Abstract
Experimental data have shown that antiepileptic drugs cause neurodegeneration in developing rats. Valproate (VPA) is the drug of choice in primary generalized epilepsies, and carbamazepine (CBZ) is one of the most prescribed drugs in partial seizures. These drugs block sodium channels, thereby reducing sustained repetitive neuronal firing. The intracellular mechanisms whereby AEDs induce neuronal cell death are unclear. We examined whether AEDs induce apoptotic cell death in cultured cortical cells and whether calcium ions are involved in the AED-induced cell death. VPA and CBZ increased apoptotic cell death and induced morphological changes that were characterized by cell shrinkage and nuclear condensation or fragmentation. Incubation of cortical cultures with VPA or CBZ decreased phospho-Akt levels. CBZ decreased the intracellular calcium levels. On the other hand, FPL64176, an L-type calcium channel activator, increased the intracellular calcium levels and prevented the AED-induced apoptosis. Glycogen synthase kinase-3 inhibitors, such as alsterpaullone and azakenpaullone, prevented the AED-induced apoptosis. These results suggest that intracellular calcium level changes are associated with AEDs and apoptosis and that the activation of glycogen synthase kinase-3 is involved in the death of rat cortical neurons.
Highlights
Antiepileptic drugs (AEDs) are administered to patients to prevent epileptic seizures
Glycogen synthase kinase-3 inhibitors, such as alsterpaullone and azakenpaullone, prevented the AED-induced apoptosis. These results suggest that intracellular calcium level changes are associated with AEDs and apoptosis and that the activation of glycogen synthase kinase-3 is involved in the death of rat cortical neurons
The apoptotic cell death induced by VPA or CBZ was attenuated by the presence of 0.1 μg/mL cycloheximide, a protein synthesis inhibitor, which indicated that the synthesis of new proteins was required for AED-induced apoptosis (Figure 3)
Summary
Antiepileptic drugs (AEDs) are administered to patients to prevent epileptic seizures. T. Takadera et al 18 sies, and carbamazepine (CBZ) is one of the most prescribed drugs in partial seizures. Takadera et al 18 sies, and carbamazepine (CBZ) is one of the most prescribed drugs in partial seizures These drugs block sodium channels, thereby reducing sustained repetitive neuronal firing. It has been well documented that depolarizing conditions sustain neuronal survival by causing the influx of Ca2+ through L-type Ca2+ channels. When activated by elevated Ca2+, the Ca2+/calmodulin dependent protein kinase II (CaM-Kinase II) has been reported to mediate the depolarization-dependent survival of neurons [5] [6] [7]. We report here that AEDs induce apoptosis and that an L-type calcium channel activator and GSK-3 inhibitors block apoptosis in cultured rat cortical neurons
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