Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats

Abstract

Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects.

Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse

“…In epilepsy, chronic KD treatment can produce seizure control that extends well beyond cessation of the diet (e.g. [83–85]) suggesting a persistent, possibly epigenetic, effect [32] – it remains to be seen if KD amelioration of ASD symptoms can persist in a similar manner. Finally, although ASD is more common in males, our positive results in females may provide additional hope for the 4 in 1000 females (650,000 individuals in the USA) who have ASD [86].…”

“…These outcomes suggest a long-lasting antiepileptogenic effect, possibly through epigenetic mechanisms [25]. The potential of KDs for antiepileptogenesis is supported by diverse animal research [26–32]. …”

New insights into the mechanisms of the ketogenic diet

“…A subsequent study showed that a transient KD therapy restored normal adenosine levels and global DNA methylation levels in epileptic rats that were otherwise adenosine deficient and hypermethylated; importantly, transient KD therapy reduced seizure activity long-term, even after diet reversal to control diet [47 •• ]. Because KD therapy increases adenosine [47,48] and because adenosine blocks DNA methylation [49] it is likely that the KD exerts its disease modifying effects through an adenosine-dependent epigenetic mechanism.…”

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

“…The rats in KD-fed groups do not display a post-SE elevation of hippocampal pS6 levels that are observed in control animals after kainate induced SE [280]. Additionally, KD has also been shown to increase adenosine in the brain, and convey both acute anticonvulsant [281] and extended antiepileptogenic effects [282,283]. In a rat kainate-SE model, KD animals experienced fewer and less intense SRS, and reduced mossy fiber sprouting in the supragranular layer of the DG compared to control groups.…”

“…However, no difference in pyramidal cell loss was observed between treatment and control groups [284]. KD treatment has been shown to not only inhibit or delay kindling epileptogenesis in rats and mice, but also to prevent the progression of the disease after pilocarpine induced SE in rats [283]. Furthermore, KD treatment improves deficits in spatial memory function in kindled rats [285].…”