title: 2-Chloro-N6-cyclopentyladenosine enhances the anticonvulsant action of carbamazepine in the mouse maximal electroshock-induced seizure model.
abstract: This study examines the anticonvulsant profile of interactions between 2-chloro-N6-cyclopentyladenosine (CCPA, a selective adenosine A1 receptor agonist) and four conventional antiepileptic drugs (AEDs: carbamazepine--CBZ, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure (MES) model. Acute adverse effects produced by AEDs in combination with CCPA were determined in the chimney test (motor performance) and passive avoidance task (long-term memory). Results indicate that CCPA administered alone at 0.25 and 0.5 mg/kg significantly elevated the electroconvulsive threshold in mice. Additionally, the agent at a sub-threshold dose of 0.125 mg/kg potentiated the anticonvulsant activity of CBZ by reducing its ED50 in the MES test from 11.2 to 7.7 mg/kg (p < 0.01). In contrast, 8-cyclopentyl-1,3-dimethylxanthine (DPCPX, a selective adenosine A1 receptor antagonist at 5 mg/kg) abolished the enhanced anticonvulsant effects offered by the combination of CBZ with CCPA (0.125 mg/kg). Moreover, CCPA (0.125 mg/kg) co-administered with other tested AEDs had no significant impact on their antiseizure properties in the MES test in mice. Neither CCPA (0.125 mg/kg) administered singly, nor in combinations with conventional AEDs (at their ED50s) affected motor performance in the chimney test and long-term memory in the passive avoidance task. No pharmacokinetic alterations in brain CBZ concentrations were observed after administration of CCPA at 0.125 mg/kg. It may be concluded that CCPA, acting selectively on adenosine A1 receptors, enhances pharmacodynamically the antiseizure effect of CBZ in the MES test.
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland. jarogniew.luszczki@am.lublin.pl
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Łuszczki
authors.forename: Maria
authors.initials: M
authors.lastname: Kozicka
authors.forename: Mariusz J
authors.initials: MJ
authors.lastname: Swiader
authors.forename: Stanisław J
authors.initials: SJ
authors.lastname: Czuczwar
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004597:Electroshock; D008297:Male; D051379:Mice; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000378:metabolism / Q000517:prevention & control*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D043682:Receptor, Adenosine A1; D014970:Xanthines; D002220:Carbamazepine; C058394:2-chloro-N(6)cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine