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

Abstract

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.

The Effects of Ketogenic Diet Treatment in Kcna1-Null Mouse, a Model of Sudden Unexpected Death in Epilepsy

“…In addition, improvement of mitochondria function leads to energy reserve, then activates ATP-sensitive potassium channels, which would stabilize synapse and attenuate neuronal excitability (36). Moreover, adenosine may be play a crucial role associated with this procession via an adenosine-dependent DNA methylation modulation (37). Furthermore, other researchers have showed that the KD has a protection against oxidative stress and mitochondrial dysfunction derived from epilepsy.…”

Role of Adenosine in Epilepsy and Seizures

“…Indeed, the few available clinical studies indicate that a KD has significant disease-modifying impacts, leaving some patients seizurefree even after discontinuation of the KD. 237,238 Notably, the KD has been most successful in mediating seizures in pediatric epilepsy. In a randomized controlled clinical trial, the impacts of a 3-month long trial of a KD was studied in children between the ages of 2 and 16 years, diagnosed with either generalized or focal epilepsy who had at least a seizure per day.…”

“…239 Another pediatric study, which focused on children with pharmacoresistant epilepsy, showed after introducing a modified Atkins diet (a less restrictive variation of the KD), 30% of children experienced 90% seizure reduction and 52% of children experienced 50% seizure reduction after 3 months. 238,240 In an adult model, 32% of adult patients with pharmacoresistant epilepsy showed >50% seizure reduction using a KD. 237,238 While the therapeutic impact of adenosine augmentation is the focus of this section, it is important to note that the KD offers seizure control through other mechanisms as well.…”

“…238,240 In an adult model, 32% of adult patients with pharmacoresistant epilepsy showed >50% seizure reduction using a KD. 237,238 While the therapeutic impact of adenosine augmentation is the focus of this section, it is important to note that the KD offers seizure control through other mechanisms as well. There is evidence that the presence of ketone EPILEPSY AND SEIZURES 51 bodies, free fatty acids, and overall glucose restriction has anticonvulsant properties and can lead to seizure protection.…”

How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

“…Moreover, it is also a good way to prevent the development of epilepsy in clinic by identifying and avoiding the risk factors for epileptogenesis after certain precipitating events [ 23 , 24 ]. Additionally, a ketogenic diet, the high-fat, low-carbohydrate composition, as an alternative metabolic therapy for paediatric DRE, has also proved to be a promising disease-modifying for epilepsy or anti epileptogenic therapy [ 25 ]. However both of these are beyond the scope of this review.…”