Ketogenic Diet Metabolites Reduce Firing in Central Neurons by Opening K_ATPChannels

Abstract

A low-carbohydrate ketogenic diet remains one of the most effective (but mysterious) treatments for severe pharmacoresistant epilepsy. We have tested for an acute effect of physiological ketone bodies on neuronal firing rates and excitability, to discover possible therapeutic mechanisms of the ketogenic diet. Physiological concentrations of ketone bodies (␤-hydroxybutyrate or acetoacetate) reduced the spontaneous firing rate of neurons in slices from rat or mouse substantia nigra pars reticulata. This region is thought to act as a "seizure gate," controlling seizure generalization. Consistent with an anticonvulsant role, the ketone body effect is larger for cells that fire more rapidly. The effect of ketone bodies was abolished by eliminating the metabolically sensitive K ATP channels pharmacologically or by gene knock-out. We propose that ketone bodies or glycolytic restriction treat epilepsy by augmenting a natural activity-limiting function served by K ATP channels in neurons.

The Neuropharmacology of the Ketogenic Diet

“…ATP-sensitive potassium channels (K ATP ), which are inhibited by high intra-cellular ATP levels, are of particular relevance [1,69]. A role for K ATP channels in the ketogenic diet was suggested by data showing that the ketone bodies β-hydroxybutyrate and acetoacetate decreased the firing rate of rodent substantia nigra pars reticulata neurons in vitro; blockade of these channels abolished the effect, indicating that the decrease in neuronal firing is due to opening of K ATP channels induced by the ketone bodies [70]. To date, however, it has been difficult to show a role for K ATP channels in the regulation of seizure susceptibility except in conditions of metabolic stress [71,72].…”

Food for thought: the ketogenic diet for epilepsy

“…5 Between 10 and 15 per cent of patients are seizurefree a year after starting the diet, while 30 per cent have more than a 90 per cent reduction in seizures. 5 For example, a literature review reported that after following the ketogenic diet for between three and 36 months, 16 per cent of children with the Lennox-Gastaut syndrome were seizure free and 47 per cent showed more than a 50 per cent reduction in seizure frequency. In other words, the ketogenic diet seems to show similar efficacy to anticonvulsants -such as lamotrigine, topiramate and rufinamide -in this difficult-to-treat syndrome.…”

“…4 Phenytoin's (diphenylhydantoin) discovery in 1938 ushered in the medical era of epilepsy care. Unfortunately, even today, the limitations of AEDs remain all too apparent, including not effectively controlling seizures in approximately a third of patients 5 and impaired cognition. 6 Yet despite compelling evidence of the benefits offered by the ketogenic diet even when AEDs fail, it remains underused for several reasons including: tolerability issues; poor compliance; lack of training; and 'a general reluctance on the part of neurologists to employ dietary therapy'.…”

Combination treatment of epilepsy with ketogenic diet and concurrent pharmacological inhibition of cytochrome P450 2E1

“…In brain tissue slices, acetoacetate and β-hydroxybutyrate promote opening of K ATP channels [4] and promote the presynaptic accumulation of GABA [5]; both of these effects might reduce neuronal excitability. However, recent experiments with animal models of epilepsy point to acetone as the anticonvulsant mediator [6].…”

“…Acetoacetate, which is the precursor of acetone, has lower anticonvulsant activity than acetone; β-hydroxybutyrate, which is not converted to acetone, has none [12]. 4. Metabolites of acetone (see Figure 1) have either weak anticonvulsant activity or none at all [13].…”