title: Adenosine A2Areceptor and ecto-5'-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE).
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 A2Areceptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A1receptors. Gain of function of the excitatory A2Areceptor 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 A2Areceptor 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 A2Areceptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A2Areceptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No co-localization was observed between the A2Areceptor 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 A2Areceptor and ecto-5'-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A2Areceptors 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.
authors.affiliation: 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.
authors.forename: Aurora R
authors.initials: AR
authors.lastname: Barros-Barbosa
authors.affiliation: 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.
authors.forename: Fátima
authors.initials: F
authors.lastname: Ferreirinha
authors.affiliation: 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.
authors.forename: Ângela
authors.initials: Â
authors.lastname: Oliveira
authors.affiliation: 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.
authors.forename: Marina
authors.initials: M
authors.lastname: Mendes
authors.affiliation: 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.
authors.forename: M Graça
authors.initials: MG
authors.lastname: Lobo
authors.affiliation: Serviço de Patologia Forense, Instituto Nacional de Medicina Legal e Ciências Forenses-Delegação do Norte (INMLCF-DN), Porto, Portugal.
authors.forename: Agostinho
authors.initials: A
authors.lastname: Santos
authors.affiliation: Serviço de Neurocirurgia, Centro Hospitalar do Porto-Hospital Geral de Santo António (CHP-HGSA), Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Rangel
authors.affiliation: Centre de Recherche du CHU de Québec-Université Laval, CHUL, QC, Québec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Centre de Recherche du CHU de Québec-Université Laval, CHUL, QC, Québec, Canada.|Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médicine, Université Laval, QC, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: 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.
authors.forename: J Miguel
authors.initials: JM
authors.lastname: Cordeiro
authors.affiliation: 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. farmacol@icbas.up.pt.
authors.forename: Paulo
authors.identifier: 0000-0002-6114-9189
authors.initials: P
authors.lastname: Correia-de-Sá
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D005904:Glial Fibrillary Acidic Protein; D043705:Receptor, Adenosine A2A; D015720:5'-Nucleotidase
keywords: Adenosine A2A receptor; Antiepileptic drugs; Astrogliosis; Ecto-5′-nucleotidase/CD73; Human hippocampus; Mesial temporal lobe epilepsy (MTLE)