title: Influence of WIN 55,212-2 on the anticonvulsant and acute neurotoxic potential of clobazam and lacosamide in the maximal electroshock-induced seizure model and chimney test in mice.
abstract: The influence of WIN 55,212-2 mesylate (WIN) on the anticonvulsant activity and acute neurotoxic potential of clobazam (CLB) and lacosamide (LCM) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice.
  
  
  RESULTS
  indicate that WIN administered intraperitoneally, at doses of 2.5 and 5 mg/kg significantly enhanced the anticonvulsant action of CLB in the MES test by reducing its median effective dose (ED50) from 20.80 mg/kg to 12.05 mg/kg (P<0.05), and 8.22 mg/kg (P<0.001), respectively. In contrast, WIN (1.25 mg/kg) did not significantly potentiate the anticonvulsant activity of CLB against MES-induced seizures. Similarly, WIN at doses of 1.25, 2.5 and 5 mg/kg had no significant impact on the anticonvulsant action of LCM in the MES test. On the other hand, WIN (5 mg/kg) had no impact on the acute neurotoxic effects of CLB and LCM in the chimney test and the median toxic doses (TD50) for CLB and LCM were almost unchanged. Thus, WIN (5 mg/kg) elevated the protective index values for CLB (from 1.41 to 3.07) and LCM (from 3.60 to 4.91). In conclusion, WIN potentiates suppression of tonic-clonic seizures produced by CLB in the mouse MES model, without affecting acute neurotoxic adverse effects of CLB in the chimney test in mice, which is favorable from a preclinical point of view.
authors.affiliation: Department of Public Health, Institute of Rural Health, Jaczewskiego 2, PL 20-950 Lublin, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Florek-Luszczki
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, PL 20-950 Lublin, Poland.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Zagaja
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, PL 20-950 Lublin, Poland; Department of Pathophysiology, Medical University, Ceramiczna 1, PL 20-150 Lublin, Poland. Electronic address: jarogniew.luszczki@gmail.com.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
mesh_terms: D000081:Acetamides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D001569:Benzodiazepines / Q000494:pharmacology* / Q000633:toxicity; D048588:Benzoxazines / Q000494:pharmacology* / Q000633:toxicity; D000078306:Clobazam; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004597:Electroshock; D007274:Injections, Intraperitoneal; D000078334:Lacosamide; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology* / Q000633:toxicity; D009043:Motor Activity / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology* / Q000633:toxicity; D011897:Random Allocation; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D001569:Benzodiazepines; D000078306:Clobazam; D000078334:Lacosamide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: Cannabinoids; Chimney test; Clobazam; Lacosamide; Maximal electroshock-induced seizures; WIN 55,212-2