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Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the KV3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K+ current (IK(DR)) in a concentration-dependent manner with an IC50 value of 37 µM. LEV (30 µM) shifted the steady-state activation of IK(DR) to a more positive potential by 10 mV, without shifting the steady-state inactivation of IK(DR). Neither Na+, nor erg (ether-a-go-go-related)-mediated K+ and ATP-sensitive K+ currents were affected by LEV (100 µM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating IK(DR) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating IK(DR) (KV3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.
The aim of the present study was to characterize the anticonvulsant effects of levetiracetam in combination with ethosuximide in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes; type II isobolographic analysis was used to characterize the consequent anticonvulsant interactions between the drug combinations for fixed-ratios of 1:1, 1:2, 1:5 and 1:10. With type II isobolographic analysis, the combinations of levetiracetam with ethosuximide for the fixed-ratios of 1:5 and 1:10 were supra-additive (synergistic; P<0.05 and P<0.01, respectively) in terms of seizure suppression, while the combinations for the fixed-ratios of 1:1 and 1:2 were additive in the mouse 6 Hz psychomotor seizure model. The combinations of levetiracetam with ethosuximide for the fixed-ratios of 1:5 and 1:10 appear to be particularly favorable combinations exerting supra-additive interaction in the mouse 6 Hz psychomotor seizure model. Finally, it may be concluded that because of the synergistic interactions between levetiracetam and ethosuximide, the combination might be useful in clinical practice.
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