An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates.

Autor: Charvin D; Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland., Di Paolo T; Neuroscience Research Unit CHU de Québec, CHUL Pavillon and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada., Bezard E; Motac Neuroscience Ltd, Manchester, United Kingdom., Gregoire L; Neuroscience Research Unit CHU de Québec, CHUL Pavillon and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada., Takano A; Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden., Duvey G; Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland., Pioli E; Motac Neuroscience Ltd, Manchester, United Kingdom., Halldin C; Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm, Sweden., Medori R; Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland., Conquet F; Prexton Therapeutics SA, 1228 Plan-les-Ouates, Geneva, Switzerland.
Jazyk: angličtina
Zdroj: Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2018 Oct; Vol. 33 (10), pp. 1619-1631. Date of Electronic Publication: 2018 Sep 14.
DOI: 10.1002/mds.27462
Abstrakt: Background: Levodopa remains the gold-standard treatment for PD. However, it becomes less effective as the disease progresses and produces debilitating side effects, such as motor fluctuations and l-dopa-induced dyskinesia. Modulation of metabotropic glutamate receptor 4 represents a promising antiparkinsonian approach in combination with l-dopa, but it has not been demonstrated in primates.
Objective: We studied whether a novel positive allosteric modulator of the metabotropic glutamate receptor 4, PXT002331 (foliglurax), could reduce parkinsonism in primate models.
Methods: We assessed the therapeutic potential of PXT002331 in three models of MPTP-induced parkinsonism in macaques. These models represent three different stages of disease evolution: early stage and advanced stage with and without l-dopa-induced dyskinesia.
Results: As an adjunct to l-dopa, PXT002331 induced a robust and dose-dependent reversal of parkinsonian motor symptoms in macaques, including bradykinesia, tremor, posture, and mobility. Moreover, PXT002331 strongly decreased dyskinesia severity, thus having therapeutic efficacy on both parkinsonian motor impairment and l-dopa-induced dyskinesia. PXT002331 brain penetration was also assessed using PET imaging in macaques, and pharmacodynamic analyses support target engagement in the therapeutic effects of PXT002331.
Conclusions: This work provides a demonstration that a positive allosteric modulator of metabotropic glutamate receptor 4 can alleviate the motor symptoms of PD and the motor complications induced by l-dopa in primates. PXT002331 is the first compound of its class to enter phase IIa clinical trials. © 2018 International Parkinson and Movement Disorder Society.
(© 2018 International Parkinson and Movement Disorder Society.)
Databáze: MEDLINE
Externí odkaz: