Neurotoxic/neuroprotective profile of carbamazepine, oxcarbazepine and twonew putative antiepileptic drugs, BIA 2-093 and BIA 2-024

We investigated and compared the toxicity profile, as well as possible neur oprotective effects, of some antiepileptic drugs in cultured rat hippocampa l neurons. We used two novel carbamazepine derivatives, (S)-(-)-10-acetoxy- 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-093) and 10,11-dih ydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-024), and c ompared their effects with the established compounds carbamazepine and oxca rbazepine. The assessment of neuronal injury was made by using the 3-(4,5-d imethylthiazol-2-yl)-2,5-diphenyl (MTT) assay, as well as by analysing morp hology and nuclear chromatin condensation (propidium iodide staining), afte r hippocampal neurons were exposed to the drugs for 24 h. The putative anti epileptic drugs, BIA 2-093 or BIA 2-024 (at 300 mu M), only slightly decrea sed MTT reduction, whereas carbamazepine or oxcarbazepine were much more to xic at lower concentrations. Treatment with the antiepileptic drugs caused nuclear chromatin condensation in some neurons, which is characteristic of apoptosis, and increased the activity of caspase-3-like enzymes, mainly in neurons treated with carbamazepine and oxcarbazepine. The toxic effect caus ed by carbamazepine was not mediated by N-methyl-D-aspartate (NMDA) or by a lpha-amino-3-hydroxy5-methyl-isoxazole-4-propionate (AMPA) receptors. Moreo ver, the antiepileptic drugs failed to protect hippocampal neurons from the toxicity caused by kainate, veratridine, or ischaemia-like conditions. (C) 2000 Elsevier Science B.V. All rights reserved.