title: SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy.
abstract: SV2A, a synaptic vesicle protein, has been recently identified as a binding target for levetiracetam (Keppra). The specific mechanism by which SV2A binding leads to seizure protection has not yet been fully elucidated. However, a functional correlation between SV2A binding affinity and anticonvulsant potency has been observed in the mouse audiogenic seizure model. The present study was undertaken to test whether similar correlations exist in rodent models of partial and generalized epilepsies. As expected, there was a high degree of correlation between anticonvulsant potency and SV2A binding affinity in the mouse audiogenic seizure model (r(2)=0.77; p<0.001). A similar correlation was also observed in the mouse corneal kindling (r(2)=0.80; p<0.01) and in the rat model of generalized absence epilepsy (GAERS) (r(2)=0.72; p<0.01). Moreover, there were no significant differences between the slopes and intercepts of regression lines in these models. Interestingly, the protective potencies in these three epilepsy models were also well correlated with each other. As such, protective doses of a given SV2A ligand in one model could be easily predicted based on the data obtained in another model. Taken together, these results support the concept that SV2A protein is an important target for both partial and generalized epilepsies and thereby relevant for the generation of new antiepileptic drugs with potential broad-spectrum efficacy.
authors.affiliation: CNS Research, UCB PHARMA SA, Chemin du Foriest R9, Braine-l'Alleud, Belgium. rafal.kaminski@ucb-group.com
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
authors.forename: Alain
authors.initials: A
authors.lastname: Matagne
authors.forename: Karine
authors.initials: K
authors.lastname: Leclercq
authors.forename: Michel
authors.initials: M
authors.lastname: Gillard
authors.forename: Philippe
authors.initials: P
authors.lastname: Michel
authors.forename: Benoit
authors.initials: B
authors.lastname: Kenda
authors.forename: Patrice
authors.initials: P
authors.lastname: Talaga
authors.forename: Henrik
authors.initials: H
authors.lastname: Klitgaard
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004828:Epilepsies, Partial / Q000178:diet therapy / Q000209:etiology / Q000378:metabolism*; D004829:Epilepsy, Generalized / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D005260:Female; D020128:Inhibitory Concentration 50; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D000927:Anticonvulsants; D008024:Ligands; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C489614:Sv2a protein, mouse