Triheptanoin alters anaplerosis and glutamate production in the chronic pilocarpine model of epilepsy (LB78)

Abstract

Growing evidence suggests that dysfunctions in glucose metabolism that reduce ATP production play a role in the pathophysiology of epilepsy. Triheptanoin, an anaplerotic molecule through propionyl‐CoA carboxylase (PCC) pathway is anticonvulsant in four rodent seizure models. We aim to determine the effects of triheptanoin on brain glucose metabolism in chronic epilepsy. Mice were fed a standard or 35% (caloric value) triheptanoin diet for three weeks following pilocarpine injections, which results in spontaneous recurrent seizures in mice that developed status epileptics (SE) (n= 7‐15 mice per group). The levels of glycolytic and TCA cycle metabolites in hippocampal tissue were measured by LCMS‐MS. Spectrophotometric enzyme assays measured the activity levels of enzymes involved in these pathways. The levels of several glycolytic intermediates were reduced in SE mice, independent of diet (Two way ANOVAs p<0.05). Despite a reduction in levels of glycolytic intermediates there was no change in enzyme activity (Two‐way ANOVA P>0.05) suggesting that glucose uptake is reduced. In SE mice pyruvate carboxylase activity increased indicating an increased requirement for anaplerosis. This increase was attenuated by triheptanoin feeding, suggesting an alternate anaplerotic pathway is utilised. Furthermore triheptanoin increased the activity of aspartate transaminase and glutamate dehydrogenase, indicating an increase in glutamate production. Overall this study suggests that triheptanoin entry via PCC refills TCA cycle intermediates, allowing increased production of glutamate. The fate of this glutamate still needs to be investigated.