Abstracts

Rationale:
Despite numerous therapies for the treatment of epilepsy, over 30% of patients remain resistant to available antiseizure drugs (ASDs). However, the pathways and processes that contribute to pharmacoresistant epilepsy are unclear. We have previously demonstrated that administration of the ASD, lamotrigine, which preferentially inhibits the fast-inactivation state of sodium channels, during the corneal kindling process can also promote pharmacoresistance to other ASDs that preferentially block the fast-inactivated state of sodium channels (e.g. carbamazepine), as well as valproic acid and retigabine (Koneval, Knox et al. 2018). A clinical case report in twin patients with epilepsy even recently suggested that early ASD selection may dramatically alter subsequent pharmacoresistance and disease course (Pawluski, Kuchenbuch et al. 2018). However, it is unknown the extent to which inhibition of slow inactivation state of sodium channels leads to pharmacoresistance in epilepsy models. Therefore, we sought to determine whether the chronic administration of lacosamide (LCM), which preferentially inhibits the slow inactivation state of sodium channels, during the corneal kindling process would induce a pharmacoresistant phenotype.
Method:
Male CF-1 mice (n=9-10/group; 18-25 g at kindling start, Envigo) were administered an anticonvulsant dose of LCM (4.5 mg/kg, ip) or vehicle (0.5% methylcellulose) one hour prior to each twice daily corneal kindling session for three weeks until animals achieved criterion of five consecutive Racine stage 5 seizures, consistent with our methods for development of the lamotrigine-resistant corneal kindled mouse. Once mice had achieved criterion, mice were given a two-week stimulation-free period. We then determined the sensitivity of kindled seizures in both treatment groups to 9 mg/kg (ip) LCM. To assess the neuronal mechanism of pharmacoresistance, the extent of neuroinflammation in LCM- versus VEH-kindled mice was assessed by immunohistochemistry.
Results:
LCM administration led to fewer mice that achieved kindling criterion: 7/9 (77.7%) vehicle-kindled mice achieved criterion versus 3/10 (30%) LCM-kindled mice (p=0.0698). There was a significant time x treatment interaction on kindled seizure severity (F(23, 391) = 2.169, p< 0.002) during the kindling process, demonstrating that chronic LCM administration significantly delayed acquisition of kindling criterion. Further, administration of 9 mg/kg LCM to all fully kindled mice effectively and equally reduced seizure severity in both LCM- and VEH-kindled mice, indicating that LCM-kindled mice were not resistant to escalating doses of LCM. Subsequent evaluations of the antiseizure efficacy of mechanistically distinct ASDs, valproic acid, phenytoin, carbamazepine, and phenobarbital, as well as neuroinflammation, will be further discussed.