A positive allosteric modulator of mGlu4 receptors restores striatal plasticity in an animal model of l-Dopa-induced dyskinesia.

Autor: Calabrese V; San Raffaele University, Rome, 00166, Italy; Laboratory of Experimental Neurophysiology, IRCCS San Raffaele Roma, Rome, 00166, Italy., Picconi B; San Raffaele University, Rome, 00166, Italy; Laboratory of Experimental Neurophysiology, IRCCS San Raffaele Roma, Rome, 00166, Italy., Heck N; CNRS, INSERM, Sorbonne University, Institut de Biologie Paris Seine, Neuroscience Paris Seine, 75005, Paris, France., Campanelli F; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy., Natale G; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy., Marino G; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy; Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy., Sciaccaluga M; Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy., Ghiglieri V; San Raffaele University, Rome, 00166, Italy; Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy., Tozzi A; Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy., Anceaume E; CNRS, INSERM, Sorbonne University, Institut de Biologie Paris Seine, Neuroscience Paris Seine, 75005, Paris, France., Cuoc E; CNRS, INSERM, Sorbonne University, Institut de Biologie Paris Seine, Neuroscience Paris Seine, 75005, Paris, France., Caboche J; CNRS, INSERM, Sorbonne University, Institut de Biologie Paris Seine, Neuroscience Paris Seine, 75005, Paris, France., Conquet F; H. Lundbeck A/S, 2500, Valby, Denmark., Calabresi P; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy; Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy. Electronic address: paolo.calabresi@policlinicogemelli.it., Charvin D; H. Lundbeck A/S, 2500, Valby, Denmark. Electronic address: delphine.charvin@mindeedconsulting.com.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2022 Nov 01; Vol. 218, pp. 109205. Date of Electronic Publication: 2022 Aug 05.
DOI: 10.1016/j.neuropharm.2022.109205
Abstrakt: By decreasing glutamate transmission, mGlu4 receptor positive allosteric modulators (mGlu4-PAM), in combination with levodopa (l-DOPA) may restore the synergy between glutamatergic and dopaminergic transmissions, thus maximizing the improvement of motor function in Parkinson's disease (PD). This study aimed to clarify the effects of foliglurax, a selective mGlu4-PAM, on the loss of bidirectional synaptic plasticity associated with l-DOPA-induced dyskinesia (LID). Behavioral assessments compared dyskinesia intensity in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with l-DOPA or l-DOPA plus foliglurax. In slices from the same rats, patch-clamp techniques were used to examine electrophysiological differences in glutamatergic synapses, evaluating the EPSCs mediated by NMDA and AMPA receptors in striatal spiny projection neurons. High-frequency stimulation of corticostriatal fibers was used as long-term potentiation (LTP)-inducing protocol. Conversely, 15 min of low-frequency stimulation was applied to depotentiate LTP. The density of dendritic spines was measured in striatal slices in the same experimental conditions. Our results show that, in corticostriatal slices, foliglurax decreased spontaneous glutamatergic transmission in both sham-operated and 6-OHDA lesioned rats. When co-administered with l-DOPA in 6-OHDA-lesioned rats, foliglurax fully restored dendritic spine density in a dose-dependent manner. Moreover, this co-treatment rescued striatal bidirectional plasticity and attenuated the intensity of l-DOPA-induced dyskinesia. This is the first demonstration in an animal model of PD and dyskinesia that a mGlu4 PAM can restore striatal synaptic plasticity.
Competing Interests: Declaration of competing interest DC and FC have been employees for Lundbeck A/S, which owns patent rights to foliglurax that was used in this study.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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