title: Influence of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of various novel antiepileptic drugs against maximal electroshock-induced seizures in mice.
abstract: The aim of this study was to determine the effects of xanthotoxin (8-methoxypsoralen) on the protective action of 5 various second- and third-generation antiepileptic drugs (i.e., lacosamide, lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock-induced seizure model. Seizure activity was evoked in adult male albino Swiss mice by a current (25mA, 500V, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were determined in the chimney, grip-strength and passive avoidance tests. Total brain antiepileptic drug concentrations were measured to confirm pharmacodynamic nature of observed interactions with xanthotoxin. Results indicate that xanthotoxin (100mg/kg, i.p.) significantly enhanced the anticonvulsant action of lacosamide (P<0.01), oxcarbazepine (P<0.05), pregabalin (P<0.01), and topiramate (P<0.001), but not that of lamotrigine in the maximal electroshock-induced seizure test. Moreover, xanthotoxin (50mg/kg) still significantly potentiated the anticonvulsant action of lacosamide (P<0.05), pregabalin (P<0.05), and topiramate (P<0.001) in this seizure test. Xanthotoxin had no significant impact on total brain concentrations of the studied antiepileptic drugs in mice. Furthermore, combinations of xanthotoxin with oxcarbazepine or topiramate produced no adverse effects. However, xanthotoxin in combination with lacosamide, lamotrigine or pregabalin significantly reduced muscular strength in mice in the grip-strength test. In the chimney test, only the combinations of xanthotoxin with pregabalin significantly impaired motor coordination in mice. In conclusion, the combinations of xanthotoxin with oxcarbazepine and topiramate produce beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced seizure test. A special caution is advised when combining xanthotoxin with pregabalin due to appearance of acute adverse effects.
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland. Electronic address: lasius1981@wp.pl.
authors.forename: Mirosław
authors.initials: M
authors.lastname: Zagaja
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Andres-Mach
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Lublin, Poland; Department of Plant Physiology and Biotechnology, The John Paul II Catholic University of Lublin, Lublin, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Patrzylas
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pyrka
authors.affiliation: Faculty of Medicine and Health Sciences, The Jan Kochanowski University in Kielce, Kielce, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Szpringer
authors.affiliation: Centre of Public Health and Health Promotion, Institute of Rural Health, Lublin, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Florek-Łuszczki
authors.affiliation: Department of Neurology, School of Medicine, University of California-Davis, Sacramento, CA, USA.
authors.forename: Dorota
authors.initials: D
authors.lastname: Żółkowska
authors.affiliation: Department of Pharmacognosy with Medicinal Plant Unit, Medical University of Lublin, Lublin, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Skalicka-Woźniak
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland; Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Łuszczki
mesh_terms: D000081:Acetamides; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000031:analogs & derivatives; D004357:Drug Synergism; D004597:Electroshock / Q000009:adverse effects*; D005632:Fructose / Q000031:analogs & derivatives; D000078334:Lacosamide; D000077213:Lamotrigine; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology*; D051379:Mice; D000078330:Oxcarbazepine; D000069583:Pregabalin; D012640:Seizures / Q000188:drug therapy*; D000077236:Topiramate; D014227:Triazines
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D000069583:Pregabalin; D000078334:Lacosamide; D000077213:Lamotrigine; D008730:Methoxsalen; D000078330:Oxcarbazepine
keywords: Coumarins; Lacosamide (PubChem CID: 219078); Lamotrigine (PubChem CID: 3878); Maximal electroshock-induced seizure test; Novel antiepileptic drugs; Oxcarbazepine (PubChem CID: 34312); Pharmacodynamic interaction; Pregabalin (PubChem CID: 5486971); Topiramate (PubChem CID: 5284627); Xanthotoxin; Xanthotoxin (PubChem CID: 4114)