Triheptanoin is
anticonvulsant in several seizure models. Here, we investigated changes in
glucose metabolism by
triheptanoin interictally in the chronic stage of the
pilocarpine mouse
epilepsy model. After injection of [U-13C6]-
glucose (i.p.), enrichments of 13C in intermediates of glycolysis and the
tricarboxylic acid (TCA) cycle were quantified in hippocampal extracts and maximal activities of
enzymes in each pathway were measured. The enrichment of 13C
glucose in plasma was similar across all groups. Despite this, we observed reductions in incorporation of 13C in several glycolytic intermediates compared to control mice suggesting
glucose utilization may be impaired and/or glycogenolysis increased in the untreated interictal hippocampus.
Triheptanoin prevented the interictal reductions of 13C incorporation in most glycolytic intermediates, suggesting it increased
glucose utilization or - as an additional astrocytic fuel - it decreased
glycogen breakdown. In the TCA cycle metabolites, the incorporation of 13C was reduced in the interictal state.
Triheptanoin restored the correlation between 13C enrichments of
pyruvate relative to most of the TCA cycle intermediates in "epileptic" mice.
Triheptanoin also prevented the reductions of hippocampal
pyruvate dehydrogenase and
2-oxoglutarate dehydrogenase activities. Decreased
glycogen breakdown and increased
glucose utilization and metabolism via the TCA cycle in epileptogenic brain areas may contribute to
triheptanoin's
anticonvulsant effects.