Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet

Bough, Kristopher J.; Wetherington, Jonathon P.; Hassel, Bjørnar; Paré, Jean Francois; Gawryluk, Jodie R.; Greene, James G.; Shaw, Reneé; Smith, Yoland; Geiger, Jonathan D.; Dingledine, Raymond

doi:10.1002/ana.20899

Cited by 519 publications

(483 citation statements)

References 70 publications

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“…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].…”

Section: Effects Of the Ketogenic Diet On Gaba Synthesismentioning

confidence: 98%

“…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].…”

Section: Excitatory Amino Acid Systemsmentioning

confidence: 99%

“…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.…”

Section: Effects On Ion Channels and Proteins Associated With Synaptimentioning

confidence: 99%

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The Neuropharmacology of the Ketogenic Diet

Hartman

Gąsior

Vining

et al. 2007

Pediatric Neurology

280

169

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The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease.

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Section: Effects Of the Ketogenic Diet On Gaba Synthesismentioning

confidence: 98%

Section: Excitatory Amino Acid Systemsmentioning

confidence: 99%

Section: Effects On Ion Channels and Proteins Associated With Synaptimentioning

confidence: 99%

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The Neuropharmacology of the Ketogenic Diet

Hartman

Gąsior

Vining

et al. 2007

Pediatric Neurology

280

169

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Julio-Amilpas

Montiel

Soto‐Tinoco

et al. 2015

J Cereb Blood Flow Metab

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Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury. INTRODUCTIONGlucose is the main energy source in brain. However, under certain conditions other energy substrates such as the ketone bodies (KB), acetoacetate (AcAc), and β-hydroxybutyrate (BHB) can be used by brain, including the suckling period, 1,2 prolonged fasting, 3 and the ketogenic diet; 4 all these situations are associated with increased KB levels in blood. Several studies have shown that KB can protect the brain against damage associated with diverse neurotoxic insults such as hypoxia, 5 ischemia, 6-8 hypoglycemia, 9,10 and excitotoxicity. 11,12 In addition, the ketogenic diet has been used for a long time for the treatment of refractory epilepsy. 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. 10,18 The mechanism underlying the reduction of ROS by BHB has not been elucidated but we have previously reported that KB display a scavenging action of ROS, in particular of the hydoxyl radical ( • OH). 10 The physiologic and the

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“…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.…”

Section: Increase In Mitochondrial Numbermentioning

confidence: 99%

The Ketogenic Diet: Proposed Mechanisms of Action

2009

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Summary:The ketogenic diet is a high-fat, low-carbohydrate diet used to treat drug-resistant seizures, especially in children. A number of possible mechanisms of action have been proposed to explain the anticonvulsant effects of the diet. Four of these hypothetical mechanisms are discussed in the present article: the pH hypothesis, the metabolic hypotheses, the amino acid hypothesis, and the ketone hypothesis.

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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.

Cited by 519 publications

References 70 publications

The Neuropharmacology of the Ketogenic Diet

The Neuropharmacology of the Ketogenic Diet

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

The Ketogenic Diet: Proposed Mechanisms of Action

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