Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet

Abstract

These data show that a calorie-restricted KD enhances brain metabolism. We propose an anticonvulsant mechanism of the KD involving mitochondrial biogenesis leading to enhanced alternative energy stores.

The Neuropharmacology of the Ketogenic Diet

“…The equilibrium of the transamination reaction toward oxaloacetate in the presence of increased α-ketoglutarate implies that availability of glutamate will be enhanced. Total brain glutamate is not increased by the ketogenic diet [38,39], although there may be small regional increases [40]. Radiotracer study has demonstrated increased synthesis of glutamate in ketotic mice consuming a ketogenic diet [38].…”

“…2). The shift in this transamination reaction would be expected to reduce aspartate, and substantial (23%) decreases in whole brain aspartate levels have been observed in mice receiving a ketogenic diet for 3 days [38], although this is not a consistent finding [39]. Anticonvulsant effects of the diet are not seen until after 7 to 10 days in rodents [42,58].…”

“…Indeed, a recent microarray study of gene expression in the hippocampus of rats fed a ketogenic diet for three weeks revealed changes in the transcripts of a total of 39 genes that encode such proteins [39]. Most transcripts were reduced in animals receiving the diet, including the voltage-dependent calcium channel subunits γ4 and α1D, the ClCN1 chloride channel, the KCNH3 and KCNE1-like potassium channels, P2X3 and P2X7 purinergic receptors, and synapto-tagmins 6 and XI.…”

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

“…4,13,14 The protective effect of KB has been mostly attributed to their conversion to AcetylCoA improving mitochondrial metabolism and preserving energy levels. [15][16][17] However, studies suggest that besides providing energy to neurons, KB reduce the production of reactive oxygen species (ROS) contributing to their protective effect. It has been observed in vitro that AcAc reduces ROS levels induced by glutamate exposure and glycolysis inhibition in cultured neurons, 12,16 and previous in vivo studies have shown that BHB decreases hypoglycemia and glutamate-mediated lipoperoxidation in the rat brain.…”

The Ketogenic Diet: Proposed Mechanisms of Action

“…Bough et al 15 have reported that rats on the ketogenic diet produce more mitochondria than rats on normal rodent chow. Presumably, more mitochondria would also mean more energy for the brain, and, therefore, possibly, fewer seizures.…”