AbstractThe discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that better represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 minutes after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, weekly SRS frequencies, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d), and diazepam (0.4 mg/kg, b.i.d). Both valproate and diazepam significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. The data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) but not to a GABA receptor modulating ASD (diazepam) or a mixed-mechanism ASD (valproate). Further work with this experimental paradigm will evaluate its suitability for inclusion in the ETSP pharmacoresistance screening platform.HighlightsAn intra-amygdala kainate model of TLE was evaluated for pharmacoresistant seizuresAdministration of midazolam during status epilepticus did not affect mortalityModel characteristics were evaluated over a 90-day natural history studySpontaneous recurrent seizures were resistant to phenytoin and carbamazepineSpontaneous recurrent seizures were sensitive to valproic acid and diazepam
The “Natural” History of Medically Treated Temporal Lobe Epilepsy: What Can an Evidence-Based Approach Tell Us?
