Effect of mGluR 2 and mGluR 2/3 activators on parkinsonism in the MPTP-lesioned non-human primate.

Autor: Frouni I; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, Quebec, H3A 2B4, Canada., Kwan C; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, Quebec, H3A 2B4, Canada., Bédard D; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, Quebec, H3A 2B4, Canada., Hamadjida A; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, Quebec, H3A 2B4, Canada., Kang W; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, Quebec, H3A 2B4, Canada., Belliveau S; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, Quebec, H3A 2B4, Canada., Nuara SG; Comparative Medicine & Animal Resource Centre, McGill University, Montreal, Quebec, Canada., Gourdon JC; Comparative Medicine & Animal Resource Centre, McGill University, Montreal, Quebec, Canada., Huot P; Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, Quebec, H3A 2B4, Canada. philippe.huot@mcgill.ca.; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. philippe.huot@mcgill.ca.; Movement Disorder Clinic, Division of Neurology, Department of Neurosciences, McGill University Health Centre, Montreal, Quebec, Canada. philippe.huot@mcgill.ca.
Jazyk: angličtina
Zdroj: Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2024 Nov; Vol. 397 (11), pp. 9135-9147. Date of Electronic Publication: 2024 Jun 20.
DOI: 10.1007/s00210-024-03216-2
Abstrakt: We have previously discovered that the selective activation of metabotropic glutamate type 2 receptors (mGluR 2 ) and concurrent stimulation of metabotropic glutamate types 2 and 3 receptors (mGluR 2/3 ) enhance the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA). Here, we sought to determine the effects of the mGluR 2/3 orthosteric agonists LY-354,740 and LY-404,039, as well as the effects of the mGluR 2 positive allosteric modulators LY-487,379 and CBiPES on the range of movement, bradykinesia, posture and alertness as adjuncts to L-DOPA. Ten 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets entered 4 experimental streams: L-DOPA + LY-354,740 (vehicle, 0.1, 0.3 and 1 mg/kg), L-DOPA + LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + CBiPES (vehicle, 0.1, 1 and 10 mg/kg). For each molecule, treatments were randomised, and the range of movement, bradykinesia, posture and alertness were assessed by a blinded rater. None of the tested compounds significantly altered the global range of movement. LY-404,039 and CBiPES both reduced global bradykinesia, by up to 46% (both P < 0.05). LY-354,740, LY-404,039 and CBiPES each improved global posture by 35%, 44% and 39% (each P < 0.05), respectively. LY-404,039 and CBiPES both enhanced alertness by 54% (P < 0.05) and 79% (P < 0.01), respectively. LY-487,379 did not improve any of the parameters. Our results suggest that selective mGluR 2 positive allosteric modulation and combined mGluR 2/3 orthosteric stimulation might benefit bradykinesia, posture and alertness in PD when added to L-DOPA, which potentially represent novel therapeutic indications for molecules acting via these mechanisms.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
Externí odkaz: