Abstract
In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZ-induced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM).
Highlights
Epilepsy, which affects about 1% of the world population, belongs to the most common, heterogeneous, and debilitating neurological diseases with a high risk of drug resistance [1]
We investigated the effect of 24 h-long incubation with AS-1 on the number and duration of electroencephalographic (EEG) epileptiform-like discharges induced by acute PTZ administration in 7-day post-fertilization zebrafish larvae
The ability of AS-1 to passively penetrate through the biological membranes was estimated by Gentest Pre-coated parallel artificial membrane permeability assay (PAMPA) Plate System (Corning, Tewksbury, MA) and expressed as the permeability coefficient Pe
Summary
Epilepsy, which affects about 1% of the world population, belongs to the most common, heterogeneous, and debilitating neurological diseases with a high risk of drug resistance [1]. The refractory epilepsy usually requires the application of two or three various antiepileptic drugs (AEDs), preferentially with different mechanisms of action. This therapeutic regimen increases the risk of drug–drug interactions (DDIs), and may lead to potentiation of side effect and, to discontinuation of the treatment. Current pharmacotherapy is only symptomatic, as the available AEDs inhibit seizures but these medications are devoid of antiepileptogenic, as well as disease-modifying properties. As a result, both old- and new-generation AEDs do not cure epilepsy and cannot be used as prophylaxis especially of idiopathic disease. Bearing in mind the aforementioned facts, the search for new AEDs is still hugely necessary and should be directed on broad-spectrum anticonvulsants, preferentially with complex mechanisms of action and favorably with antiepileptogenic and/or disease-modifying properties [6, 7]
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