title: Influence of MPEP (a selective mGluR5 antagonist) on the anticonvulsant action of novel antiepileptic drugs against maximal electroshock-induced seizures in mice.
abstract: The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)pyridine (MPEP - a selective antagonist for the glutamate metabotropic receptor subtype mGluR5) on the protective action of some novel antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) against maximal electroshock-induced seizures in mice. Brain concentrations of antiepileptic drugs were measured to determine whether MPEP altered pharmacokinetics of antiepileptic drugs. Intraperitoneal injection of 1.5 and 2mg/kg of MPEP significantly elevated the threshold for electroconvulsions in mice, whereas MPEP at a dose of 1mg/kg considerably enhanced the anticonvulsant activity of pregabalin and topiramate, but not that of lamotrigine or oxcarbazepine in the maximal electroshock-induced seizures in mice. Pharmacokinetic results revealed that MPEP (1mg/kg) did not alter total brain concentrations of pregabalin and topiramate, and the observed effect in the mouse maximal electroshock seizure model was pharmacodynamic in nature. Collectively, our preclinical data suggest that MPEP may be a safe and beneficial adjunct to the therapeutic effects of antiepileptic drugs in human patients.
authors.affiliation: Department of Neurology, School of Medicine, University of California-Davis, Sacramento, CA, USA.
authors.forename: Dorota
authors.initials: D
authors.lastname: Zolkowska
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
authors.forename: Maria W
authors.initials: MW
authors.lastname: Kondrat-Wrobel
authors.affiliation: Department of Public Health, Institute of Rural Health, Lublin, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Florek-Luszczki
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Lublin, Poland; Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland. Electronic address: jluszczki@yahoo.com.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005632:Fructose / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D000078330:Oxcarbazepine; D000069583:Pregabalin / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism; D000077236:Topiramate; D014227:Triazines / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D000069583:Pregabalin; C121465:6-methyl-2-(phenylethynyl)pyridine; D000077213:Lamotrigine; D000078330:Oxcarbazepine
keywords: Antiepileptic drugs; Lamotrigine; MPEP; Maximal electroshock-induced seizures; Metabotropic glutamate receptors; Oxcarbazepine; Pharmacokinetic/pharmacodynamic interaction; Pregabalin; Topiramate