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Selective modulation of epileptic tissue by an adenosine A3 receptor-activating drug.
Ghosh, Anwesha; Ribeiro-Rodrigues, Leonor; Ruffolo, Gabriele; Alfano, Veronica; Domingos, Cátia; Rei, Nádia; Tosh, Dilip K; Rombo, Diogo M; Morais, Tatiana P; Valente, Cláudia A; Xapelli, Sara; Bordadágua, Beatriz; Rainha-Campos, Alexandre; Bentes, Carla; Aronica, Eleonora; Diógenes, Maria José; Vaz, Sandra H; Ribeiro, Joaquim A; Palma, Eleonora; Jacobson, Kenneth A; Sebastião, Ana M.
Affiliation
  • Ghosh A; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
  • Ribeiro-Rodrigues L; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal.
  • Ruffolo G; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
  • Alfano V; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal.
  • Domingos C; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
  • Rei N; IRCCS San Raffaele Roma, Rome, Italy.
  • Tosh DK; IRCCS San Raffaele Roma, Rome, Italy.
  • Rombo DM; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
  • Morais TP; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal.
  • Valente CA; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
  • Xapelli S; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal.
  • Bordadágua B; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • Rainha-Campos A; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
  • Bentes C; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal.
  • Aronica E; Neuroscience Division, School of Bioscience, Cardiff University, Cardiff, UK.
  • Diógenes MJ; Department of Physiology and Biochemistry, University of Malta, Msida, Malta.
  • Vaz SH; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
  • Ribeiro JA; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal.
  • Palma E; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
  • Jacobson KA; Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal.
  • Sebastião AM; Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany.
Br J Pharmacol ; 2024 Sep 19.
Article de En | MEDLINE | ID: mdl-39300608
ABSTRACT
BACKGROUND AND

PURPOSE:

Adenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. The 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 (50-500 nM) was devoid of effect upon rodent excitatory synaptic signals in hippocampal slices, except when hyperexcitability was previously induced in vivo or ex vivo. MRS5474 inhibited GABA transporter type 1 (GAT-1)-mediated γ-aminobutyric acid (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.
Mots clés

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Langue: En Journal: Br J Pharmacol Année: 2024 Type de document: Article Pays d'affiliation: Portugal Pays de publication: Royaume-Uni

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Langue: En Journal: Br J Pharmacol Année: 2024 Type de document: Article Pays d'affiliation: Portugal Pays de publication: Royaume-Uni