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Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia

Statins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflam...

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Autores principales: Lopez-Lopez, Andrea, Valenzuela, Rita, Rodriguez-Perez, Ana Isabel, Guerra, María J., Labandeira-Garcia, Jose Luis, Muñoz, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10376833/
https://www.ncbi.nlm.nih.gov/pubmed/37507992
http://dx.doi.org/10.3390/antiox12071454
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author Lopez-Lopez, Andrea
Valenzuela, Rita
Rodriguez-Perez, Ana Isabel
Guerra, María J.
Labandeira-Garcia, Jose Luis
Muñoz, Ana
author_facet Lopez-Lopez, Andrea
Valenzuela, Rita
Rodriguez-Perez, Ana Isabel
Guerra, María J.
Labandeira-Garcia, Jose Luis
Muñoz, Ana
author_sort Lopez-Lopez, Andrea
collection PubMed
description Statins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflammation-related mechanisms such as angiotensin II and Rho-kinase (ROCK) inhibition may be involved. The nigra and striatum of dyskinetic rats showed increased levels of cholesterol, ROCK, and the inflammatory marker IL-1β, which were reduced by the angiotensin type-1 receptor (AT1) antagonist candesartan, simvastatin, and the ROCK inhibitor fasudil. As observed for LID, angiotensin II-induced, via AT1, increased levels of cholesterol and ROCK in the rat nigra and striatum. In cultured dopaminergic neurons, angiotensin II increased cholesterol biosynthesis and cholesterol efflux without changes in cholesterol uptake. In astrocytes, angiotensin induced an increase in cholesterol uptake, decrease in biosynthesis, and no change in cholesterol efflux, suggesting a neuronal accumulation of cholesterol that is reduced via transfer to astrocytes. Our data suggest mutual interactions between angiotensin/AT1, cholesterol, and ROCK pathways in LID, which are attenuated by the corresponding inhibitors. Interestingly, these three drugs have also been suggested as neuroprotective treatments against Parkinson’s disease. Therefore, they may reduce dyskinesia and the progression of the disease using common mechanisms.
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spelling pubmed-103768332023-07-29 Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia Lopez-Lopez, Andrea Valenzuela, Rita Rodriguez-Perez, Ana Isabel Guerra, María J. Labandeira-Garcia, Jose Luis Muñoz, Ana Antioxidants (Basel) Article Statins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflammation-related mechanisms such as angiotensin II and Rho-kinase (ROCK) inhibition may be involved. The nigra and striatum of dyskinetic rats showed increased levels of cholesterol, ROCK, and the inflammatory marker IL-1β, which were reduced by the angiotensin type-1 receptor (AT1) antagonist candesartan, simvastatin, and the ROCK inhibitor fasudil. As observed for LID, angiotensin II-induced, via AT1, increased levels of cholesterol and ROCK in the rat nigra and striatum. In cultured dopaminergic neurons, angiotensin II increased cholesterol biosynthesis and cholesterol efflux without changes in cholesterol uptake. In astrocytes, angiotensin induced an increase in cholesterol uptake, decrease in biosynthesis, and no change in cholesterol efflux, suggesting a neuronal accumulation of cholesterol that is reduced via transfer to astrocytes. Our data suggest mutual interactions between angiotensin/AT1, cholesterol, and ROCK pathways in LID, which are attenuated by the corresponding inhibitors. Interestingly, these three drugs have also been suggested as neuroprotective treatments against Parkinson’s disease. Therefore, they may reduce dyskinesia and the progression of the disease using common mechanisms. MDPI 2023-07-19 /pmc/articles/PMC10376833/ /pubmed/37507992 http://dx.doi.org/10.3390/antiox12071454 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lopez-Lopez, Andrea
Valenzuela, Rita
Rodriguez-Perez, Ana Isabel
Guerra, María J.
Labandeira-Garcia, Jose Luis
Muñoz, Ana
Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia
title Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia
title_full Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia
title_fullStr Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia
title_full_unstemmed Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia
title_short Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia
title_sort interactions between angiotensin type-1 antagonists, statins, and rock inhibitors in a rat model of l-dopa-induced dyskinesia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10376833/
https://www.ncbi.nlm.nih.gov/pubmed/37507992
http://dx.doi.org/10.3390/antiox12071454
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