Triheptanoin alters [U-13C6]-glucose incorporation into glycolytic intermediates and increases TCA cycling by normalizing the activities of pyruvate dehydrogenase and oxoglutarate dehydrogenase in a chronic epilepsy mouse model. Issue 3 (March 2020)

• Record Type: Journal Article
• Authors: McDonald, Tanya; Hodson, Mark P; Bederman, Ilya; Puchowicz, Michelle; Borges, Karin
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 40:Issue 3(2020)
• Page Start: 678
• Page End: 691
• Publication Date: 2020-03
• Subjects: Glucose metabolism -- pilocarpine -- temporal lobe epilepsy -- medium chain fatty acid -- anaplerosis; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X19837380
• Languages: English
• ISSNs: 0271-678X

Abstract

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- 13 C6 ]-glucose (i.p.), enrichments of 13 C 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 13 C glucose in plasma was similar across all groups. Despite this, we observed reductions in incorporation of 13 C 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 13 C 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 13 C was reduced in the interictal state. Triheptanoin restored the correlation between 13 C 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.