Dietary
therapy has been used to treat many individuals with
epilepsy whose
seizures are refractory to
antiepileptic drugs. The mechanisms for how dietary
therapy confers seizure protection are currently not well understood. We evaluated the acute effects of
glucose and β-hydroxybutyrate (the major circulating
ketone body) in conferring seizure protection to the EL mouse, a model of multifactorial
idiopathic generalized epilepsy. EL mice were fed either an unrestricted standard diet or a calorie-restricted standard diet to achieve a
body weight reduction of 20-23%.
D-Glucose,
2-deoxy-D-glucose, and β-hydroxybutyrate were supplemented in the
drinking water of calorie-restricted mice for 2.5 h prior to seizure testing to simulate the effect of increased
glucose availability, decreased
glucose utilization, and increased
ketone availability, respectively. Seizure susceptibility,
body weight, plasma
glucose, and β-hydroxybutyrate were measured over a nine-week treatment period. Additionally, excitatory and inhibitory
amino acids were measured in the brains of mice using (1)H NMR.
Glutamate decarboxylase activity was also measured to evaluate the connection between dietary
therapy and brain metabolism. We found that lowering of
glucose utilization is necessary to confer seizure protection with long-term (>4 weeks) calorie restriction, whereas increased
ketone availability did not affect seizure susceptibility. In the absence of long-term calorie restriction, however, reduced
glucose utilization and increased
ketone availability did not affect seizure susceptibility. Brain excitatory and inhibitory
amino acid content did not change with treatment, and
glutamate decarboxylase activity was not associated with seizure susceptibility. We demonstrated that reduced
glucose utilization is necessary to confer seizure protection under long-term calorie restriction in EL mice, while acute
ketone supplementation did not confer seizure protection. Further studies are needed to uncover the mechanisms by which
glucose utilization influences seizure susceptibility.