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.
Keywords: AEDs; AIF; BCA; BSA; CBZ; CNS; Carbamazepine; DTT; ERK; ESL; Eslicarbazepine; GABA; LTG; Lamotrigine; MAPK; Neurotoxicity; OXC; Oxcarbazepine; PARP; PBS; PMSF; R-Lic; R-licarbazepine; S-Lic; S-licarbazepine; SAPK/JNK; SDS; TBS; Thr; Tyr; VPA; Valproate; antiepileptic drugs; apoptosis-inducing factor; bicinchoninic acid; bovine serum albumin; carbamazepine; central nervous system; dithiothreitol; eslicarbazepine acetate; extracellular signal-regulated kinase; gamma-aminobutyric acid; lamotrigine; mitogen-activated protein kinase; oxcarbazepine; phenylmethylsulphonyl fluoride; phosphate-buffered saline; poly-ADP ribose polymerase; sodium dodecyl sulphate; stress-activated protein kinase/c-Jun N-terminal kinase; threonine; tris-buffered saline; tyrosine; valproate.
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