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Metabolic Therapies

Metabolic Therapies

Food for Thought

A ketogenic diet (KD) is an alternative metabolic treatment for epilepsy, and multiple retrospective and prospective studies confirm its clinical benefits.

The KD’s high-fat low-carbohydrate composition forces ketone-based rather than glucose-based metabolism, but it is not known how this shift leads to anticonvulsant consequences. Primary applications of KD therapy include pediatric and medically refractory epilepsy; its use is increasing globally, and clinical benefits are similar across cultures and age groups. Despite its success, side effects and requisite strict compliance have limited widespread use of KDs, and a diet-based approach is often considered as a last resort. By better understanding the mechanisms involved in the anticonvulsant actions of a KD, pharmacological strategies might be developed that take advantage of beneficial aspects and limit problems associated with diet therapy. 

Adenosine acting at adenosine A1 receptors (A1Rs) is a logical candidate for the effects of KD therapy. Adenosine is well-established as a powerful anticonvulsant, and endogenous adenosine acting at A1Rs is an important seizure-control mechanism; deletion of A1Rs or increased adenosine clearance by elevated adenosine kinase (ADK) both cause spontaneous intrahippocampal electrographic seizures and increase the brain’s susceptibility to injury. Conversely, therapeutic adenosine augmentation is highly effective in controlling seizures.

Adenosine is the core of ATP, a key molecule in basic biochemistry, and a ligand at its own family of G protein-coupled cell-surface receptors. Thus, adenosine is a homeostatic bioenergetic network regulator involved in metabolism and ongoing neuronal activity, and well-positioned to translate metabolic changes into altered brain activity. Using three lines of transgenic mice that all exhibit electrographic seizures due to deficient adenosine signaling, we presented the first direct evidence that adenosine acting at A1Rs contributes to the therapeutic effects of KDs. Because 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.

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.

Further Reading:

A ketogenic diet suppresses seizures in mice through adenosine A1 receptors

Ketogenic Diet Prevents Epileptogenesis and Disease Progression in Adult Mice and Rats

New insights into the mechanisms of the ketogenic diet