Elsevier

European Journal of Pharmacology

Volume 855, 15 July 2019, Pages 149-159
European Journal of Pharmacology

Pathophysiological clues to therapeutic applications of glutamate mGlu5 receptor antagonists in levodopa-induced dyskinesia

https://doi.org/10.1016/j.ejphar.2019.05.004Get rights and content

Abstract

Levodopa remains to be the mainstay for treatment of Parkinson disease (PD). Long-term levodopa treatment bears a risk for developing levodopa-induced dyskinesia (LID). LID significantly overshadows patients' quality of life and therapeutic efficacy of levodopa. Pre- and post-synaptic changes in dopamine secretion and signaling, along with altered glutamate receptor expression and glutamatergic signaling in striatal neurons, and the resulting disinhibition-like changes in the corticostriatal circuitry, lead to aberrant activity of motor cortex and formation of LID. Research has highlighted the role of group I metabotropic glutamate receptors especially the metabotropic glutamate receptor 5 (mGlu5) in formation of LID through potentiating of ionotropic glutamate NMDA receptors and dopamine D1/D5 receptors in direct pathway. Accordingly, MTEP and MPEP were the first mGlu5 receptor antagonists which were shown to attenuate LID in animal models through suppression of downstream signaling cascades involving mitogen-activated protein kinase (MAPK) and FosB/delta FosB activation, as well as modulation of prodynorphinegic, preproenkephalinergic, and GABA-ergic neurotransmission systems. Beneficial effects of other mGlu5 receptor antagonists such as AFQ056/mavoglurant and ADX48621/dipraglurant in amelioration of LID has been shown not only in animal models but also in clinical trials. Considering the presence of mGlu receptor dysregulation in rapid eye movement (REM) sleep behavior disorder and depression, which are prodromal signs of PD, along with the neuroprotective effects of mGlu receptor antagonists, and their cognitive benefits, potential effectiveness of mGlu receptor antagonists in early prevention of PD remains to be investigated.

Section snippets

Theories on pathophysiology and formation of levodopa-induced dyskinesia

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta (SNc), giving rise to bradykinesia, rigidity and tremor as its hallmark clinical signs. Dopamine replacement therapy with levodopa (L-DOPA) comprises the mainstay of symptomatic treatment for PD (Cotzias et al., 1967). L-DOPA effectively mitigates main motor manifestations of PD, at the expense of extra-CNS decarboxylation into dopamine leading to

Role of glutamatergic transmission in LID pathophysiology

The above-mentioned mechanisms together constitute an oversimplified view of LID pathophysiology. Formation and chronicity of LID is known to result from the interplay of a complex network of neurotransmitters, consisting of dopamine and glutamate transmission, GABAergic transmission, enkephalins and opioids (Bastide et al., 2015; Cerri et al., 2017). For example, long term potentiation and depression (LTP and LTD) in postsynaptic potential in believed to be mainly due to aberrant glutamate

Glutamate receptors in striatum and implications in LID pathophysiology

There are two families of glutamate receptors: first, glutamate ionotropic receptors (iGlu), which are designated after their high-affinity ligands: NMDA, GluN, AMPA, GluA, and kainite, GluK, respectively, and second, glutamate metabotropic receptors (mGlu), which are members of group C family of G-protein coupled receptors (GPCRs) and are further classified into three groups:

  • 1)

    Group I mGlu receptors, including mGlu1 and mGlu5 receptors which are coupled to Gq, which activates phospholipase C,

Future avenues on therapeutic applications

Although research on synthesized selective glutamate mGlu5 receptor antagonists has been quite successful, the main limitation is identification of highly selective compounds (Johnson et al., 2009). Until recently, most studies have investigated the effects of mGlu5 receptor antagonists on motor complications of levodopa and overlooked the potential positive or negative effects on non-motor symptoms, importantly the cognitive function (Matosin et al., 2018). Moreover, evidence is accumulating

Funding

The authors have no financial interest to disclose.

Conflict of interest

The authors declare no conflict of interest. This research did not involve Human Participants and/or Animals.

Financial disclosure/conflict of interest

Authors do not have any potential conflict of interest or funding source to disclose.

References (127)

  • M. Crabbe et al.

    Altered mGluR5 binding potential and glutamine concentration in the 6-OHDA rat model of acute Parkinson's disease and levodopa-induced dyskinesia

    Neurobiol. Aging

    (2018)
  • A. Dekundy et al.

    Effects of group I metabotropic glutamate receptors blockade in experimental models of Parkinson's disease

    Brain Res. Bull.

    (2006)
  • H. Domin et al.

    Antidepressant-like effect of the mGluR5 antagonist MTEP in an astroglial degeneration model of depression

    Behav. Brain Res.

    (2014)
  • F. Gasparini et al.

    2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist

    Neuropharmacology

    (1999)
  • L. Gregoire et al.

    The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in L-Dopa-treated parkinsonian monkeys

    Park. Relat. Disord.

    (2011)
  • L. Grégoire et al.

    The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in l-Dopa-treated parkinsonian monkeys

    Park. Relat. Disord.

    (2011)
  • P. Jenner

    From the MPTP-treated primate to the treatment of motor complications in Parkinson's disease

    Park. Relat. Disord.

    (2009)
  • J. Katz et al.

    Comparative effects of acute or chronic administration of levodopa to 6-hydroxydopamine-lesioned rats on the expression of glutamic acid decarboxylase in the neostriatum and GABAA receptors subunits in the substantia nigra, pars reticulata

    Neuroscience

    (2005)
  • H. Kubas et al.

    Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators

    Bioorg. Med. Chem. Lett

    (2013)
  • G. Levandis et al.

    Systemic administration of an mGluR5 antagonist, but not unilateral subthalamic lesion, counteracts l-DOPA-induced dyskinesias in a rodent model of Parkinson's disease

    Neurobiol. Dis.

    (2008)
  • R. Lujan et al.

    Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites

    J. Chem. Neuroanat.

    (1997)
  • S. Maranis et al.

    Investigation of the antidyskinetic site of action of metabotropic and ionotropic glutamate receptor antagonists. Intracerebral infusions in 6-hydroxydopamine-lesioned rats with levodopa-induced dyskinesia

    Eur. J. Pharmacol.

    (2012)
  • N. Morin et al.

    Effect of the metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys

    Neuropharmacology

    (2010)
  • N. Morin et al.

    MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates

    Neuropharmacology

    (2013)
  • N. Morin et al.

    Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys

    Neuropharmacology

    (2013)
  • K.M. Nielsen et al.

    Normalization of glutamate decarboxylase gene expression in the entopeduncular nucleus of rats with a unilateral 6-hydroxydopamine lesion correlates with increased gabaergic input following intermittent but not continuous levodopa

    Neuroscience

    (2004)
  • B. Ouattara et al.

    Metabotropic glutamate receptor type 5 in levodopa-induced motor complications

    Neurobiol. Aging

    (2011)
  • J.D. Parkes et al.

    Amantadine dosage in treatment of Parkinson's disease

    Lancet

    (1970)
  • J.P. Pin et al.

    The metabotropic glutamate receptors: structure and functions

    Neuropharmacology

    (1995)
  • A. Pisani et al.

    Targeting striatal cholinergic interneurons in Parkinson's disease: focus on metabotropic glutamate receptors

    Neuropharmacology

    (2003)
  • O. Rascol et al.

    Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias

    Park. Relat. Disord.

    (2014)
  • J.E. Ahlskog et al.

    Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature

    Mov. Disord. : official journal of the Movement Disorder Society

    (2001)
  • H. Awad et al.

    Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus

    J. Neurosci. : the official journal of the Society for Neuroscience

    (2000)
  • H. Bading et al.

    N-methyl-D-aspartate Receptors Are Critical for Mediating the Effects of Glutamate on Intracellular Calcium Concentration and Immediate Early Gene Expression in Cultured Hippocampal Neurons

    (1995)
  • P. Barroso-Chinea et al.

    Glutamatergic and cholinergic pedunculopontine neurons innervate the thalamic parafascicular nucleus in rats: changes following experimental parkinsonism

    Brain Struct. Funct.

    (2011)
  • G. Battaglia et al.

    Endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the development of nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice

    J. Neurosci. : the official journal of the Society for Neuroscience

    (2004)
  • D. Berg et al.

    AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials

    Mov. Disord. : official journal of the Movement Disorder Society

    (2011)
  • E. Bezard et al.

    Pathophysiology of levodopa-induced dyskinesia: potential for new therapies

    Nat. Rev. Neurosci.

    (2001)
  • E. Bezard et al.

    The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model

    Mov. Disord. : official journal of the Movement Disorder Society

    (2014)
  • P.J. Blanchet et al.

    Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys

    Mov. Disord. : official journal of the Movement Disorder Society

    (1998)
  • T. Boraud et al.

    Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey

    Brain : J. Neurol.

    (2001)
  • D.B. Calne et al.

    Idiopathic Parkinsonism treated with an extracerebral decarboxylase inhibitor in combination with levodopa

    Br. Med. J.

    (1971)
  • A.R. Carta et al.

    Selective modifications in GAD67 mRNA levels in striatonigral and striatopallidal pathways correlate to dopamine agonist priming in 6-hydroxydopamine-lesioned rats

    Eur. J. Neurosci.

    (2003)
  • A.R. Carta et al.

    Different responsiveness of striatonigral and striatopallidal neurons to L-DOPA after a subchronic intermittent L-DOPA treatment

    Eur. J. Neurosci.

    (2005)
  • M.A. Cenci et al.

    L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA

    Eur. J. Neurosci.

    (1998)
  • M.A. Cenci et al.

    Post‐ versus presynaptic plasticity in L‐DOPA‐induced dyskinesia

    J. Neurochem.

    (2006)
  • S. Cerri et al.

    Investigational drugs in phase I and phase II for levodopa-induced dyskinesias

    Expert Opin. Investig. Drugs

    (2017)
  • C.E. Clarke et al.

    Unchanged basal ganglia N-acetylaspartate and glutamate in idiopathic Parkinson's disease measured by proton magnetic resonance spectroscopy

    Mov. Disord.

    (1997)
  • P.J. Conn et al.

    Metabotropic glutamate receptors in the basal ganglia motor circuit

    Nat. Rev. Neurosci.

    (2005)
  • N.D. Cosford et al.

    3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity

    J. Med. Chem.

    (2003)
  • Cited by (19)

    • Restoration and targeting of aberrant neurotransmitters in Parkinson's disease therapeutics

      2022, Neurochemistry International
      Citation Excerpt :

      Data collected from both in vitro and in vivo studies indicate that mGluRs and subtypes possess desirable characteristics that possess a huge impact on the neurodegeneration process during PD (Bruno et al., 2017; Ribeiro et al., 2017). For instance, neuroinflammation can be regulated via modulation of degradation of mGluR5 through the lysosome-dependent pathway shown in HEK293T cells as well as in rodents (Zhang et al., 2021), and mGluR5 antagonists can also be targeted for the treatment of LID (Pourmirbabaei et al., 2019). Modulation of mGluR2 via LY-487,379 (positive allosteric modulator) has shown antipsychotic and anti-dyskinetic effects in the MPTP-lesioned primate model, and it also decreases the global parkinsonian score by approximately 15%, which in turn, cause an increase in the anti-parkinsonian effect of L-DOPA (Sid-Otmane et al., 2020).

    • Striatal Synaptic Dysfunction in Dystonia and Levodopa-Induced Dyskinesia

      2022, Neurobiology of Disease
      Citation Excerpt :

      Thus, mGluR5s potentiate the effect of direct pathway in the basal ganglia (Voulalas et al., 2005) suggesting that antagonizing mGluR5s might reduce glutamate hyperexcitability and involuntary movements associated with LID. Pre-clinical and clinical evidence support this idea, showing that mGluR5 antagonism attenuates both the acute and the long-term effects of L-DOPA in inducing involuntary movements; these behavioral effects are accompanied by a normalization of molecular and neurochemical correlates of LID (for review, see (Pourmirbabaei et al., 2019) and (Sebastianutto and Cenci, 2018)). In dystonia, negative allosteric modulation of mGluR5 receptors has been shown to normalize dysfunctional cholinergic activity in a model of TOR1A dystonia (Sciamanna et al., 2014) and reverse synaptic plasticity deficits in two distinct genetic models of dystonia, TOR1A and GNAL (Martella et al., 2021).

    • Are ion channels potential therapeutic targets for Parkinson's disease?

      2021, NeuroToxicology
      Citation Excerpt :

      By blocking the abnormal glutamate signaling, they are able to provide relief in motor symptoms of PD (Greenamyre and O’brien, 1991). Several studies have demonstrated that NMDA receptor antagonists such as Amantadine can reduce Parkinsonian rigidity induced by dopamine receptor antagonists suggesting that their use, along with present treatment, can improve the efficacy and tolerability of dopaminergic therapies (Fox et al., 2017; Pourmirbabaei et al., 2019; Uitti et al., 1996). Adamantine works as non-competitive antagonist at the phencyclidine (PCP) site within the NMDA-receptor (Crosby et al., 2003a), It also enhances release of dopamine from nerve terminals and delay its re-uptake (Mizoguchi et al., 1994; Takahashi et al., 1996).

    View all citing articles on Scopus
    View full text