Alterations in Cytosolic and Mitochondrial [U-¹³C]Glucose Metabolism in a Chronic Epilepsy Mouse Model

Abstract

Temporal lobe epilepsy is a common form of adult epilepsy and shows high resistance to treatment. Increasing evidence has suggested that metabolic dysfunction contributes to the development of seizures, with previous studies indicating impairments in brain glucose metabolism. Here we aim to elucidate which pathways involved in glucose metabolism are impaired, by tracing the hippocampal metabolism of injected [U-13C]glucose (i.p.) during the chronic stage of the pilocarpine-status epilepticus mouse model of epilepsy. The enrichment of 13C in the intermediates of glycolysis and the TCA cycle were quantified in hippocampal extracts using liquid chromatography–tandem mass spectroscopy, along with the measurement of the activities of enzymes in each pathway. We show that there is reduced incorporation of 13C in the intermediates of glycolysis, with the percentage enrichment of all downstream intermediates being highly correlated with those of glucose 6-phosphate. Furthermore, the activities of all enzymes in this pathway including hexokinase and phosphofructokinase were unaltered, suggesting that glucose uptake is reduced in this model without further impairments in glycolysis itself. The key findings were 33% and 55% losses in the activities of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase, respectively, along with reduced 13C enrichment in TCA cycle intermediates. This lower 13C enrichment is best explained in part by the reduced enrichment in glycolytic intermediates, whereas the reduction of key TCA cycle enzyme activity indicates that TCA cycling is also impaired in the hippocampal formation. Together, these data suggest that multitarget approaches may be necessary to restore metabolism in the epileptic brain.

Impaired hippocampal glucose metabolism during and after flurothyl‐induced seizures in mice: Reduced phosphorylation coincides with reduced activity of pyruvate dehydrogenase

“…Together this suggests that glucose entry into the TCA cycle is impaired postictally. This is also consistent with finding during the chronic stage of the pilocarpine‐SE mouse model . PDH activity is regulated via the phosphorylation of three serine residues located at positions 232, 293 and 300.…”

“…There are limitations to this model, for example, a lack of histopathologic changes, 17 which do occur in both chronic seizure models 18 and in human temporal lobe epilepsy. 19 Despite this we found similar changes in glucose metabolism in this model compared with the chronic pilocarpine-SE mouse model, 9 suggesting that these changes are not limited to either the model or to histopathologic changes, but are a consequence of the seizure activity itself.…”

“…Moreover, we just demonstrated that glucose entry into the TCA cycle is impaired during the chronic phase of the pilocarpine mouse model, due to a decrease in PDH activity …”

“…7,8 Moreover, we just demonstrated that glucose entry into the TCA cycle is impaired during the chronic phase of the pilocarpine mouse model, due to a decrease in PDH activity. 9 Few studies have investigated changes in glucose metabolism during seizures. During flurothyl-and kainateinduced seizures there is only indirect evidence of increased glycolytic activity based on increases in lactate levels.…”

Randomized trial of add‐on triheptanoin vs medium chain triglycerides in adults with refractory epilepsy

“…[1][2][3][4][5][6] This may result in local shortages of carbon and adenosine triphosphate (ATP), which likely contributes to seizure generation. In addition, glucose metabolism has been shown to be reduced in epileptogenic areas in people with epilepsy and in animal models.…”