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.

No abstract

Summary:The ketogenic diet (KD) is a broadly effective treatment for medically refractory epilepsy. Despite nearly a century of use, the mechanisms underlying its clinical efficacy remain unknown. In this review, we present one intersecting view of how the KD may exert its anticonvulsant activity against the backdrop of several seemingly disparate mechanistic theories. We summarize key insights gleaned from experimental and clinical studies of the KD, and focus particular attention on the role that ketone bodies, fatty acids, and limited glucose may play in seizure control. Chronic ketosis is anticipated to modify the tricarboxcylic acid cycle to increase GABA synthesis in brain, limit reactive oxygen species (ROS) generation, and boost energy production in brain tissue. Among several direct neuro-inhibitory actions, polyunsaturated fatty acids increased after KD induce the expression of neuronal uncoupling proteins (UCPs), a collective up-regulation of numerous energy metabolism genes, and mitochondrial biogenesis. These effects further limit ROS generation and increase energy production. As a result of limited glucose and enhanced oxidative phosphorylation, reduced glycolytic flux is hypothesized to activate metabolic K ATP channels and hyperpolarize neurons and/or glia. Although it is unlikely that a single mechanism, however well substantiated, will explain all of the diet's clinical benefits, these diverse, coordinated changes seem poised to stabilize synaptic function and increase the resistance to seizures throughout the brain. Key Words: Ketogenic dietEpilepsy-Metabolism-Polyunsaturated fatty acids.The ketogenic diet (KD) is a high-fat, low-protein, lowcarbohydrate diet that has been employed as a treatment for medically refractory epilepsy for 86 years. The "classic" KD is based upon consumption of long-chain saturated triglycerides (LCTs) in a 3:1-4:1 ketogenic diet ratio (KD ratio) of fats to carbohydrates + protein (by weight). The vast majority of calories (>90%) are derived from fat. While clinical implementation of the KD has varied from center to center (Kossoff and McGrogan, 2005), diet treatment generally begins with a period of fasting followed by gradual increase in calories to a target KD ratio of 3:1-4:1. This is conducted in the inpatient setting over the course of several days, where blood glucose, urine ketones, and several other metabolic variables are closely monitored. The hallmark feature of KD treatment is the production of ketone bodies by the liver. Ketone bodies provide an alternative substrate to glucose for energy utilization, and in developing brain, also constitute essential building blocks for biosynthesis of cell membranes and lipids.While the clinical effectiveness of the KD is widely accepted, surprisingly little is understood about its under-

No abstract

Summary:Purpose: The ketogenic diet (KD) is an effective treatment for intractable epilepsy. However, little is known about its underlying mechanisms.Methods: In this study, in vivo extracellular field responses to angular bundle stimulation were recorded in the dentate gyrus of Sprague-Dawley rats fed one of three diets: ketogenic calorie-restricted (KCR), normal calorie-restricted (NCR), or normal ad libitum (NAL). Input/output curves and paired-pulse relations were used to assess network excitability. A maximal dentate activation (MDA) protocol was used to measure electrographic seizure threshold and duration.Results: Animals fed calorie-restricted (CR) diets exhibited greater paired-pulse inhibition, an elevated MDA threshold, and an absence of spreading depression-like events compared with ad libitum-fed controls. In the MDA model of epileptogenesis, the rate of increase in electrographic seizure duration after repeated stimuli was markedly reduced in KCR-fed animals compared with NCR-and NAL-fed controls.Conclusions: These data suggest that CR, by itself, can be anticonvulsant, and treatment with a KCR diet may be both anticonvulsant and antiepileptogenic.

Summary:Purpose: The purpose of this study was to test the hypothesis that a ketogenic diet would increase the resistance of rats to pentylenetetrazole (PTZ)-induced seizures and to understand the relation of ketonemia to seizure resistance.Methods: A freely consumed, high-fat (ketogenic) diet was administered to male Sprague-Dawley rats for 5-10 weeks, while control animals were fed either rodent chow or a highcarbohydrate diet. Ketonemia was measured as plasma levels of P-hydroxybutyric acid (P-OHB). Seizures were induced by tail-vein infusion of pentylenetetrazole.Results: The ketogenic diet produced a highly significant (p < 0.01) increase in P-OHB levels within 5 days. Induction ofseizures by PTZ 35 days after animals were placed on their respective diets showed that ketogenic animals had a significantly (p < 0.01) increased threshold for seizure induction compared with those fed an isocaloric diet of either highcarbohydrate or normal rodent chow. Ketogenic animals did not exhibit increased seizure severity relative to controls, despite receiving consistently higher doses of PTZ. Conclusions:The ketogenic diet resulted in an increased seizure threshold, confirming the hypothesis, and seizure threshold was found to be a direct function of the level of ketonemia. Key Words: Rat-Seizure-Threshold-Ketogenic diet-Pentylenetetrazole.Historical accounts have described improved seizure control with abstinence from food and drink (1,2). In an attempt to mimic the physiology of fasting, Wilder (3) formulated a high-fat, low-carbohydrate, low-protein diet (a ketogenic diet) to determine whether seizure control could be attained. Wilder and others subsequently showed that the ketogenic diet was an effective means for treating epilepsy in children (3-7). Despite the reported clinical success of the diet in the early years, the development of efficacious antiepileptic drugs (AEDs) led to its near-abandonment, clinically, resulting in few studies into the mechanism of action of the ketogenic diet.The purpose of this study was to determine whether a ketogenic diet would protect rats from a chemically induced seizure and to define the relation between ketonemia and seizure protection. In both clinical (8,9) and animal (10,ll) studies, ketonemia has been shown to result from consumption of high-fat diets. Huttenlocher (12) suggested that it was the basis of the seizure pro-

SUMMARYThe efficacy of the ketogenic diet (KD) develops gradually over a period of 1-3 weeks, suggesting that adaptive changes in gene expression are involved in its anticonvulsant effects. Previously, microarrays were employed to define patterns of gene expression in the hippocampus of rats maintained on either a KD or a control diet for 3 weeks. The density of mitochondria in hippocampal tissue was assessed by electron microscopy. Levels of selected energy metabolites, enzyme activities, and the effect of low glucose on synaptic transmission were also investigated in hippocampal tissue taken from either KD-or control-fed animals. We found a coordinated up-regulation of transcripts encoding energy metabolism enzymes and a dramatic 46% increase in the density of mitochondria observed in neuronal processes. These changes were accompanied by an increased phosphocreatine (PCr):creatine (Cr) energy-store ratio. Consistent with heightened energy reserves, hippocampal synaptic transmission in KD-fed animals was maintained ∼50% longer compared to controls after exposure to a mild metabolic stressor. Taken together, several lines of evidence indicate that the KD enhances energy production in the brain. As a consequence, brain tissue appears to become more resistant to metabolic stress. It is proposed . . . that the observed KD-induced enhancements in energy metabolism help to compensate for the metabolic deficits exhibited (interictally) within epileptic foci and transient failures of gamma-aminobutyric acid (GABA) ergic inhibition, which would otherwise favor the initiation and propagation of seizure activity. KEY WORDS: Ketogenic diet, Epilepsy, Microarray, Mitochondria, Hippocampus, Rat.The ketogenic diet (KD) has long been used as an alternative treatment for intractable pediatric epilepsy and is remarkably effective against multiple seizure types. It is composed of >90% fat by weight, is low in carbohydrates, adequate in proteins, vitamins, and minerals, and is typically calorie restricted by 10-25%. During diet treatment, the body synthesizes ketone bodies as an energy supplement to the brain, since dietary sources of glucose are dramatically reduced. Despite its successful use for nearly a century, we still do not know how the KD results in improved seizure control.Both clinical and experimental data suggest that adaptations to the KD underlie its anticonvulsant effects. In ro-

No abstract