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Selective modulation of epileptic tissue by an adenosine A3 receptor-activating drug
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  • Ana Maria Sebastião,
  • Anwesha Ghosh,
  • Leonor Ribeiro-Rodrigues,
  • Gabriele Ruffolo,
  • Veronica Alfano,
  • Catia Domingos,
  • Nadia Rei,
  • Dilip Tosh,
  • Diogo Rombo ,
  • Tatiana Morais,
  • Claudia Valente,
  • Sara Xapelli,
  • Beatriz Bordadágua,
  • Alexandre Rainha-Campos,
  • Carla Bentes,
  • Eleonora Aronica,
  • Maria José Diógenes,
  • Sandra Vaz,
  • Joaquim Alexandre Ribeiro,
  • Eleonora Palma,
  • Kenneth Jacobson
Ana Maria Sebastião
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal

Corresponding Author:anaseb@medicina.ulisboa.pt

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Anwesha Ghosh
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
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Leonor Ribeiro-Rodrigues
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
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Gabriele Ruffolo
University of Rome La Sapienza
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Veronica Alfano
IRCCS San Raffaele Roma
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Catia Domingos
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
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Nadia Rei
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
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Dilip Tosh
National Institute of Diabetes and Digestive and Kidney Diseasesand Infectious Disease
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Diogo Rombo
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
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Tatiana Morais
Cardiff University
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Claudia Valente
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
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Sara Xapelli
Instituto de Medicina Molecular
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Beatriz Bordadágua
Heidelberg Institute for Theoretical Studies
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Alexandre Rainha-Campos
Centro Hospitalar Universitario de Lisboa Norte
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Carla Bentes
Centro Hospitalar Universitario de Lisboa Norte
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Eleonora Aronica
University of Amsterdam Faculty of Medicine
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Maria José Diógenes
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
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Sandra Vaz
Universidade de Lisboa Faculdade de Medicina
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Joaquim Alexandre Ribeiro
Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal
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Eleonora Palma
University of Rome La Sapienza
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Kenneth Jacobson
NIDDK
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Abstract

Background and Purpose Adenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. Development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A1R-selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizing that this drug could act through other than A1R and/or through a disease specific mechanism, we assessed the effect of MRS5474 on the hippocampus. Experimental Approach Excitatory synaptic currents, field potentials, spontaneous activity, [3H]GABA uptake and GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in adenosine A3 receptor (A3R) density in human tissue were assessed by Western Blot. Key Results MRS5474 (50-500nM) was devoid of effect upon rodent excitatory synaptic signals in hippocampal slices, except when hyperexcitability was previously induced in vivo or ex vivo. This contrasted with the effect of other A1R agonists. MRS5474 inhibited GAT-1 mediated GABA uptake, an action not blocked by an A1R antagonist but blocked by an A3R antagonist and mimicked by an A3R agonist. A3R was overexpressed in human hippocampal tissue samples from patients with epilepsy that had focal resection from surgery. MRS5474 induced a concentration-dependent potentiation of GABA-evoked currents in oocytes micro-transplanted with human hippocampal membranes prepared from epileptic hippocampal tissue but not from non-epileptic tissue, an action blocked by an A3R antagonist. Conclusion and Implications We identified a drug that activates A3R and has selective actions on epileptic hippocampal tissue. This underscores A3R as a promising target for the development of antiseizure medications.
27 Mar 2024Submitted to British Journal of Pharmacology
29 Mar 2024Reviewer(s) Assigned
17 Jun 20241st Revision Received
18 Jun 2024Assigned to Editor
18 Jun 2024Submission Checks Completed
18 Jun 2024Review(s) Completed, Editorial Evaluation Pending
18 Jun 2024Reviewer(s) Assigned