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Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model

Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson’s disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced...

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Autores principales: Pagliaroli, Luca, Widomska, Joanna, Nespoli, Ester, Hildebrandt, Tobias, Barta, Csaba, Glennon, Jeffrey, Hengerer, Bastian, Poelmans, Geert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647536/
https://www.ncbi.nlm.nih.gov/pubmed/30484112
http://dx.doi.org/10.1007/s12035-018-1433-x
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author Pagliaroli, Luca
Widomska, Joanna
Nespoli, Ester
Hildebrandt, Tobias
Barta, Csaba
Glennon, Jeffrey
Hengerer, Bastian
Poelmans, Geert
author_facet Pagliaroli, Luca
Widomska, Joanna
Nespoli, Ester
Hildebrandt, Tobias
Barta, Csaba
Glennon, Jeffrey
Hengerer, Bastian
Poelmans, Geert
author_sort Pagliaroli, Luca
collection PubMed
description Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson’s disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-018-1433-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-66475362019-08-06 Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model Pagliaroli, Luca Widomska, Joanna Nespoli, Ester Hildebrandt, Tobias Barta, Csaba Glennon, Jeffrey Hengerer, Bastian Poelmans, Geert Mol Neurobiol Original Paper Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson’s disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-018-1433-x) contains supplementary material, which is available to authorized users. Springer US 2018-11-27 2019 /pmc/articles/PMC6647536/ /pubmed/30484112 http://dx.doi.org/10.1007/s12035-018-1433-x Text en © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Paper
Pagliaroli, Luca
Widomska, Joanna
Nespoli, Ester
Hildebrandt, Tobias
Barta, Csaba
Glennon, Jeffrey
Hengerer, Bastian
Poelmans, Geert
Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model
title Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model
title_full Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model
title_fullStr Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model
title_full_unstemmed Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model
title_short Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model
title_sort riluzole attenuates l-dopa-induced abnormal involuntary movements through decreasing creb1 activity: insights from a rat model
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647536/
https://www.ncbi.nlm.nih.gov/pubmed/30484112
http://dx.doi.org/10.1007/s12035-018-1433-x
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