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Neuronal adenosine A2A receptor overexpression is neuroprotective towards 3-nitropropionic acid-induced striatal toxicity: a rat model of Huntington’s disease

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Abstract

The A2A adenosine receptor (A2AR) 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 A2ARs 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 A2ARs under the control of the neural-specific enolase promoter (NSEA2A rats). We recorded extracellular field potentials (FP) in corticostriatal slice and found that the synaptotoxic effect of 3-NP was significantly reduced in NSEA2A 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 NSEA2A 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 NSEA2A compared to WT rats. These results demonstrate that the overexpression of the A2AR selectively at the neuronal level reduced 3-NP-induced neurodegeneration, and suggest an important function of the neuronal A2AR in the modulation of neurodegeneration.

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Acknowledgments

We thank Adriano Urcioli and Alessio Gugliotta for the assistance with animal work.

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Authors and Affiliations

  1. National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy

    Maria Rosaria Domenici, Valentina Chiodi, Mirko Averna, Monica Armida, Antonella Pèzzola, Rita Pepponi, Antonella Ferrante & Patrizia Popoli

  2. Max-Delbrűck-Center for Molecular Medicine, Berlin, Germany

    Michael Bader

  3. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Kjell Fuxe

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  1. Maria Rosaria Domenici
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  2. Valentina Chiodi
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  3. Mirko Averna
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  5. Antonella Pèzzola
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  9. Kjell Fuxe
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Correspondence to Maria Rosaria Domenici.

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Domenici, M.R., Chiodi, V., Averna, M. et al. Neuronal adenosine A2A receptor overexpression is neuroprotective towards 3-nitropropionic acid-induced striatal toxicity: a rat model of Huntington’s disease. Purinergic Signalling 14, 235–243 (2018). https://doi.org/10.1007/s11302-018-9609-4

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