Seizure tests distinguish intermittent fasting from the ketogenic diet

Abstract

Summary Purpose: Calorie restriction can be anticonvulsant in animal models. The ketogenic diet was designed to mimic calorie restriction and has been assumed to work by the same mechanisms. We challenged this assumption by profiling the effects of these dietary regimens in mice subjected to a battery of acute seizure tests. Methods: Juvenile male NIH Swiss mice received ketogenic diet or a normal diet fed in restricted quantities (continuously or intermittently) for ∼12 days, starting at 3–4 weeks of age. Seizures were induced by the 6 Hz test, kainic acid, maximal electroshock, or pentylenetetrazol. Results: The ketogenic and calorie‐restricted diets often had opposite effects depending on the seizure test. The ketogenic diet protected from 6 Hz–induced seizures, whereas calorie restriction (daily and intermittent) increased seizure activity. Conversely, calorie restriction protected juvenile mice against seizures induced by kainic acid, whereas the ketogenic diet failed to protect. Intermittent caloric restriction worsened seizures induced by maximal electroshock but had no effect on those induced by pentylenetetrazol. Discussion: In contrast to a longstanding hypothesis, calorie restriction and the ketogenic diet differ in their acute seizure test profiles, suggesting that they have different underlying anticonvulsant mechanisms. These findings highlight the importance of the 6 Hz test and its ability to reflect the benefits of ketosis and fat consumption.

Reduced glucose utilization underlies seizure protection with dietary therapy in epileptic EL mice

“…Calorie restriction results in lowered circulating glucose, while the ketogenic diet may lower circulating glucose, depending on the amount of calories consumed [5, 8, 9]. While calorie restriction and the ketogenic diet are hypothesized to have similar mechanisms in conferring seizure protection, preclinical evidence suggests that these mechanisms are not the same [10]. Additionally, while changes in circulating glucose and ketone bodies are associated with changes in seizure susceptibility, the influence of circulating glucose and ketone bodies on seizure susceptibility and brain metabolism are not well understood [11, 12].…”

Neuroprotection in metabolism-based therapy

“…These forms of metabolism-based therapy have anticonvulsant mechanisms of action that are distinct from commercially available medicines. The longstanding belief that metabolism-based therapies shares anticonvulsant mechanisms with one another also has been challenged (Hartman et al, 2010). Thus, they will be discussed separately here to facilitate comparisons and contrasts (data on polyunsaturated fats have been discussed extensively in the literature, so they will not be considered in detail here).…”

Food for thought: the ketogenic diet for epilepsy

“…However, neither glucose nor beta-hydroxybutyrate levels related to the extent of seizure protection in either the 6Hz or kainic acid test. 13 Other studies confirm that ketone production correlates poorly with the diet's antiepileptic efficacy. Indeed, in some models, ketones are antiepileptic only at toxic doses.…”