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Purinergic Signalling

, Volume 12, Issue 4, pp 719–734 | Cite as

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

  • Aurora R. Barros-Barbosa
  • Fátima Ferreirinha
  • Ângela Oliveira
  • Marina Mendes
  • M. Graça Lobo
  • Agostinho Santos
  • Rui Rangel
  • Julie Pelletier
  • Jean Sévigny
  • J. Miguel Cordeiro
  • Paulo Correia-de-Sá
Original Article

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.

Keywords

Mesial temporal lobe epilepsy (MTLE) Human hippocampus Adenosine A2A receptor Ecto-5′-nucleotidase/CD73 Astrogliosis Antiepileptic drugs 

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

Notes

Compliance with ethical standards

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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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Aurora R. Barros-Barbosa
    • 1
  • Fátima Ferreirinha
    • 1
  • Ângela Oliveira
    • 1
  • Marina Mendes
    • 1
  • M. Graça Lobo
    • 1
  • Agostinho Santos
    • 2
  • Rui Rangel
    • 3
  • Julie Pelletier
    • 4
  • Jean Sévigny
    • 4
    • 5
  • J. Miguel Cordeiro
    • 1
  • Paulo Correia-de-Sá
    • 1
  1. 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)PortoPortugal
  2. 2.Serviço de Patologia ForenseInstituto Nacional de Medicina Legal e Ciências Forenses–Delegação do Norte (INMLCF-DN)PortoPortugal
  3. 3.Serviço de NeurocirurgiaCentro Hospitalar do Porto–Hospital Geral de Santo António (CHP–HGSA)PortoPortugal
  4. 4.Centre de Recherche du CHU de Québec–Université Laval, CHULQCCanada
  5. 5.Département de Microbiologie-Infectiologie et d’Immunologie, Faculté de MédicineUniversité LavalQCCanada

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