Current epilepsy therapies are inadequate: at least 30% of epilepsy patients suffer residual or medically- refractory seizures and/or comorbidities as well as significant side-effects from antiepileptic drugs. Some of these patients are treated successfully with a ketogenic diet (KD), a poorly understood and potentially underutilized metabolic therapy established in 1921. The consistent clinical success of the KD in suppressing seizures in refractory adult and pediatric epilepsies has been verified in multi-center, international and randomized prospective clinical studies. Clinical observations and recent translational work strongly suggest that a KD has antiepileptogenic and disease-modifying properties, and recent work indicates that metabolic therapy may benefit a greatly expanded spectrum of diseases including pain, autism, brain cancer, and Alzheimer?s disease. Nevertheless, therapeutic use of the KD has been limited largely to pediatric refractory epilepsy: there are virtually no data on using a metabolic therapy as a first-line therapy, and thus its true clinical efficacy and ability to prevent epileptogenesis is unknown. Understanding key mechanisms by which the clinical benefits of a KD are exerted is urgent and of the highest biomedical significance because it is anticipated that these mechanisms will lead to the rapid genesis of effective new metabolism-based therapeutics with disease-modifying capabilities for epilepsy. Here we test our OVERALL HYPOTHESIS that epigenetic changes in DNA methylation are mobilized during epileptogenesis and provide a therapeutic target for epilepsy prevention through diet-based metabolic therapy.
In Aim 1 we will identify epigenetic epileptogenic mechanisms that are (i) common to etiologically different rodent models of temporal lobe epilepsy (TLE) and (ii) laboratory independent ? thus fulfilling an unmet need in epilepsy research and establishing a high degree of scientific rigor among our team.
In Aim 2 we will quantify antiepileptogenesis and test mechanisms mobilized by KD therapy, including increased adenosine as a key downstream antiepileptogenic mechanism. Finally, in Aim 3 we will validate whether candidate epigenetic changes are required for KD-based antiepileptogenic effects and thereby provide mechanistic evidence for a causal relationship among metabolic therapy, epigenetic alterations, and antiepileptogenesis. Our approach represents the first systematic and comprehensive mechanistic analysis of an understudied metabolic treatment that can stop ? and even permanently resolve ? seizures. The expected outcome is the identification and characterization of epigenetic mechanisms through which metabolic therapy interferes with the process of epileptogenesis. In particular we will determine whether the expected antiepileptogenic effects are specific to KD-therapy and dependent on identified epigenetic mechanisms. A thorough mechanistic understanding of the KD may reveal an entirely new class of therapies for epilepsy and its prevention.

Public Health Relevance

Seizures and their progression can be prevented by metabolic therapy with a ketogenic diet ? a disease- modifying strategy with clinically significant benefits that have been observed consistently for nearly 100 years. This benefit is not found with anticonvulsant drugs used to treat epilepsy, and evidence published by us and others suggests that the ketogenic diet and one of its key anti-seizure mechanisms ? the neuromodulator adenosine ? mobilizes lasting epigenetic changes that can prevent and reverse the clinical conditions known as epilepsy. Here we quantify the ability of a ketogenic diet to prevent progression of epileptic seizures and identify epigenetic mechanisms that restore and maintain normal brain activity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1)
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Whittemore, Vicky R
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Trinity College
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