AMPK and cardiac dysfunction in chronic epilepsy: a prognostic indicator of SUDEP risk

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PROPOSAL SUMMARY The increased risk of sudden unexplained/unexpected death in epilepsy (SUDEP) is particularly high in drug- refractory patients. In fact, 40% of adult patients with pharmacoresistant epilepsy have one or more abnormalities in cardiac function3. One of the main risk factors for SUDEP is frequent, convulsive seizures in humans4-6,26. Rodents with chronic, acquired epilepsy die suddenly and unexpectedly7,8. Continuously recorded EKG in rats with pilocarpine-induced epilepsy demonstrates that alterations in QT interval, PR interval, and T- wave amplitude are associated with increased seizure burden. These data, combined with previous human and animal studies, support further investigation of a shared mechanism underlying cardiac arrhythmia development in adult acquired and genetic epilepsies that may be used as a universal prognostic biomarker of SUDEP risk. The major goal of this proposal is to characterize the role of AMP-activated protein kinase (AMPK) activation as a potential therapeutic target in chronic epilepsy and specifically, to evaluate the hypothesis that spontaneous seizures impair energy metabolism in the hearts and brains of acquired and genetic models of epilepsy contributing to increased seizure burden and SUDEP risk. Molecular methods will be used to characterize impairment in AMPK activation and altered expression of AMPK subunits. Abnormal cardiac function will be quantitatively measured in response to seizure-induced metabolic stress using simultaneous video/EEG/EKG monitoring. AMPK activity will be pharmacologically modulated to determine whether AMPK phosphorylation is preventative or pathological. We hypothesize that potential increases in seizure frequency and severity associated with longer duration postictal depression and arrhythmogenesis mediated by impaired AMPK phosphorylation can be prevented using clinically available AMPK activators in both genetic and acquired epilepsies. We expect our results to unmask a shared mechanism contributing to SUDEP risk in genetic and acquired epilepsies. Results of these studies may inspire new strategies for the prevention of SUDEP and provide more effective treatments for chronic, pharmacoresistant epilepsy. The proposal will provide valuable translational information about the role of impaired energy metabolism in epileptogenesis and acquired cardiac dysfunction contributing to SUDEP risk.