Impairments in Oxidative Glucose Metabolism in Epilepsy and Metabolic Treatments Thereof

Abstract

There is mounting evidence that oxidative glucose metabolism is impaired in epilepsy and recent work has further characterized the metabolic mechanisms involved. In healthy people eating a traditional diet, including carbohydrates, fats and protein, the major energy substrate in brain is glucose. Cytosolic glucose metabolism generates small amounts of energy, but oxidative glucose metabolism in the mitochondria generates most ATP, in addition to biosynthetic precursors in cells. Energy is crucial for the brain to signal “normally,” while loss of energy can contribute to seizure generation by destabilizing membrane potentials and signaling in the chronic epileptic brain. Here we summarize the known biochemical mechanisms that contribute to the disturbance in oxidative glucose metabolism in epilepsy, including decreases in glucose transport, reduced activity of particular steps in the oxidative metabolism of glucose such as pyruvate dehydrogenase activity, and increased anaplerotic need. This knowledge justifies the use of alternative brain fuels as sources of energy, such as ketones, TCA cycle intermediates and precursors as well as even medium chain fatty acids and triheptanoin.

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.…”

“…[1][2][3][4][5][6] This may result in local shortages of carbon and adenosine triphosphate (ATP), which likely contributes to seizure generation. 6,12 Few approaches can address these impairments in energy metabolism. Therefore, alternative sources of carbons for the brain, such as medium chain fatty acids or ketone bodies, are needed to address reduced glucose metabolism (reviewed by Ref.…”

“…6,12 Few approaches can address these impairments in energy metabolism. 6,[21][22][23][24][25][26][27] Thirty-five percent of energy intake triheptanoin and MCTs have shown anticonvulsant, beneficial metabolic and antioxidant effects in several epilepsy models. 13 These diets can be very effective, specifically for certain childhood epilepsies 14,15 and also for some adults with refractory epilepsy (reviewed in Ref.…”

“…In addition, glucose metabolism has been shown to be reduced in epileptogenic areas in people with epilepsy and in animal models. [1][2][3][4][5][6] This may result in local shortages of carbon and adenosine triphosphate (ATP), which likely contributes to seizure generation. Glucose-derived carbons are metabolized to amino acids, lipids, and energy, which are all vital for regulated neuronal signaling.…”

“…Thus, refilling of the pools of C5 and C4 TCA cycle metabolites (anaplerosis) is also needed. 6,12 Few approaches can address these impairments in energy metabolism. Ketone bodies are able to supply the majority of fuel to the human brain during low-carbohydrate, high-fat ketogenic diets.…”