Selective modulation of epileptic tissue by an adenosine A 3 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. and Sebastião, Ana M. 2024. Selective modulation of epileptic tissue by an adenosine A 3 receptor‐activating drug. British Journal of Pharmacology 10.1111/bph.17319

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
Publisher:	Wiley
ISSN:	0007-1188
Date of First Compliant Deposit:	23 September 2024
Date of Acceptance:	2 July 2024
Last Modified:	23 Sep 2024 12:45
URI:	https://orca.cardiff.ac.uk/id/eprint/172324

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