Abstracts

Rationale: Despite the availability of more than 20 antiseizure drugs (ASDs), one-third of patients with epilepsy do not experience adequate seizure reduction. The lamotrigine (LTG)-resistant amygdala kindling model has demonstrated utility as a useful animal model to aid in the differentiation of compounds that may be useful in pharmacoresistant epilepsy.  Although carbamazepine, valproate, and ezogabine have been evaluated in this model, no comprehensive data about ASD prototypes has been reported.  Therefore, we sought to evaluate several prototype ASDs in this model, comprising several mechanisms of action.   Methods: Male Sprague-Dawley rats were implanted with bipolar electrodes in the right basolateral amygdala. Kindling was initiated 1-2 weeks following surgery by daily (5 days/week) amygdala stimulation (200 μA, 50 Hz, 2 sec). Each day, 1 hour prior to amygdala stimulation, LTG (5 mg/kg, intraperitoneal injection) was administered.  Kindling proceeded until animals displayed at least 5 consecutive generalized seizures, at which they were considered to be “fully kindled.”  Two days following, all kindled animals were challenged with LTG (30 mg/kg) in order to verify LTG resistance.  Prototype ASDs including carbamazepine, clobazam, clonazepam, ethosuximide, lacosamide, lamotrigine, phenytoin, rufinamide, topiramate, and valproate were administered (intraperitoneal administration) to LTG-resistant kindled rats and evaluated for the ability to prevent seizures at their previously determined time of peak effect.  Results: Compounds evaluated fell into three major categories: 1) efficacy without concomitant side effects, 2) efficacy with concomitant side effects (lethargy, ataxia), and 3) no efficacy observed.  Of the compounds evaluated, valproate (ED50 126 mg/kg) was effective without any observable side effects.  Though efficacy was observed for carbamazepine (ED50 37.6 mg/kg), clobazam (ED50 9.2 mg/kg), clonazepam (ED50 1.3 mg/kg), and lacosamide (ED50 60 mg/kg), treatment with each respective compound was associated with motor impairment and/or lethargy at the highest doses tested.  Ethosuximide, lamotrigine, phenytoin, rufinamide, and topiramate were not efficacious.  Conclusions: These data suggest that seizures induced in the LTG-resistant model of kindling is refractory to a wide array of commonly used ASDs with multiple mechanisms of action and as such, is an important assay for identifying novel compounds that might be useful in the treatment of pharmacoresistant seizures in patients.   Funding: NINDS: HHSN271201600048C