Felbamate, a novel antiepileptic agent, does not affect cognition in rodents.
Felbamate is a novel anticonvulsant agent recently approved by the FDA for treatment of epilepsy in the US. While the mechanism of action of felbamate has not been fully eludicated, recent evidence has accumulated to suggest that felbamate may act at the strychnine-insensitive glycine binding site on the NMDA receptor complex. Since this receptor has been strongly implicated in cognitive processes, the current study was designed to investigate the potential effects of felbamate on learning performance. Doses of felbamate up to 1000mg/kg, administered subcutaneously (s.c.), did not produce deleterious effects on performance in either mice or rats, using a passive avoidance task. In contrast, the non-competitive NMDA antagonist dizocilpine produced performance deficits at doses from 0.1 to 1.0mg/kg s.c. in both rats and mice. Felbamate and dizocilpine prevented NMDA-induced convulsions with ED(50)s of 20.3 and 0.82mg/kg s.c., respectively. Calculations for the therapeutic index (ratio of the deficit-producing to anticonvulsant doses) for dizocilpine resulted in less than a 1-fold separation in dose, while the therapeutic index for felbamate was greater than 50. Taken together, these results indicate that felbamate does not produce cognitive deficits at doses more than 50 times the dose needed to block seizure activity in animals.
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
R.D.
RD
Smith
M.E.
ME
Grzelak
V.L.
VL
Coffin