Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5-[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3 H -
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ORIGINAL PAPER
Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3H-1,2,4-triazole-3thione (TPL-16) in Mice Magdalena Drabik1 · Mariusz Głuszak1 · Paula Wróblewska‑Łuczka1 · Zbigniew Plewa2 · Marek Jankiewicz3 · Justyna Kozińska4 · Magdalena Florek‑Łuszczki5 · Tomasz Plech6 · Jarogniew J. Łuszczki1,7 Received: 15 August 2020 / Revised: 11 October 2020 / Accepted: 10 November 2020 © The Author(s) 2020
Abstract Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were determined in the tonic-clonic seizure model and rotarod test in mice. The interaction profile of four classic antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) with TPL-16 was also determined in the tonic-clonic seizure model in mice. The protective effects of TPL-16 from tonic-clonic seizures (as ED50 values) and acute neurotoxic effects of TPL-16 (as T D50 values) were determined in 4 pretreatment times (15, 30, 60 and 120 min after its i.p. administration), in adult male albino Swiss mice. The interaction profile of TPL-16 with carbamazepine, phenobarbital, phenytoin and valproate in the tonic-clonic seizure model was determined with isobolographic analysis. Total concentrations of carbamazepine, phenobarbital, phenytoin and valproate were measured in the mouse brain homogenates. The candidate for novel antiepileptic drug (TPL-16) administered separately 15 min before experiments, has a beneficial profile with protective index (as ratio of TD50 and ED50 values) amounting to 5.58. The combination of TPL-16 with valproate produced synergistic interaction in the tonic-clonic seizure model in mice. The combinations of TPL-16 with carbamazepine, phenobarbital and phenytoin produced additive interaction in terms of protection from tonic-clonic seizures in mice. None of the total brain concentrations of classic AEDs were changed significantly after TPL-16 administration in mice. Synergistic interaction for TPL-16 with valproate and the additive interaction for TPL-16 with carbamazepine, phenobarbital and phenytoin in the tonic-clonic seizures in mice allows for recommending TPL-16 as the promising drug for further experimental and clinical testing. Keywords Antiepileptic drugs · Tonic-clonic seizures · Pharmacokinetic/pharmacodynamic interaction · Protective index · 1,2,4-triazole-3-thione Abbreviations AEDs Antiepileptic drugs MES Maximal electroshock-induced seizure model TPL-16 4-butyl-5-[(4-chloro-2-methylphenoxy) methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione
Introduction
* Jarogniew J. Łuszczki [email protected]; [email protected]
4
Department and Clinic of Hematolooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland
5
Department of Medical Anthropology, Institute of Rural Health, Lublin, Poland
6
Department of Pharmacology, Medical University of Lublin, Lublin, Poland
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