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 TD50 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.
Highlights
Epilepsy is a neurological disease, which occurs in 6 per 1000 people worldwide with morbidity that differs according to ethnic origin [1]
In this article we present in vivo experiments based on acute seizure model and the test assessing the drug’s toxicity potential in mice, along with evaluation of TPL-16 interactions with 4 classic antiepileptic drugs (AEDs)
The investigated substance TPL-16, after a single administration showed a protective effect against tonic-clonic seizures in the maximal electroshock-induced seizure (MES) test in mice at 4 established intervals when administrated systemically (i.p.) i.e., 15, 30, 60 and 120 min before the MES test
Summary
Epilepsy is a neurological disease, which occurs in 6 per 1000 people worldwide with morbidity that differs according to ethnic origin [1]. Thereupon accurate treatment should be based on precise medical experience and investigation of brain activity by using EEG or MRI [2, 3]. Because of diversity among signs and symptoms of epilepsy seizures, choice of appropriate drug might be difficult [2]. In 70% of patients, monotherapy with current frontline antiepileptic drugs (AEDs) provides sufficient treatment of epileptic seizures [4, 5]. Despite a variety of available AEDs there are still 30% of drug-resistant patients [3, 6]. Polytherapy is necessary and obligatory if physicians want to increase efficiency of the treatment or when two previous medications have failed [2, 4, 5]
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