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

Animals Antiparkinson Agents / adverse effects Corpus Striatum Disease Models, Animal Dyskinesia, Drug-Induced / drug therapy Levodopa / adverse effects Oxidopamine / toxicity Parkinson Disease Parkinsonian Disorders / chemically induced Rats
Basal ganglia Dyskinesia Glutamate Movement disorder Positive allosteric modulator Spines Striatum Synaptic plasticity mGlu4

Journal

Neuropharmacology
ISSN: 1873-7064
Titre abrégé: Neuropharmacology
Pays: England
ID NLM: 0236217

Informations de publication

Date de publication:
01 11 2022
Historique:
received: 13 03 2022
revised: 21 07 2022
accepted: 23 07 2022
pubmed: 9 8 2022
medline: 14 9 2022
entrez: 8 8 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.neuropharm.2022.109205 PMID: 35940348
pubmed: 35940348
pii: S0028-3908(22)00264-7
doi: 10.1016/j.neuropharm.2022.109205
pii:
doi:

Substances chimiques

Antiparkinson Agents 0
Levodopa 46627O600J
Oxidopamine 8HW4YBZ748

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

109205

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Valeria Calabrese (V)

San Raffaele University, Rome, 00166, Italy; Laboratory of Experimental Neurophysiology, IRCCS San Raffaele Roma, Rome, 00166, Italy.

Barbara Picconi (B)

San Raffaele University, Rome, 00166, Italy; Laboratory of Experimental Neurophysiology, IRCCS San Raffaele Roma, Rome, 00166, Italy.

Nicolas Heck (N)

CNRS, INSERM, Sorbonne University, Institut de Biologie Paris Seine, Neuroscience Paris Seine, 75005, Paris, France.

Federica Campanelli (F)

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy.

Giuseppina Natale (G)

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy.

Gioia Marino (G)

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, 00168, Italy; Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy.

Miriam Sciaccaluga (M)

Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy.

Veronica Ghiglieri (V)

San Raffaele University, Rome, 00166, Italy; Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy.

Alessandro Tozzi (A)

Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy.

Estelle Anceaume (E)

CNRS, INSERM, Sorbonne University, Institut de Biologie Paris Seine, Neuroscience Paris Seine, 75005, Paris, France.

Emeline Cuoc (E)

CNRS, INSERM, Sorbonne University, Institut de Biologie Paris Seine, Neuroscience Paris Seine, 75005, Paris, France.

Jocelyne Caboche (J)

CNRS, INSERM, Sorbonne University, Institut de Biologie Paris Seine, Neuroscience Paris Seine, 75005, Paris, France.

François Conquet (F)

H. Lundbeck A/S, 2500, Valby, Denmark.

Paolo 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.

Delphine Charvin (D)

H. Lundbeck A/S, 2500, Valby, Denmark. Electronic address: delphine.charvin@mindeedconsulting.com.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › Antidyskinésiques › Antiparkinsoniens › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Noyaux gris centraux › Corps strié › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Troubles dus à des produits chimiques › Intoxication › Syndromes neurotoxiques › Dyskinésie due aux médicaments › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés cycliques › Acides aminés aromatiques › Tyrosine › Dopa › Lévodopa › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Phénols › Catéchols › Catécholamines › Dopamine › Hydroxydopamines › Oxidopamine › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Troubles de la motricité › Syndromes parkinsoniens › A positive allosteric modulator of mGlu4...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › A positive allosteric modulator of mGlu4...