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Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia

BACKGROUND: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP - protein kinase A and of the Ras-extracellular signal-regulated kinase (ERK) signalling pathways. However,...

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Autores principales: Santini, Emanuela, Sgambato-Faure, Veronique, Li, Qin, Savasta, Marc, Dovero, Sandra, Fisone, Gilberto, Bezard, Erwan
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925943/
https://www.ncbi.nlm.nih.gov/pubmed/20808799
http://dx.doi.org/10.1371/journal.pone.0012322
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author Santini, Emanuela
Sgambato-Faure, Veronique
Li, Qin
Savasta, Marc
Dovero, Sandra
Fisone, Gilberto
Bezard, Erwan
author_facet Santini, Emanuela
Sgambato-Faure, Veronique
Li, Qin
Savasta, Marc
Dovero, Sandra
Fisone, Gilberto
Bezard, Erwan
author_sort Santini, Emanuela
collection PubMed
description BACKGROUND: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP - protein kinase A and of the Ras-extracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. METHODOLOGY/RESULTS: We here studied, in the gold-standard non-human primate model of Parkinson's disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. CONCLUSION: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure. While cAMP signalling enhancement is associated with dyskinesia, abnormal ERK signalling is associated with priming.
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spelling pubmed-29259432010-08-31 Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia Santini, Emanuela Sgambato-Faure, Veronique Li, Qin Savasta, Marc Dovero, Sandra Fisone, Gilberto Bezard, Erwan PLoS One Research Article BACKGROUND: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP - protein kinase A and of the Ras-extracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. METHODOLOGY/RESULTS: We here studied, in the gold-standard non-human primate model of Parkinson's disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. CONCLUSION: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure. While cAMP signalling enhancement is associated with dyskinesia, abnormal ERK signalling is associated with priming. Public Library of Science 2010-08-23 /pmc/articles/PMC2925943/ /pubmed/20808799 http://dx.doi.org/10.1371/journal.pone.0012322 Text en Santini et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Santini, Emanuela
Sgambato-Faure, Veronique
Li, Qin
Savasta, Marc
Dovero, Sandra
Fisone, Gilberto
Bezard, Erwan
Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia
title Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia
title_full Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia
title_fullStr Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia
title_full_unstemmed Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia
title_short Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia
title_sort distinct changes in camp and extracellular signal-regulated protein kinase signalling in l-dopa-induced dyskinesia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925943/
https://www.ncbi.nlm.nih.gov/pubmed/20808799
http://dx.doi.org/10.1371/journal.pone.0012322
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