Abstracts

Rationale: SV2A, a synaptic vesicle protein, has been recently identified as a binding target for levetiracetam (Keppra®) and its new structural analogs that are currently in clinical development. Specific mechanisms by which SV2A binding leads to seizure protection have not been fully elucidated. However, clear correlation between SV2A binding affinity and anticonvulsant activity has been observed in the audiogenic seizure model in mice, which strongly suggests a mechanistic link between the two. The present study was undertaken to test whether similar correlations exist in rodent models of partial and generalized epilepsies.Methods: Dose-response curves have been constructed for a range of SV2A ligands in the audiogenic seizure and corneal kindling models in mice as well as in the rat model of generalized absence epilepsy (GAERS). The protective potencies obtained in these models were correlated with SV2A binding affinities using linear regression analysis.Results: The present results confirmed that there is a high degree of correlation between anticonvulsant potency of SV2A ligands in the audiogenic seizure model and their binding to SV2A (r²=0.81; p < 0.001). Importantly, a similar correlation has also been observed in the mouse corneal kindling (r²=0.67; p < 0.01) and GAERS models (r²=0.80; p < 0.001). There were no significant differences between the slopes and intercepts of regression lines in these three models. Finally, the potencies of SV2A ligands for seizure protection show excellent correlation between the models.Conclusions: Our results indicate that binding affinity of SV2A ligands strongly correlates with their protective effects in models of both partial and generalized epilepsy. Moreover, protective doses of these compounds obtained in one model could be easily predicted based on the data obtained in another model. Taken together, these data strongly suggest that SV2A protein is a broad spectrum anticonvulsant target relevant for both partial and generalized epilepsies.