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Published on: January 7, 2019
The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model
Erwan Bezard1, Elsa Y Pioli, Qin Li
1Motac neuroscience, Manchester, UK; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; Service de Neurologie, CHU de Bordeaux, Pessac, France; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.
Background:
Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model.
Methods:
Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8).
Results:
Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy.
Conclusion:
Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.
Insights
Dipraglurant effectively reduced levodopa-induced dyskinesias (LID) in Parkinson's disease models. This potent mGluR5 antagonist showed efficacy without compromising levodopa's therapeutic benefits.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Metabotropic glutamate receptor type 5 (mGluR5) antagonists are potential treatments for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD).
- Dipraglurant is a selective mGluR5 negative allosteric modulator.
Purpose of the Study:
- To evaluate the efficacy of dipraglurant in reducing LID in a non-human primate model.
- To assess the impact of dipraglurant on levodopa efficacy.
Main Methods:
- A four-way crossover study using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID.
- Dipraglurant was administered orally at doses of 3, 10, and 30 mg/kg.
Main Results:
- Dipraglurant demonstrated significant inhibition of choreic and dystonic LID.
- The optimal dose for efficacy was 30 mg/kg, with no observed reduction in levodopa's therapeutic effect.
Conclusions:
- Dipraglurant is efficacious in treating LID in the MPTP-macaque model.
- Pharmacokinetic profiles suggest co-administration with levodopa is feasible for future studies.
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