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Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease

The oral antidiabetic drug metformin is known to exhibit anti-inflammatory properties through activation of AMP kinase, thus protecting various brain tissues as cortical neurons, for example. However, the effect of metformin on the substantia nigra (SN), the main structure affected in Parkinson’s di...

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Autores principales: Tayara, Khadija, Espinosa-Oliva, Ana M., García-Domínguez, Irene, Ismaiel, Afrah Abdul, Boza-Serrano, Antonio, Deierborg, Tomas, Machado, Alberto, Herrera, Antonio J., Venero, José L., de Pablos, Rocío M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258993/
https://www.ncbi.nlm.nih.gov/pubmed/30519161
http://dx.doi.org/10.3389/fncel.2018.00440
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author Tayara, Khadija
Espinosa-Oliva, Ana M.
García-Domínguez, Irene
Ismaiel, Afrah Abdul
Boza-Serrano, Antonio
Deierborg, Tomas
Machado, Alberto
Herrera, Antonio J.
Venero, José L.
de Pablos, Rocío M.
author_facet Tayara, Khadija
Espinosa-Oliva, Ana M.
García-Domínguez, Irene
Ismaiel, Afrah Abdul
Boza-Serrano, Antonio
Deierborg, Tomas
Machado, Alberto
Herrera, Antonio J.
Venero, José L.
de Pablos, Rocío M.
author_sort Tayara, Khadija
collection PubMed
description The oral antidiabetic drug metformin is known to exhibit anti-inflammatory properties through activation of AMP kinase, thus protecting various brain tissues as cortical neurons, for example. However, the effect of metformin on the substantia nigra (SN), the main structure affected in Parkinson’s disease (PD), has not yet been studied in depth. Inflammation is a key feature of PD and it may play a central role in the neurodegeneration that takes place in this disorder. The aim of this work was to determine the effect of metformin on the microglial activation of the SN of rats using the animal model of PD based on the injection of the pro-inflammogen lipopolysaccharide (LPS). In vivo and in vitro experiments were conducted to study the activation of microglia at both the cellular and molecular levels. Our results indicate that metformin overall inhibits microglia activation measured by OX-6 (MHCII marker), IKKβ (pro-inflammatory marker) and arginase (anti-inflammatory marker) immunoreactivity. In addition, qPCR experiments reveal that metformin treatment minimizes the expression levels of several pro- and anti-inflammatory cytokines. Mechanistically, the drug decreases the phosphorylated forms of mitogen-activated protein kinases (MAPKs) as well as ROS generation through the inhibition of the NADPH oxidase enzyme. However, metformin treatment fails to protect the dopaminergic neurons of SN in response to intranigral LPS. These findings suggest that metformin could have both beneficial and harmful pharmacological effects and raise the question about the potential use of metformin for the prevention and treatment of PD.
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spelling pubmed-62589932018-12-05 Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease Tayara, Khadija Espinosa-Oliva, Ana M. García-Domínguez, Irene Ismaiel, Afrah Abdul Boza-Serrano, Antonio Deierborg, Tomas Machado, Alberto Herrera, Antonio J. Venero, José L. de Pablos, Rocío M. Front Cell Neurosci Neuroscience The oral antidiabetic drug metformin is known to exhibit anti-inflammatory properties through activation of AMP kinase, thus protecting various brain tissues as cortical neurons, for example. However, the effect of metformin on the substantia nigra (SN), the main structure affected in Parkinson’s disease (PD), has not yet been studied in depth. Inflammation is a key feature of PD and it may play a central role in the neurodegeneration that takes place in this disorder. The aim of this work was to determine the effect of metformin on the microglial activation of the SN of rats using the animal model of PD based on the injection of the pro-inflammogen lipopolysaccharide (LPS). In vivo and in vitro experiments were conducted to study the activation of microglia at both the cellular and molecular levels. Our results indicate that metformin overall inhibits microglia activation measured by OX-6 (MHCII marker), IKKβ (pro-inflammatory marker) and arginase (anti-inflammatory marker) immunoreactivity. In addition, qPCR experiments reveal that metformin treatment minimizes the expression levels of several pro- and anti-inflammatory cytokines. Mechanistically, the drug decreases the phosphorylated forms of mitogen-activated protein kinases (MAPKs) as well as ROS generation through the inhibition of the NADPH oxidase enzyme. However, metformin treatment fails to protect the dopaminergic neurons of SN in response to intranigral LPS. These findings suggest that metformin could have both beneficial and harmful pharmacological effects and raise the question about the potential use of metformin for the prevention and treatment of PD. Frontiers Media S.A. 2018-11-21 /pmc/articles/PMC6258993/ /pubmed/30519161 http://dx.doi.org/10.3389/fncel.2018.00440 Text en Copyright © 2018 Tayara, Espinosa-Oliva, García-Domínguez, Ismaiel, Boza-Serrano, Deierborg, Machado, Herrera, Venero and de Pablos. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Tayara, Khadija
Espinosa-Oliva, Ana M.
García-Domínguez, Irene
Ismaiel, Afrah Abdul
Boza-Serrano, Antonio
Deierborg, Tomas
Machado, Alberto
Herrera, Antonio J.
Venero, José L.
de Pablos, Rocío M.
Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease
title Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease
title_full Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease
title_fullStr Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease
title_full_unstemmed Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease
title_short Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease
title_sort divergent effects of metformin on an inflammatory model of parkinson’s disease
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258993/
https://www.ncbi.nlm.nih.gov/pubmed/30519161
http://dx.doi.org/10.3389/fncel.2018.00440
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