CONICET | Buscador de Institutos y Recursos Humanos

New drug-resistant seizure model in mice to evaluate P-gp non-substrate anticonvulsant drugs.Andrea Enrique1,2, Sofía Goicoechea1, Facundo Taborda1, Rocío Castaño1, Luis Bruno Blanch1, Elena Girardi2.1-LIDeB . Fac. Cs. Exactas. UNLP. 2- Laboratorio de Epilepsia Experimental y Excitotoxicidad . IBCN UBA-CONICET. Fac. Medicina.About 30% of epileptic patients do not respond to clinically established AED plasma concentrations; therefore to identify new AEDs and incorporate models of refractory epilepsy (RE) into its development is a necessary event. We have developed a drug-resistant seizure model in Swiss mice associated with P-glycoprotein (P-gp) overexpression with low mortality (20%) and high performance of antiepileptic drug resistant animals for using in the early stages of pre-clinical trials. 3-mercaptopropionic acid (MP, 36 mg/kg, i.p.) was administered to mice (25-30 grs.) during 23 consecutive days, showing generalized clonic crisis. Day 24th 80% of animals were resistant to the P-gp substrate drug phenytoin (18 mg/kg, i.p.) an effect that was reversed with the P-gp blocker nimodipine (3.5 mg/kg, i.p.). Furthemore mice showed resistance to phenobarbital (P-gp substrate drug); although P-gp non-substrate antiepileptic drugs like carbamacepine, levetiracetam and diazepam induced anticonvulsant effect. The resistance are strongly associated with P-gp overexpression which was observed by western blot in cerebral cortex (34%), hippocampus (86%) and striatum (30%). Immunohistochemistry assays showed increase in P-gp expression in the same brain regions.This model is an useful tool for in vivo screening of new anticonvulsant drugs selected as P-gp non-substrate by virtual screening in our laboratory.