title: Adenosine A1 receptor-mediated suppression of carbamazepine-resistant seizure-like events in human neocortical slices.
abstract: 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 (TLE) even up to 80% of patients are pharmacoresistant, and surgical resection of the ictogenic tissue is only possible for a minority of TLE patients. In this study we investigate purinergic modulation of drug-resistant seizure-like events (SLEs) in human temporal cortex slices.
  
  
  
  Layer V/VI field potentials from a total of 77 neocortical slices from 17 pharmacoresistant patients were recorded to monitor SLEs induced by application of 8 mM [K(+) ] and 50 μm bicuculline.
  
  
  
  Activating A1 receptors with a specific agonist completely suppressed SLEs in 73% of human temporal cortex slices. In the remaining slices, incidence of SLEs was markedly reduced. Because a subportion of slices can be pharmacosensitive, we tested effects of an A1 agonist, in slices insensitive to a high dose of carbamazepine (50 μm). Also in these cases the A1 agonist was equally efficient. Moreover, ATP and adenosine blocked or modulated SLEs, an effect mediated not by P2 receptors but rather by adenosine A1 receptors.
  
  
  
  Selective activation of A1 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 (AED) candidates.
authors.affiliation: Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Zin-Juan
authors.initials: ZJ
authors.lastname: Klaft
authors.affiliation: Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jan-Oliver
authors.initials: JO
authors.lastname: Hollnagel
authors.affiliation: Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Seda
authors.initials: S
authors.lastname: Salar
authors.affiliation: Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Gürsel
authors.initials: G
authors.lastname: Calişkan
authors.affiliation: Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Steffen B
authors.initials: SB
authors.lastname: Schulz
authors.affiliation: Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulf C
authors.initials: UC
authors.lastname: Schneider
authors.affiliation: Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Horn
authors.affiliation: Department of Neuropathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Arend
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Epilepsy-Center Berlin-Brandenburg, Krankenhaus Königin Elisabeth Herzberge, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Holtkamp
authors.affiliation: Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Siegrun
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Gerevich
authors.affiliation: Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Neuroscience Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D002220:Carbamazepine / Q000009:adverse effects / Q000494:pharmacology; D000069279:Drug Resistant Epilepsy / Q000188:drug therapy / Q000473:pathology*; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D058905:Purinergic Agents / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult
chemical_list: D058905:Purinergic Agents; D018047:Receptors, Purinergic P1; C090949:N(6)-cyclohexyl-2-O-methyladenosine; D002220:Carbamazepine; C017069:bicuculline methiodide; D000255:Adenosine Triphosphate; D000241:Adenosine; D011188:Potassium; D001640:Bicuculline
keywords: Epilepsy; Human brain slices; Pharmacoresistance; Seizure models; Temporal lobe