Development and Characterization of Pre-Clinical Epilepsy Models to Evaluate Potential Anti-Seizure Targets.

Abstract

Epilepsy is the oldest known neurological disorder in humans and has been extensively studied for decades. Nevertheless ~30% epilepsy patients remain refractory to pharmacological intervention today. Limitations of animal models that are used in anti-epileptic drug screening, and a lack of novel translatable therapeutic targets hamper progress in drug development. In the following projects, we have attempted to address these obstacles. First, we have developed a model for seizure kindling using inhaled chemo-convulsant flurothyl that can be rapidly developed and is appropriate to use in research for epileptogenesis as well as screening for potential disease modifying theories. Next, we have pharmacologically characterized Kv1.1 KO mice to be potentially incorporated in the anti-epileptic drug development program as a model for drug resistant epilepsy (DRE). We report that ~32% Kv1.1 KO mice are resistant to the first ASD in addition to exhibiting multiple other risk factors observed in human DRE patients. Finally, we have used Kv1.1 KO mice and other acute seizure models to evaluate ser273 phosphorylation of PPARγ as a potential anti-seizure target. We find that seizures are closely associated with increased ser273 phosphorylation of PPARγ. We also find dysregulation in gene transcription of PPARγ regulated histone deacetylates (SIRT3), anti-oxidants (SOD1), and mitochondrial solute carriers (FABP7 and SLC25a1). However, PPARγ modulators that block ser273 phosphorylation in adipose tissue could not block this phosphorylation in the hippocampus, and ser273 phosphorylation did not seem to be associated with the gene set analyzed. In summary, we report (a) a novel model for chronic epilepsy with potential to use in screening procedures and to study epileptogenesis (b) that Kv1.1 KO mice are a potential model for drug resistant epilepsy (c) that ser273 phosphorylation of PPARγ may be a potential target for anti-epilepsy therapy.