Neurotoxicity Induced by Antiepileptic Drugs in Cultured Hippocampal Neurons: A Comparative Study between Carbamazepine, Oxcarbazepine, and Two New Putative Antiepileptic Drugs, BIA 2-024 and BIA 2-093

摘要

Purpose: Newly designed antiepileptic drugs (AEDs) are being evaluated for their efficacy in preventing seizures and for their toxic profiles. We investigated and compared the toxic effects of two dibenz[b,f]azepine derivatives with anticonvulsant activity, 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide (BIA2-024) and (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f] azepine-5-carboxamide (BIA2-093), with the structurally related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), both in current use for the treatment of epilepsy. Methods: Primary rat hippocampal neurons were used to evaluate neuronal morphology and biochemical changes induced by the AEDs used in this study. Immunocytochemical staining against MAP-2 was used to evaluate neuronal morphology. Reactive oxygen species (ROS) and changes in mitochondrial membrane potential (03A8m) were measured by fluorescence techniques. Intracellular adenosine triphosphate (ATP) levels were quantified by high-performance liquid chromatography (HPLC). Results: Hippocampal neurons treated for 24 h with CBZ or OXC (300 03BCM) showed degeneration and swelling of neurites, but this effect was not observed in neurons treated with BIA 2-024 or BIA 2-093 (300 03BCM). ROS production also was increased in neurons treated with OXC, but not in neurons treated with the other AEDs. ATP levels were significantly decreased only in neurons treated with OXC, although the energy charge was not altered. Furthermore, OXC led to a decrease of 03A8m. Conclusions: In all parameters assayed, OXC was more toxic than the other AEDs used. Because the new putative AEDs have previously been shown to have an efficacy in preventing seizures similar to that of CBZ and OXC, and are less toxic to neuronal cells, they may be considered as alternatives to the current available therapies for the treatment of epilepsy.