Selective modulation of epileptic tissue by an adenosine A3 receptor-activating drug

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Anwesha Ghosh, Leonor Ribeiro-Rodrigues, Gabriele Ruffolo, Veronica Alfano, Cátia Domingos, Nádia Rei, Dilip K. Tosh, Diogo M. Rombo, Tatiana P. Morais, Cláudia A. Valente, Sara Xapelli, Beatriz Bordadágua, Alexandre Rainha-Campos, Carla Bentes, Eleonora Aronica, Maria José Diógenes, Sandra H. Vaz, Joaquim A. Ribeiro, Eleonora Palma, Kenneth A. Jacobson, Ana M. Sebastião
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引用次数: 0

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.

Abstract Image

腺苷 A3 受体激活药物对癫痫组织的选择性调节
腺苷通过 A1 受体(A1R)是一种内源性抗惊厥药。腺苷受体激动剂作为抗癫痫药物的开发一直受到其心脏副作用的阻碍。据报道,一种中度 A1R 选择性激动剂 MRS5474 可抑制癫痫发作,但不会对心脏产生很大影响。我们推测这种药物可能通过 A1R 以外的途径和/或特定疾病机制发挥作用,因此我们评估了 MRS5474 对海马的影响。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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