Advanced

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 LU ; Deierborg, Tomas LU ; Machado, Alberto; Herrera, Antonio J.; Venero, José L. and de Pablos, Rocío M. (2018) In Frontiers in Cellular Neuroscience 12.
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AMPK, Animal model, Metformin, Microglia activation, Neuroinflammation, Parkinson’s disease
in
Frontiers in Cellular Neuroscience
volume
12
publisher
Frontiers
external identifiers
  • scopus:85058929654
ISSN
1662-5102
DOI
10.3389/fncel.2018.00440
language
English
LU publication?
yes
id
b55cd21f-eaef-4798-8e27-f3cac9b2a591
date added to LUP
2019-01-04 13:04:39
date last changed
2019-10-08 03:43:45
@article{b55cd21f-eaef-4798-8e27-f3cac9b2a591,
  abstract     = {<p>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.</p>},
  articleno    = {440},
  author       = {Tayara, Khadija and Espinosa-Oliva, Ana M. and García-Domínguez, Irene and Ismaiel, Afrah Abdul and Boza-Serrano, Antonio and Deierborg, Tomas and Machado, Alberto and Herrera, Antonio J. and Venero, José L. and de Pablos, Rocío M.},
  issn         = {1662-5102},
  keyword      = {AMPK,Animal model,Metformin,Microglia activation,Neuroinflammation,Parkinson’s disease},
  language     = {eng},
  month        = {11},
  publisher    = {Frontiers},
  series       = {Frontiers in Cellular Neuroscience},
  title        = {Divergent effects of metformin on an inflammatory model of Parkinson’s disease},
  url          = {http://dx.doi.org/10.3389/fncel.2018.00440},
  volume       = {12},
  year         = {2018},
}