Role of DNA Methylation and Adenosine in Ketogenic Diet for Pharmacoresistant Epilepsy: Focus on Epileptogenesis and Associated Comorbidities

Epilepsy is a neurological disorder characterized by a long term propensity to produce unprovoked seizures and by the associated comorbidities including neurological, cognitive, psychiatric, and impairment the quality of life. Despite the clinic availability of several novel antiepileptic drugs (AEDs) with different mechanisms of action, more than one-third of patients with epilepsy suffer with pharmacoresistant epilepsy. Until now, no AEDs have been proven to confer the efficacy in alteration of disease progression or inhibition of the development of epilepsy. The ketogenic diet, the high-fat, low-carbohydrate composition is an alternative metabolic therapy for epilepsy, especially for children with drug-resistant epilepsy. Recently clinical and experimental results demonstrate its efficacy in ameliorating both seizures and comorbidities associated with epilepsy, such as cognitive/psychiatric concerns for the patients with refractory epilepsy. Of importance, ketogenic diet demonstrates to be a promising disease-modifying or partial antiepileptogenesis therapy for epilepsy. The mechanisms of action of ketogenic diet in epilepsy have been revealed recently, such as epigenetic mechanism for increase the adenosine level in the brain and inhibition of DNA methylation. In the present review, we will focus on the mechanisms of ketogenic diet therapies underlying adenosine system in the prevention of epileptogenesis and disease modification. In addition, we will review the role of ketogenic diet therapy in comorbidities associated epilepsy and the underlying mechanisms of adenosine.