Interactions of levetiracetam with ethosuximide in the mouse 6 Hz psychomotor seizure model - a type II isobolographic analysis

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

A combination of NMDA and AMPA receptor antagonists retards granule cell dispersion and epileptogenesis in a model of acquired epilepsy.

Epilepsy may arise following acute brain insults, but no treatments exist that prevent epilepsy in patients at risk. Here we examined whether a combination of two glutamate receptor antagonists, NBQX and ifenprodil, acting at different receptor subtypes, exerts antiepileptogenic effects in the intrahippocampal kainate mouse model of epilepsy. These drugs were administered over 5 days following kainate. Spontaneous seizures were recorded by video/EEG at different intervals up to 3 months. Initial trials showed that drug treatment during the latent period led to higher mortality than treatment after onset of epilepsy, and further, that combined therapy with both drugs caused higher mortality at doses that appear safe when used singly. We therefore refined the combined-drug protocol, using lower doses. Two weeks after kainate, significantly less mice of the NBQX/ifenprodil group exhibited electroclinical seizures compared to vehicle controls, but this effect was lost at subsequent weeks. The disease modifying effect of the treatment was associated with a transient prevention of granule cell dispersion and less neuronal degeneration in the dentate hilus. These data substantiate the involvement of altered glutamatergic transmission in the early phase of epileptogenesis. Longer treatment with NBQX and ifenprodil may shed further light on the apparent temporal relationship between dentate gyrus reorganization and development of spontaneous seizures.peerReviewe