The effect of anaplerotic diet in epilepsy models



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The Citric Acid Cycle (CAC) is critical for oxidative metabolism in neurons. Also, CAC intermediates are the precursor of neurotransmitters. Impaired CAC activity leads to decreases in GABA and ATP that could lead to generation/progression of epileptic disorders. Anaplerosis is the metabolic replenishment of CAC catalytic intermediates. We wanted to determine if an anaplerotic diet is anticonvulsant and/or antiepileptogenic. Mice were fed either control diet or diet containing triheptanoin (C7), containing heptanoate as an anaplerotic molecule. Metabolic studies showed there was no statistically significant difference in body weights or kilocalories consumed/kg/day on either diet, which indicates the diets are calorically equivalent. The C7 diet was not anticonvulsant in three acute seizure models; the pentylenetetrazole, 6 Hertz, or the flurothyl models, as demonstrated by the lack of effect on seizure thresholds. The effect of the C7 diet was also tested in two chronic seizure models, pilocarpine-induced status epilepticus (SE) or corneal kindling. In the first model, mice that developed SE in response to pilocarpine were subsequently fed the C7 or control diet for three weeks. Brains of mice on the C7 diet showed statistically significant increases in β-hydroxybutyrate and the anaplerotic CAC precursors, propionyl-CoA and methylmalonyl-CoA. SE mice were then tested for seizure susceptibility upon administration of pentylenetetrazole. SE mice were more sensitive than non-SE mice to pentylenetetrazole-induced seizures. SE mice fed C7 diet had an increase in seizure threshold compared to SE mice fed the control diet. Analysis of hippocampal neurodegeneration shows there was a statistically significant increase in hilar neurons in the dentate gyrus of the hippocampus. In the second model, mice on either diet were kindled by corneal electroshock. The anaplerotic diet produced a statistically significant delay in kindling and decrease in median seizure score. These data show an anaplerotic diet may be antiepileptic and beneficial for the treatment of human seizure disorders.



Citric acid cycle (CAC), Anaplerotic diet, Epilepsy, Human seizure disorders