Pharmacoresistant epilepsy affects roughly 30% of the over 65 million individuals worldwide with the disease. Unfortunately, these patients are still in need of improved treatment options. While we have over 20 antiseizure drugs on the market, the number of individuals with pharmacoresistant epilepsy has remained relatively unchanged.

The Translational Epilepsy Research Laboratory has recently developed a novel mouse model of pharmacoresistant epilepsy that is useful for early drug discovery applications: the lamotrigine-resistant corneal kindled mouse. This moderate-throughput model is based on the well-established corneal kindled mouse model of chronic network hyperexcitability. Using the lamotrigine-resistant amygdala-kindled rat model described by Srivastava and White, we sought to scale down this approach to develop a more suitable platform for early drug screening, where compound supply and/or lead compound selection may limit availability of the active pharmaceutical ingredient (API). The lamotrigine-resistant corneal kindled mouse exhibits resistance to sodium channel-blocking antiseizure drugs (lamotrigine and carbamazepine), as well as resistance to the K+ channel activator, retigabine. Furthermore, valproic acid demonstrates a reduction in potency in this model, attesting to the shift in pharmacosensitivity of this model.

Whether investigational agents that are found to be effective in this pharmacoresistant seizure model will necessarily have to await further validation, but the lamotrigine-resistant corneal kindled mouse clearly provides a relevant platform on which to  differentiate potential agents from approved antiseizure drug standards of care.