Abstracts

Rationale: Despite the advent of newer medications, 30-40% of epileptic patients are refractory to any known drugs and continue to have unremitting recurrent seizures and attendant life-long cognitive, behavioral and mental health problems. The continued persistence of this refractory population suggests that new drugs with unexpected mechanisms of action are needed. Thus, we developed a phenotypic screen to identify new molecular targets for antiseizure drug discovery. Since we conduct all screens using libraries of repurposed drugs for which their molecular targets are well characterized, and given that our readout assays are unbiased, we can reverse identify new pathways for future epilepsy drug screening efforts. Methods: We use CRIPSR/cas9 to create zebrafish epilepsy models and then we assay for drugs that restore increased bioenergetics observed in the ‘epileptic’ zebrafish to baseline levels. We also rely on behavioral activity as well as EEG recordings in zebrafish epilepsy models. Finally, we conduct video-EEG in mice genetic models of epilepsy, namely Kv1.1-null animals. Results: From a 900 compound screen in kcna1-deficient zebrafish we uncovered the pan-HDAC inhibitor vorinostat. In Kv1.1-null mice, daily treatment with vorinostat (40mg/kg/bw/day) led to a 60% reduction in the number of seizures/day as measured by video-EEG. However, given that vorinostat functions as a broad HDAC inhibitor, we suspected that the clinical utility of this compound might be limited due to unwanted side effects, especially in developing pediatric patients. Thus, we systematically screened 27 selective HDAC inhibitors and uncovered that that dual inhibition of HDAC 1 and HDAC 3 blocked spontaneous seizures in Kv1.1-null mice. Conclusions: Here we propose that targeted inhibition of HDAC 1, 3 might represent a novel molecular target against which future antiseizure drug discovery could be designed. Funding: Brain Canada Platform Support Grant