Adenosine A(1) receptor-mediated suppression of carbamazepine-resistant seizure-like events in human neocortical slices

作者：Klaft Zin Juan; Hollnagel Jan Oliver; Salar Seda; Caliskan Gursel; Schulz Steffen B; Schneider Ulf C; Horn Peter; Koch Arend; Holtkamp Martin; Gabriel Siegrun; Gerevich Zoltan; Heinemann Uwe

来源：Epilepsia, 2016, 57(5): 746-756.

DOI：10.1111/epi.13360

<jats:title>Summary</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>The need for alternative pharmacologic strategies in treatment of epilepsies is pressing for about 30% of patients with epilepsy who do not experience satisfactory seizure control with present treatments. In temporal lobe epilepsy (<jats:styled-content style="fixed-case">TLE</jats:styled-content>) even up to 80% of patients are pharmacoresistant, and surgical resection of the ictogenic tissue is only possible for a minority of <jats:styled-content style="fixed-case">TLE</jats:styled-content> patients. In this study we investigate purinergic modulation of drug‐resistant seizure‐like events (<jats:styled-content style="fixed-case">SLE</jats:styled-content>s) in human temporal cortex slices.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Layer V/<jats:styled-content style="fixed-case">VI</jats:styled-content> field potentials from a total of 77 neocortical slices from 17 pharmacoresistant patients were recorded to monitor <jats:styled-content style="fixed-case">SLE</jats:styled-content>s induced by application of 8 <jats:styled-content style="fixed-case">mM</jats:styled-content> [K<jats:sup>+</jats:sup>] and 50 μ<jats:sc>m</jats:sc> bicuculline.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Activating A<jats:sub>1</jats:sub> receptors with a specific agonist completely suppressed <jats:styled-content style="fixed-case">SLE</jats:styled-content>s in 73% of human temporal cortex slices. In the remaining slices, incidence of <jats:styled-content style="fixed-case">SLE</jats:styled-content>s was markedly reduced. Because a subportion of slices can be pharmacosensitive, we tested effects of an A<jats:sub>1</jats:sub> agonist, in slices insensitive to a high dose of carbamazepine (50 μ<jats:sc>m</jats:sc>). Also in these cases the A<jats:sub>1</jats:sub> agonist was equally efficient. Moreover, <jats:styled-content style="fixed-case">ATP</jats:styled-content> and adenosine blocked or modulated <jats:styled-content style="fixed-case">SLE</jats:styled-content>s, an effect mediated not by P2 receptors but rather by adenosine A<jats:sub>1</jats:sub> receptors.</jats:p></jats:sec><jats:sec><jats:title>Significance</jats:title><jats:p>Selective activation of A<jats:sub>1</jats:sub> receptors mediates a strong anticonvulsant action in human neocortical slices from pharmacoresistant patients. We propose that our human slice model of seizure‐like activity is a feasible option for future studies investigating new antiepileptic drug (<jats:styled-content style="fixed-case">AED</jats:styled-content>) candidates.</jats:p></jats:sec>

• 出版日期2016-5