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Targeting metabotropic glutamate receptors for the treatment of Parkinson’s disease

    Philippe Huot

    *Author for correspondence: Tel.: +1 514 934 8026;

    E-mail Address: philippe.huot@mcgill.ca

    Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, H3A 2B4, Canada

    Department of Neurology & Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada

    Department of Neuroscience, Movement Disorder Clinic, Division of Neurology, McGill University Health Centre, Montreal, QC, H3A 2B4, Canada

    Published Online:https://doi.org/10.2217/nmt-2023-0016
    Free first page

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. McGregor MM, Nelson AB. Circuit mechanisms of Parkinson's disease. Neuron 101(6), 1042–1056 (2019).
    • 2. DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch. Neurol. 64(1), 20–24 (2007).
    • 3. Frouni I, Huot P. Glutamate modulation for the treatment of levodopa induced dyskinesia: a brief review of the drugs tested in the clinic. Neurodegener. Dis. Manag. 12(4), 203–214 (2022).
    • 4. Reiner A, Levitz J. Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert. Neuron 98(6), 1080–1098 (2018).
    • 5. Gregory KJ, Goudet C. International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, signaling, and physiology of metabotropic glutamate receptors. Pharmacol. Rev. 73(1), 521–569 (2021).
    • 6. Lujan R, Nusser Z, Roberts JDB, Shigemoto R, Somogyi P. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8(7), 1488–1500 (1996).
    • 7. Tison F, Keywood C, Wakefield M et al. A phase IIa trial of the novel mGluR5-negative allosteric modulator dipraglurant for levodopa-induced dyskinesia in Parkinson's disease. Mov. Disord. 31(9), 1373–1380 (2016). •• This phase IIa trial demonstrates an antidyskinetic effect of the mGlu5 negative allosteric modulators dipraglurant in Parkinson’s disease (PD) patients.
    • 8. Berg D, Godau J, Trenkwalder C et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov. Disord. 26(7), 1243–1250 (2011).
    • 9. Stocchi F, Rascol O, Destee A et al. AFQ056 in Parkinson patients with levodopa-induced dyskinesia: 13-week, randomized, dose-finding study. Mov. Disord. 28(13), 1838–1846 (2013).
    • 10. Kumar R, Hauser RA, Mostillo J et al. Mavoglurant (AFQ056) in combination with increased levodopa dosages in Parkinson's disease patients. Int. J. Neurosci. 126(1), 20–24 (2016).
    • 11. Wang WW, Zhang XR, Zhang ZR et al. Effects of mGluR5 antagonists on Parkinson's patients with L-Dopa-induced dyskinesia: a systematic review and meta-analysis of randomized controlled trials. Front. Aging Neurosci. 10, 262 (2018).
    • 12. Charvin D, Di Paolo T, Bezard E et al. An mGlu4-positive allosteric modulator alleviates Parkinsonism in primates. Mov. Disord. 33(10), 1619–1631 (2018).
    • 13. Gubellini P, Melon C, Dale E, Doller D, Kerkerian-Le Goff L. Distinct effects of mGlu4 receptor positive allosteric modulators at corticostriatal vs. striatopallidal synapses may differentially contribute to their antiparkinsonian action. Neuropharmacology 85, 166–177 (2014).
    • 14. Rascol O, Medori R, Baayen C, Such P, Meulien D. AMBLED Study Group. A randomized, double-blind, controlled phase II study of foliglurax in Parkinson's disease. Mov. Disord. 37(5), 1088–1093 (2022). •• This article reports the findings of the clinical trial conducted with foliglurax in patients with PD.
    • 15. Kwan C, Kang W, Kim E, Belliveau S, Frouni I, Huot P. Metabotropic glutamate receptors in Parkinson's disease. Int. Rev. Neurobiol. 168, 1–31 (2023).
    • 16. Frouni I, Hamadjida A, Kwan C et al. Activation of mGlu2/3 receptors, a novel therapeutic approach to alleviate dyskinesia and psychosis in experimental parkinsonism. Neuropharmacology 158, 107725 (2019). • This is the first article reporting that selective mGlu2/3 orthosteric stimulation alleviates dyskinesia, psychosis-like behaviors and enhances the antiparkinsonian action of L-DOPA in the MPTP-lesioned marmoset.
    • 17. Hamadjida A, Sid-Otmane L, Kwan C et al. The highly selective mGlu2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease. Eur. J. Neurosci. 51(12), 2412–2422 (2020).
    • 18. Sid-Otmane L, Hamadjida A, Nuara SG et al. Selective metabotropic glutamate receptor 2 positive allosteric modulation alleviates L-DOPA-induced psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset. Eur. J. Pharmacol. 873, 172957 (2020). • This is the first article reporting that selective mGlu2 positive allosteric modulation alleviates dyskinesia, psychosis-like behaviors and enhances the antiparkinsonian action of L-DOPA in the MPTP-lesioned marmoset.
    • 19. Frouni I, Kwan C, Nuara SG et al. Effect of the mGlu2 positive allosteric modulator CBiPES on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset. J. Neural. Transm. (Vienna) 128(1), 73–81 (2021).
    • 20. Nuara SG, Hamadjida A, Kwan C et al. Combined mGlu2 orthosteric stimulation and positive allosteric modulation alleviates L-DOPA-induced psychosis-like behaviours and dyskinesia in the parkinsonian marmoset. J. Neural. Transm. (Vienna) 127(7), 1023–1029 (2020).
    • 21. Frouni I, Kwan C, Belliveau S et al. Anti-parkinsonian effect of the mGlu(2) positive allosteric modulator LY-487,379 as monotherapy and adjunct to a low L-DOPA dose in the MPTP-lesioned marmoset. Eur. J. Pharmacol. 939, 175429 (2023).
    • 22. Corti C, Battaglia G, Molinaro G et al. The use of knock-out mice unravels distinct roles for mGlu2 and mGlu3 metabotropic glutamate receptors in mechanisms of neurodegeneration/neuroprotection. J. Neurosci. 27(31), 8297 (2007).
    • 23. Addex Therapeutics. Allosteric modulators for human health (2023). www.addextherapeutics.com/en/pipeline/researches/dipraglurant-pd-lid/.
    • 24. Johnston TH, Fox SH, McIldowie MJ, Piggott MJ, Brotchie JM. Reduction of L-DOPA-induced dyskinesia by the selective metabotropic glutamate receptor 5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease. J. Pharmacol. Exp. Ther. 333(3), 865–873 (2010). •• Discovers that selective mGlu5 negative allosteric modulation may interfere with the antiparkinsonian action of L-DOPA, in the MPTP-lesioned macaque.