Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons

• Published in: Toxicology in vitro 2013-12, Vol.27 (8), p.2193-2202
• Main Authors: Morte, Maria I., Carreira, Bruno P., Falcão, Maria J., Ambrósio, António F., Soares-da-Silva, Patrício, Araújo, Inês M., Carvalho, Caetana M.
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - pharmacology; Carbamazepine; Caspase 3 - metabolism; Cell Survival - drug effects; Cells, Cultured; Eslicarbazepine; Hippocampus - cytology; Lamotrigine; Mitogen-Activated Protein Kinases - metabolism; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - pharmacology; Neurotoxicity; Oxcarbazepine; Rats; Rats, Wistar; Valproate
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2013.09.008

•ESL and its in vivo metabolites, as well as LTG and CBZ, are not toxic to hippocampal neurons.•Exposure to OXC and VPA induced the appearance of markers related to cell death.•OXC was the most neurotoxic AED.•AEDs affected differently the levels of phosphorylation of ERK1/2, AKT and SAPK/JNK.•Lamotrigine may be neuroprotective via the activation of the SAPK/JNK pathway. In this study we evaluated the neurotoxicity of eslicarbazepine acetate (ESL), and of its in vivo metabolites eslicarbazepine (S-Lic) and R-licarbazepine (R-Lic), as compared to the structurally-related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), in an in vitro model of cultured rat hippocampal neurons. The non-related antiepileptic drugs (AEDs) lamotrigine (LTG) and sodium valproate (VPA) were also studied. We assessed whether AEDs modulate pro-survival/pro-apoptotic pathways, such as extracellular-regulated kinase (ERK1/2), Akt and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). We found that neither ESL nor its metabolites, CBZ or LTG, up to 0.3mM, for 24h of exposure, decreased cell viability. OXC was the most toxic drug decreasing cell viability in a concentration-dependent manner, leading to activation of caspase-3 and PARP cleavage. VPA caused the appearance of the apoptotic markers, but did not alter cell viability. ESL, S-Lic and OXC decreased the levels of phospho-ERK1/2 and of phospho-Akt, when compared to basal levels, whereas CBZ decreased phospho-SAPK/JNK and phospho-Akt levels. LTG and VPA increased the phosphorylation levels of SAPK/JNK. These results suggest that ESL and its main metabolite S-Lic, as well as CBZ, LTG and VPA, are less toxic to hippocampal neurons than OXC, which was the most toxic agent.