Development of an Antiepileptogenesis Drug Screening Platform: Effects of Everolimus and Phenobarbital

Abstract

ObjectiveThe kainic acid (KA)-induced status epilepticus (SE) model in rats is an etiologically-relevant animal model of epileptogenesis. Just as in patients, who develop temporal lobe epilepsy (TLE) following SE, this rat model of KA-induced SE very closely recapitulates many of the clinical and pathological characteristics of human TLE that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (TBI, SE event, viral infection, etc.). Moreover, this rat model of TLE is ideally suited for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. This report details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the onset or severity of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS, or lead to a reduced frequency/severity of SRS. MethodsRats were administered everolimus (2-3 mg/kg, P.O. commencing at 1, 2, or 24-hrs after SE onset) or phenobarbital (60 mg/kg, beginning 1 hr after SE onset). The rats in all studies (n=12/treatment dose/study) were then followed intermittently by video-EEG monitoring; i.e., 2-weeks on/2-weeks off, 2-weeks on epochs to determine latency to onset of SRS, and disease burden following SRS onset. ResultsWhile there were no adverse side effects observed in any of our studies, no treatment conferred a significant disease modifying effect, nor did any agent prevent the presentation of SRS by 6 weeks post-SE onset. ConclusionsWhile neither phenobarbital nor everolimus administered at several time points post-SE onset prevented the development of SRS, we herein demonstrate a moderate-throughput screen for potential antiepileptogenic agents in an etiologically-relevant rodent model of TLE. Key PointsO_LIDisease-modifying therapies are needed to prevent or attenuate the burden of epilepsy in at-risk individuals. C_LIO_LIWe report a moderate-throughput screening protocol to identify disease-modifying agents in a rat post-kainic acid status epilepticus model. C_LIO_LIEverolimus was administered at multiple time points post-status epilepticus with no effect on spontaneous seizures up to 6 weeks later. C_LIO_LIRepeated administration of phenobarbital also did not prevent the development of spontaneous recurrent seizures up to 6 weeks post SE. C_LIO_LIWhile we did not identify any effect of either agent, our approach provides a moderate-throughput screen for antiepileptogenesis. C_LI