title: Effects of WIN 55,212-2 mesylate on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice.
abstract: The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN - a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four second-generation antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), the step-through passive avoidance task (assessing long-term memory) and the grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by high-pressure liquid chromatography to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5mg/kg, i.p.) significantly enhanced the anticonvulsant action of lamotrigine (P<0.05), pregabalin (P<0.001) and topiramate (P<0.05), but not that of oxcarbazepine in the maximal electroshock-induced tonic seizure test in mice. Furthermore, none of the investigated combinations of WIN with antiepileptic drugs were associated with any concurrent adverse effects with regards to motor performance, long-term memory or muscular strength. Pharmacokinetic characterization revealed that WIN had no impact on total brain concentrations of lamotrigine, oxcarbazepine, pregabalin and topiramate in mice. These preclinical data would suggest that WIN in combination with lamotrigine, pregabalin and topiramate is associated with beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced tonic seizure test.
authors.affiliation: Department of Pathophysiology, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland; Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland. Electronic address: jluszczki@yahoo.com.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wlaz
authors.forename: Slawomir
authors.initials: S
authors.lastname: Karwan
authors.forename: Magdalena
authors.initials: M
authors.lastname: Florek-Luszczki
authors.forename: Stanislaw J
authors.initials: SJ
authors.lastname: Czuczwar
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D048588:Benzoxazines / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000627:therapeutic use*; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004597:Electroshock; D005632:Fructose / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D018737:Hand Strength; D000077213:Lamotrigine; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000627:therapeutic use*; D053580:Muscle Strength / Q000187:drug effects; D009281:Naphthalenes / Q000627:therapeutic use*; D000078330:Oxcarbazepine; D000069583:Pregabalin; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D000077236:Topiramate; D014227:Triazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077213:Lamotrigine; D000078330:Oxcarbazepine
keywords: Antiepileptic drug; Cannabinoid; Maximal electroshock-induced seizure; WIN 55,212-2 mesylate