Perampanel chronic treatment does not induce tolerance and decreases tolerance to clobazam in genetically epilepsy prone rats

Tolerance to some therapeutic effects of antiepileptic drugs may account for the development of pharmacoresistance in patients with epilepsy. In the present study, following oral acute pretreatment with the new antiepileptic drug perampanel (0.1, 0.3, 1 or 3 mg/kg), we observed that the drug significantly and dose-dependently attenuated the seizure phases (clonus and tonus) of audiogenic seizures in genetically epilepsy prone rats (GEPR-9 s), a genetic model of reflex generalized epilepsy. In addition, the GEPR-9 s were administered orally with perampanel (1 or 3 mg/kg) once daily for 10 weeks in order to study the possible development of tolerance, and when animals were subjected to auditory stimulation we observed that the ED50 values against clonus or tonus were not significantly different from those observed after single administration. Furthermore, the duration of anticonvulsant effects observed between 60 min and 9 h following oral administration of perampanel (1 mg/kg) were similar in acute and after chronic treatment. In another group of experiments, clobazam (0.75, 1.5, 3, 6, 9, 12 and 15 mg/kg) after acute administration was able to dose-dependently reduce the severity of the audiogenic seizures in GEPR-9 s. When clobazam (6 or 12 mg/kg) was administered alone for 10 consecutive weeks a clear development of tolerance to its anticonvulsant effects within approximately seven weeks was observed. In addition, we observed that when clobazam (6 mg/kg) was co-administered with perampanel (1 mg/kg), the latter drug was able to attenuate the development of tolerance to the antiseizure activity of clobazam. The present data indicate that both perampanel and clobazam are effective against audiogenic seizures, however, clobazam effects are hampered by the development of tolerance. Furthermore, concomitant treatment with perampanel slows development of tolerance to the anticonvulsant effects of clobazam in GEPR-9 s.