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.
OBJECTIVE
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 (Psim) 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 microM) showed degeneration and swelling of neurites, but this effect was not observed in neurons treated with BIA 2-024 or BIA 2-093 (300 microM). 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 Psim.


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.
Araújo
Inês M
IM
Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal.
Ambrósio
António Francisco
AF
Leal
Ermelindo C
EC
Verdasca
Maria João
MJ
Malva
João Oliveira
JO
Soares-da-Silva
Patrício
P
Carvalho
Arsélio Pato
AP
Carvalho
Caetana Monteiro
CM
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003984:Dibenzazepines / Q000633:toxicity; D004827:Epilepsy / Q000188:drug therapy; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018675:Toxicity Tests
D000927:Anticonvulsants; D003984:Dibenzazepines; D017382:Reactive Oxygen Species; C476610:oxcarbamazepine; C416836:BIA 2-024; D002220:Carbamazepine; C416835:eslicarbazepine acetate