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Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

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Abstract

Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A1 receptors. Gain of function of the excitatory A2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A2A receptor and of the adenosine-generating enzyme, ecto-5′-nucleotidase/CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No co-localization was observed between the A2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A2A receptor and ecto-5′-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5′-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients.

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Abbreviations

ρ:

Pearson’s coefficient

ADK:

Adenosine kinase

BSA:

Bovine serum albumin

BDNF:

Brain-derived neurotrophic factor

DG:

Dentate gyrus

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GABA:

γ-Aminobutyric acid

GFAP:

Glial fibrillary acidic protein

MTLE:

Mesial temporal lobe epilepsy

NF200:

Neurofilament 200

PSD95:

Postsynaptic density-95

SD:

Standard deviation

SDS:

Sodium dodecyl sulfate

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Authors and Affiliations

  1. Laboratório de Farmacologia e Neurobiologia–Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), R. Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal

    Aurora R. Barros-Barbosa, Fátima Ferreirinha, Ângela Oliveira, Marina Mendes, M. Graça Lobo, J. Miguel Cordeiro & Paulo Correia-de-Sá

  2. Serviço de Patologia Forense, Instituto Nacional de Medicina Legal e Ciências Forenses–Delegação do Norte (INMLCF-DN), Porto, Portugal

    Agostinho Santos

  3. Serviço de Neurocirurgia, Centro Hospitalar do Porto–Hospital Geral de Santo António (CHP–HGSA), Porto, Portugal

    Rui Rangel

  4. Centre de Recherche du CHU de Québec–Université Laval, CHUL, QC, Québec, Canada

    Julie Pelletier & Jean Sévigny

  5. Département de Microbiologie-Infectiologie et d’Immunologie, Faculté de Médicine, Université Laval, QC, Québec, Canada

    Jean Sévigny

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  1. Aurora R. Barros-Barbosa
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Correspondence to Paulo Correia-de-Sá.

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Funding

This study was supported by the University of Porto/Santander Totta, Liga Portuguesa Contra a Epilepsia (LPCE), Tecnifar and Fundação para a Ciência e Tecnologia (FCT, Fundo Europeu de Desenvolvimento Regional - FEDER funding and COMPETE, projects PIC/IC/83297/2007 and Pest-OE/SAU/UI215/2014). J. Sévigny received support from the Canadian Institutes of Health Research (CIHR, MOP – 93683, MOP – 102472). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JMC was hired under the scope of FCT Portugal CIÊNCIA 2008 Programme (FSE-POPH-QREN, CONT_DOUT/117/ICBAS-UP/215/10824/2/2008); ABB was in receipt of a PhD studentship by FCT (SFRH/BD/79259/2011); JS was a recipient of a “Chercheur National” research award from the Fonds de Recherche du Québec–Santé (FRQS). The authors acknowledge the collaboration of Dr. Bárbara Leal in the collection of clinical information from patients with epilepsy. Authors also thank Mrs. M. Helena Costa e Silva and Belmira Silva for their technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Key Point Box

• Hippocampus from MTLE patients expresses higher amounts of adenosine A2A receptors than control individuals.

• Ecto-5′-nucleotidase/CD73 localizes in close proximity with adenosine A2A receptors in astrocytes of the human hippocampus.

• Up-regulation of A2A receptors and ecto-5′-nucleotidase/CD73 associates with astrogliosis of the hippocampus of MTLE patients.

• Targeting astrocytic A2A activation and/or adenosine formation via ecto-5′-nucleotidase/CD73 may control neuronal excitability.

• Inhibitors of astrocytic A2A receptors and ecto-5′-nucleotidase/CD73 may be a novel therapeutic strategy to control drug-refractory MTLE.

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Barros-Barbosa, A.R., Ferreirinha, F., Oliveira, Â. et al. Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE). Purinergic Signalling 12, 719–734 (2016). https://doi.org/10.1007/s11302-016-9535-2

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  • DOI: https://doi.org/10.1007/s11302-016-9535-2

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