Abstract
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.
Highlights
Prevention of acquired epilepsy in patients at risk is a major unmet clinical need[1]
Among the various drugs and drug targets that have been explored for antiepileptogenic effects in recent years, drugs that modulate excitatory transmission by blocking glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype have been reported to exert neuroprotective effects in post-status epilepticus models of acquired epilepsy[2], whereas drugs blocking the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) subtype of glutamate receptors have received relatively little attention, AMPA receptors have long been suggested to play an important role in ictogenesis and epileptogenesis[4,5,6,7]
More than 20 years ago, we reported that the anticonvulsant effect of the AMPA receptor antagonist NBQX can be potentiated by extremely low doses (0.0001–0.1 mg/kg) of the NMDA receptor antagonist MK-801 in the amygdala kindling model of TLE12
Summary
Prevention of acquired epilepsy in patients at risk is a major unmet clinical need[1]. In view of the complexity of the processes (“epileptogenesis”) that lead to epilepsy, we have proposed that rational combinations of drugs that engage different targets presumed to be involved in the epileptogenic network, may be a more effective strategy than treatment with single, highly specific drugs[1] Translation of such a network approach would benefit from repurposing of drugs that are clinically available. More than 20 years ago, we reported that the anticonvulsant effect of the AMPA receptor antagonist NBQX can be potentiated by extremely low doses (0.0001–0.1 mg/kg) of the NMDA receptor antagonist MK-801 (dizocilpine) in the amygdala kindling model of TLE12. In the present study we evaluated whether a combination of an NMDA with an AMPA receptor antagonist exerts disease-modifying or antiepileptogenic effects in the intrahippocampal kainate mouse model of mesial TLE. Our hypothesis was that combining ifenprodil with NBQX should block or modify epileptogenesis in the intrahippocampal kainate mouse model of mesial TLE, a widely used animal model that recapitulates many characteristics of mesial TLE in patients, including an epileptogenic focus in the hippocampus, development of spontaneous recurrent seizures (SRS), and hippocampal pathology resembling hippocampal sclerosis[23,24,25]
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