administration of a selective NR1A/2B NMDAr subtype antagonist CI-1041, or low doses of cabergoline, a dopamine D2 receptor agonist, a reduction in mGluR5-specific binding in these brain areas was observed [14,36]. This study has demonstrated a close relationship between the mGluR5 and the appearance of dyskinesias [87,88]. In MPTP-lesioned monkeys treated with L-DOPA and MPEP, significantly fewer motor side effects were reported, when compared to the group treated only with L-DOPA [79]. Similar results were obtained with MTEP-treated MPTP-lesioned macaques [86]. Moreover, administration of AFQ056 (mavoglurant) (Box 1), which is a selective mGluR5 NAM developed by Novartis, to MPTPlesioned and L-DOPA-treated monkeys significantly increased the antiparkinsonian activity of L-DOPA and simultaneously decreased the appearance of dyskinesias [92]. Thus, we can conclude that in animal models of PD, treatment with mGlu5 receptor antagonists relieves motor symptoms of PD-LID. Although the exact mechanism whereby mGluR5 antagonism might exert antidyskinetic actions is not well-known, the reduction in L-DOPA-induced phosphorylation of ERK 1/2 and mitogen- and stress-activated protein 1172

kinase 1 (MSK-1), may be involved. Dopamine, through binding to D1 receptor could mediate the activation of ERK1/2 and MSK-1 that may play a role in the development of L-DOPA-induced motor side effects [94]. Likewise, it was demonstrated that L-DOPA-induced phosphorylation of ERK 1/2 and MSK-1 in the striatum of 6-OHDA-lesioned rats was prevented by the administration of mGluR5 antagonist MTEP [81]. In addition, Bruno et al. were the first to demonstrate the neuroprotective properties of mGluR5 antagonists against NMDA or b-amyloid toxicity, both in cultured cortical neurons and in in vivo models of excitotoxic neurodegeneration [71]. These data highlight a potentially key role of mGluR5 function in the field of neuroprotective research [92,95]. Apart from the compounds already mentioned, other selective mGluR5 NAM that are beyond the scope of this review, have shown antidyskinetic effects in preclinical studies, these include 6, 6-dimethyl-2-phenylethynyl-7, 8-dihydro6H-quinolin-5-one (MRZ-8676), dipraglurant (ADX48621) and eltoprazine [96].

Therapeutic potential of mGluR5 NAM and mavoglurant for PD: clinical studies

7.

The therapeutic potential of drugs that act by blocking mGlu5 receptors was clearly demonstrated in preclinical studies. Mavoglurant was one of the first specific mGluR5 NAM to reach clinical trials (Table 2) stage for PD treatment. The majority of clinical trials conducted initially had focused on evaluating the efficacy of mavoglurant in reducing abnormal involuntary movements of the hands and feet (Chorea) in Huntington’s disease, obsessive--compulsive disorder, fragile



Mavoglurant

X syndrome and during smoking abstinence [74,97-99]. More recently, greater emphasis was put on evaluating the efficacy of mavoglurant as an adjuvant drug in PD treatment for the alleviation of PD-LID symptoms. Initial pharmacokinetic profiling, which confirmed the safety of mavoglurant in humans, was performed in four healthy male subjects with a single 200 mg oral dose. It was determined that the drug is mainly metabolized via oxidative metabolism with 37% recovered in urine and 59% in feces [100]. The first clinical trials that demonstrated the efficacy of mavoglurant in PD-LID were performed by Berg et al. in two randomized, double-blind, placebo-controlled, parallelgroup, in-patient studies for PD patients with moderate-tosevere PD-LID (study 1), and for patients with severe PD-LID (study 2) on stable dopaminergic therapy. In the first study, 31 patients were randomized (15 to mavoglurant and 16 to placebo), and in the second study, 28 patients were randomized (14 to mavoglurant and 14 to placebo). In the both the studies, 25 -- 150 mg of either mavoglurant or placebo was administered twice daily for 16 days, 1 h prior to L-DOPA treatment [102]. In the first study, the evaluation of the antidyskinetic efficacy of mavoglurant was performed using the Lang-Fahn Activities of Daily Living Dyskinesia Scale (LFADLDS), whereas the modified Abnormal Involuntary Movements Scale (mAIMS) was used in the second study. The other primary outcome measure in both studies was to assess the antiparkinsonian efficacy of mavoglurant in the UPDRS. The UPDRS is a classification system to monitor the longitudinal course of PD. Moreover, the safety and tolerability of mavoglurant at different doses was evaluated. The main conclusions of these studies were that the mavoglurant was well tolerated and that a significant improvement in LID symptoms was achieved [101]. The authors reported that mavoglurant improved dyskinesia symptoms without compromising the therapeutic efficiency of L-DOPA and demonstrated antidyskinetic efficacy on day 16 on LFADLDS in study 1 (p = 0.021) and on mAIMS in study 2 (p = 0.031). Significant effects of mavoglurant were also seen on the UPDRS-IV on days 12 and 16 in both studies (study 1: p = 0.012 and p = 0.014; study 2: p = 0.026 and p = 0.001). The adverse events were moderate and were most commonly localized to the nervous and gastrointestinal systems, but also included psychiatric manifestations. One of the main shortcomings of both studies was the relatively small number of recruited participants. In another randomized, double-blind, placebo-controlled, parallel-group study published by Stocchi et al., the primary outcomes were to investigate the anti-dyskinetic efficacy of mavoglurant at five different dose ranges (20, 50, 100, 150 and 200 mg daily) in PD patients with LID, using the mAIMS. Secondary outcome measures included the 26-item PD Dyskinesia Scale (PDYS-26), the Patient’s/Clinician’s Global Impression of Change and the UPDRS. At the highest dose tested (200 mg), mavoglurant treatment resulted in

significant improvement in mAIMS scores (p = 0.07) but not in the secondary outcome measures [102]. For the lower doses evaluated in the study, the reduction in PD-LID symptoms was not significant. In agreement with the previous studies, mavoglurant was generally well tolerated. The most commonly reported adverse events were dizziness, fatigue and hallucinations, and most were mild to moderate in severity. The authors of the study concluded that mavoglurant showed a slight improvement in mAIMS compared with placebo and provide evidence that mavoglurant coadministration may permit treatment with higher doses of L-DOPA in PD-LID patients. A total of 98 patients in the mavogluranttreated group completed the study and 47 patients in the placebo group. Kumar et al. have recently published the results of a randomized, double-blind, placebo-controlled study investigating the effects of mavoglurant adjunct therapy on a gradual increase in L-DOPA administration (2 weeks of continually increasing doses of mavoglurant, combined with standard L-DOPA treatment, followed by 3 weeks of combined therapy, with the daily increases in L-DOPA dosing) [103]. The primary outcome was to measure potential changes in the functional status of a patient from baseline to week 5, as well as to monitor total OFF-time (time when medication ceased to have an effect), assessed both by the clinicians and recorded by the patients themselves utilizing an in-home patient diary, as previously described by Hauser et al. [105]. The secondary outcomes were to evaluate total ON-time, ON-time without dyskinesia and ON-time with dyskinesia, using the patient’s diary. Other secondary outcome measures included mAIMS and the Unified Dyskinesia Rating Scale (UDysRS). Authors of this study reported that the results were inconclusive due to the low number of patients (n = 7 in each group) and issues related to conflicting clinician-rated functional outcomes. Nevertheless, the authors reached similar conclusions to the above-mentioned study by Stocchi et al. [102]. Unfortunately, based on the results of the most recent Phase II clinical trials (NCT01385592 and NCT01491529), assessing the safety and the efficacy of mavoglurant for the treatment of PD-LID, Novartis made a decision to discontinue further clinical trials with mavoglurant for PD-LID, due to the lack of efficacy. 8.

Conclusion

Current PD therapies are based on the use of drugs that mimic dopamine, with the initial L-DOPA treatment and other dopaminergic agents later on, which compensate for the loss of the neurotransmitter. Unfortunately, although L-DOPA and DAs have proven efficacious, chronic treatment with these agents can result in a loss of efficacy and the appearance of dyskinesia. There is a critical need in the PD research field for more effective therapies, as well as treatments that can reduce dyskinesias. In this manuscript, we have


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focused on preclinical and clinical studies demonstrating the efficacy of blocking mGluR5 for the better management of PD-LID symptoms. Preclinical reports indicate that mGluR5 NAM, including mavoglurant, can have a direct effect on glutamate neurotransmission and decrease NMDAr signaling [99]. Even though Novartis had recently terminated further clinical trials with mavoglurant for PD-LID therapy due to lack of efficacy, it has been shown that mavoglurant can, nevertheless, improve PD-LID symptoms, at least somewhat. Furthermore, the drug is well tolerated and has relatively few side effects, which may allow its use for the treatment of other CNS disorders. In light of recent withdrawal of mavoglurant for PD-LID treatment, it remains to be investigated if mGluR5 antagonists could act as disease modifiers, preventing dopaminergic loss. 9.

Expert opinion

Receptors involved in glutamatergic neurotransmission have been a target of intensive research for the treatment of CNS disorders, including PD. Despite the fact that preclinical and multiple clinical trials support the hypothesis that glutamatergic pathways are involved in PD-LID, large-scale studies, as well as the development of novel, specific receptor modulators, are necessary. We need to also be aware that an increase in glutamate neurotransmission is involved in excitotoxicity, in other words in the processes of neuronal cell death. Ionotropic GluR antagonists are effective at preventing dyskinesia in animal models, but their clinical use is limited due to the intensity of the side effects produced, which include hallucinations, cognitive perturbations and postural imbalance. Existing limitations of targeting ionotropic glutamate receptors have raised the interest in mGluRs as potential targets for modulating glutamate hyperactivity in PD and other neurological disorders. mGluRs are particularly interesting because of their diverse modulator roles and high expression in the BG. Mavoglurant is a chemical derivative of MPEP, one of the earliest discovered selective pharmacological inhibitors of mGluR5. MPEP has shown some promise in treating PDlike symptoms in experimental animal models; however, the molecule exhibits significant off-target effects, which precludes its use in humans. Modification and optimization of the chemical structure of MPEP, mainly with a carbamate and acetylene groups and the addition of aromatic substituents resulted in the creation of mavoglurant [106]. Mavoglurant is a much more specific NAM of the mGluR5 and as such, the range of potential side effects is much narrower. As mentioned earlier, mGluR5 is structurally composed of a large extracellular N-terminal domain, which harbors the orthosteric binding site (the site where glutamate binds), and of a seven-transmembrane a-helical domain. Although orthosteric ligands for mGluR5 have shown poor selectivity and bioavailability associated with low brain penetration, novel allosteric modulators display improved liposolubility 1174

and are more efficient at crossing the BBB [95]. Furthermore, mavoglurant and NAM, in general, have the advantage of binding to receptors at a distinct site to that of the endogenous ligand, thus modulating receptor function. The discontinuation of mavoglurant for PD-LID treatment should not discourage further attempts to develop novel derivatives of this compound to increase the pharmacological efficacy. PD-LIDs are complex multifactorial disorders, which demand an integrated multi-target approach to treatment. Molecular mechanisms behind mGluR5 function are still being elucidated, as demonstrated in a very recent paper by Purgert et al. [111]. In this study, authors described functional mGluR5s, which were present in the endoplasmic reticulum and nuclear membranes of dendrites, suggesting that cellsurface receptors are not solely responsible for the glutamate excitotoxicity. One possibility for the development of a successful novel compound is to preserve the basic chemical structure of mavoglurant, specifically the saturated bicyclic core that could be used as a model for new drugs targeting CNS diseases, including the ones mentioned in Table 2. Many physiological effects of mGluR5 activation depend on interactions with other receptors in vivo, as well as on the formation of functional multimers. For example, adenosine receptor A2A/mGLuR5 heterodimers are of interest, as preclinical data suggest that coadministration of drugs which bind to both receptors leads to an improvement in motor symptoms of PD. Significantly, these drugs perform better in combination, suggesting potentially synergistic effects [107-111]. Dipraglurant is another mGluR5 NAM that could potentially be used in combination with L-DOPA or DAs [52]. Additional compounds beyond the scope of this review, such as sarizotan, an agonist of the 5-HT1A receptor [44,45] and eltoprazine, a mixed 5-HT1A/1B receptor agonist, are somewhat effective in reducing PD-LID symptoms, both preclinically and clinically [47,96]. However, as is the case with many of the drugs targeting just a single receptor, eltoprazine has recently been discontinued for the treatment of PD-LIDs due to the lack of efficacy. In our opinion, significant resources should be dedicated towards the clinical trials focusing on multi-receptor modulation. For example, it has been proposed that the coadministration of eltoprazine with amantadine may significantly increase the antidyskinetic efficacy of this 5-HT1A/1B receptor agonist [47]. Similarly, it remains to be seen if a combination of mGluR5 antagonists with specific 5-HT1A receptor agonists could be a viable option for PD-LID management. Potential applications of mGluR5 antagonists as neuroprotective drugs need to be considered [112]. While pharmacological blockade of mostly post-synaptic NMDA or AMPA receptors produces neuroprotection accompanied by severe side effects, cell-surface mGluR5 inhibitors such as mavoglurant do not exhibit the typical side effects profile expected of ionotropic receptor antagonists, because these drugs primarily modulate presynaptic glutamate release. Therefore, future studies, investigating neuroprotective properties of multidrug therapy, for


Mavoglurant

example, a combination of mGluR5 antagonists, L-DOPA, 5-HT agonists and rasagiline, are of great interest for their potential to slow down or even reverse the course of PD.

Declaration of interest The authors are supported by grant 2009/SGR00853 from the Generalitat de Catalunya (autonomous government of Catalonia) as well as grants BFU2010-19119/BFI,


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Mavoglurant


Affiliation Dmitry Petrov1, Ignacio Pedros2, Maria Luisa de Lemos1, Merce` Palla`s1, Anna Maria Canudas1, Alberto Lazarowski4, Carlos Beas-Zarate5,6, Carme Auladell3, Jaume Folch2 & Antoni Camins†1 † Author for correspondence 1 Universitat de Barcelona, Institut de Biomedicina (IBUB), Centros de Investigacioń Biome´dica en Red de Enfermedades Neurodegenerativas (CIBERNED), Unitat de Farmacologia I Farmacogno`sia, Facultat de Farma`cia, Barcelona, Avda/Joan XXIII, Spain E-mail: [email protected] 2 Universitat Rovira i Virgili, Unitat de Bioquimica i Biotecnologıá, Facultat de Medicina i Cie`ncies de la Salut, Reus, Tarragona, Spain 3 Universitat de Barcelona, Departament de Biologia Cellular, Facultat de Biologia, Barcelona, Spain 4 Universidad de Buenos Aires (UBA), Instituto de Investigaciones en Fisiopatologıá y Bioquı´mica Clıńica (INFIBIOC), Facultad de Farmacia y Bioquı´mica, Buenos Aires, Argentina 5 Universidad de Guadalajara and Divisioń de Neurociencias, Departamento de Biologıá Celular y Molecular, C.U.C.B.A, Sierra Mojada 800, Col. Independencia, Guadalajara, Jalisco 44340, Me´xico 6 Instituto Mexicano del Seguro Social (IMSS), Centro de Investigacioń Biome´dica de Occidente (CIBO), Jalisco 44340, Me´xico


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Premotor Symptoms as Predictors of Outcome in Parkinsons Disease: A Case-Control Study.

Development of mavoglurant and its potential for the treatment of fragile X syndrome.

Pimavanserin as treatment for Parkinson's disease psychosis.

Cholesterol lowering as a treatment for established coronary heart disease.

Intratympanic dexamethasone as a symptomatic treatment for Ménière's disease.

Angioplasty as a treatment for coronary artery disease.

Striatal Dopamine Depletion Patterns and Early Non-Motor Burden in Parkinsons Disease.

Alpha-synuclein Toxicity in the Early Secretory Pathway: How It Drives Neurodegeneration in Parkinsons Disease.

Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease.

Deep Brain Stimulation of the Subthalamic Nucleus Improves Lexical Switching in Parkinsons Disease Patients.

Inhibitors of LRRK2 as Treatment for Parkinson's Disease: Patent Highlight.

Phototherapy as an effective treatment for Majocchi's disease--case report.

Vitamin Supplementation as an Adjuvant Treatment for Alzheimer's Disease.

Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator.

Global search for right cell type as a treatment modality for cardiovascular disease.

Lack of support for bexarotene as a treatment for Alzheimer's disease.

Ebola virus disease: potential use of melatonin as a treatment.

Selegiline as a primary treatment of Parkinson's disease.

Delayed transplantation of precursor cell-derived astrocytes provides multiple benefits in a rat model of Parkinsons.

mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization.

Interleukin-1 receptor antagonist (IL-1ra) as a probe and as a treatment for IL-1 mediated disease.

DYRK1B As Potential Treatment for Down's Syndrome or Alzheimer's Disease.

Combotherapy and current concepts as well as future strategies for the treatment of Alzheimer's disease.

Investigating sodium valproate as a treatment for McArdle disease in sheep.