Neuronal adenosine A 2A receptor overexpression is neuroprotective towards 3-nitropropionic acid-induced striatal toxicity: a rat model of Huntington’s disease

Maria Rosaria Domenici, Valentina Chiodi, Mirko Averna, Monica Armida, Antonella Pèzzola, Rita Pepponi, Antonella Ferrante, Michael Bader, Kjell Fuxe, Patrizia Popoli

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3 Citations (Scopus)

Abstract

The A 2A adenosine receptor (A 2A R) is widely distributed on different cellular types in the brain, where it exerts a broad spectrum of pathophysiological functions, and for which a role in different neurodegenerative diseases has been hypothesized or demonstrated. To investigate the role of neuronal A 2A Rs in neurodegeneration, we evaluated in vitro and in vivo the effect of the neurotoxin 3-nitropropionic acid (3-NP) in a transgenic rat strain overexpressing A 2A Rs under the control of the neural-specific enolase promoter (NSEA 2A rats). We recorded extracellular field potentials (FP) in corticostriatal slice and found that the synaptotoxic effect of 3-NP was significantly reduced in NSEA 2A rats compared with wild-type animals (WT). In addition, after exposing corticostriatal slices to 3-NP 10 mM for 2 h, we found that striatal cell viability was significantly higher in NSEA 2A rats compared to control rats. These in vitro results were confirmed by in vivo experiments: daily treatment of female rats with 3-NP 10 mg/kg for 8 days induced a selective bilateral lesion in the striatum, which was significantly reduced in NSEA 2A compared to WT rats. These results demonstrate that the overexpression of the A 2A R selectively at the neuronal level reduced 3-NP-induced neurodegeneration, and suggest an important function of the neuronal A 2A R in the modulation of neurodegeneration.

Original languageEnglish
Pages (from-to)235-243
Number of pages9
JournalPurinergic Signalling
Volume14
Issue number3
DOIs
Publication statusPublished - Sep 1 2018

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Adenosine A2A Receptors
Corpus Striatum
Huntington Disease
Wild Animals
Transgenic Rats
Phosphopyruvate Hydratase
Neurotoxins
Neurodegenerative Diseases
3-nitropropionic acid
Cell Survival
Brain

Keywords

  • 3-Nitropropionic acid
  • Adenosine A receptors
  • Huntington’s disease
  • Striatum
  • Synaptic transmission

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

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title = "Neuronal adenosine A 2A receptor overexpression is neuroprotective towards 3-nitropropionic acid-induced striatal toxicity: a rat model of Huntington’s disease",
abstract = "The A 2A adenosine receptor (A 2A R) is widely distributed on different cellular types in the brain, where it exerts a broad spectrum of pathophysiological functions, and for which a role in different neurodegenerative diseases has been hypothesized or demonstrated. To investigate the role of neuronal A 2A Rs in neurodegeneration, we evaluated in vitro and in vivo the effect of the neurotoxin 3-nitropropionic acid (3-NP) in a transgenic rat strain overexpressing A 2A Rs under the control of the neural-specific enolase promoter (NSEA 2A rats). We recorded extracellular field potentials (FP) in corticostriatal slice and found that the synaptotoxic effect of 3-NP was significantly reduced in NSEA 2A rats compared with wild-type animals (WT). In addition, after exposing corticostriatal slices to 3-NP 10 mM for 2 h, we found that striatal cell viability was significantly higher in NSEA 2A rats compared to control rats. These in vitro results were confirmed by in vivo experiments: daily treatment of female rats with 3-NP 10 mg/kg for 8 days induced a selective bilateral lesion in the striatum, which was significantly reduced in NSEA 2A compared to WT rats. These results demonstrate that the overexpression of the A 2A R selectively at the neuronal level reduced 3-NP-induced neurodegeneration, and suggest an important function of the neuronal A 2A R in the modulation of neurodegeneration.",
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T2 - a rat model of Huntington’s disease

AU - Domenici, Maria Rosaria

AU - Chiodi, Valentina

AU - Averna, Mirko

AU - Armida, Monica

AU - Pèzzola, Antonella

AU - Pepponi, Rita

AU - Ferrante, Antonella

AU - Bader, Michael

AU - Fuxe, Kjell

AU - Popoli, Patrizia

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N2 - The A 2A adenosine receptor (A 2A R) is widely distributed on different cellular types in the brain, where it exerts a broad spectrum of pathophysiological functions, and for which a role in different neurodegenerative diseases has been hypothesized or demonstrated. To investigate the role of neuronal A 2A Rs in neurodegeneration, we evaluated in vitro and in vivo the effect of the neurotoxin 3-nitropropionic acid (3-NP) in a transgenic rat strain overexpressing A 2A Rs under the control of the neural-specific enolase promoter (NSEA 2A rats). We recorded extracellular field potentials (FP) in corticostriatal slice and found that the synaptotoxic effect of 3-NP was significantly reduced in NSEA 2A rats compared with wild-type animals (WT). In addition, after exposing corticostriatal slices to 3-NP 10 mM for 2 h, we found that striatal cell viability was significantly higher in NSEA 2A rats compared to control rats. These in vitro results were confirmed by in vivo experiments: daily treatment of female rats with 3-NP 10 mg/kg for 8 days induced a selective bilateral lesion in the striatum, which was significantly reduced in NSEA 2A compared to WT rats. These results demonstrate that the overexpression of the A 2A R selectively at the neuronal level reduced 3-NP-induced neurodegeneration, and suggest an important function of the neuronal A 2A R in the modulation of neurodegeneration.

AB - The A 2A adenosine receptor (A 2A R) is widely distributed on different cellular types in the brain, where it exerts a broad spectrum of pathophysiological functions, and for which a role in different neurodegenerative diseases has been hypothesized or demonstrated. To investigate the role of neuronal A 2A Rs in neurodegeneration, we evaluated in vitro and in vivo the effect of the neurotoxin 3-nitropropionic acid (3-NP) in a transgenic rat strain overexpressing A 2A Rs under the control of the neural-specific enolase promoter (NSEA 2A rats). We recorded extracellular field potentials (FP) in corticostriatal slice and found that the synaptotoxic effect of 3-NP was significantly reduced in NSEA 2A rats compared with wild-type animals (WT). In addition, after exposing corticostriatal slices to 3-NP 10 mM for 2 h, we found that striatal cell viability was significantly higher in NSEA 2A rats compared to control rats. These in vitro results were confirmed by in vivo experiments: daily treatment of female rats with 3-NP 10 mg/kg for 8 days induced a selective bilateral lesion in the striatum, which was significantly reduced in NSEA 2A compared to WT rats. These results demonstrate that the overexpression of the A 2A R selectively at the neuronal level reduced 3-NP-induced neurodegeneration, and suggest an important function of the neuronal A 2A R in the modulation of neurodegeneration.

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