2. Ketogenic diets

In essence, a ketogenic diet is any high-fat, adequate-protein, low-carbohydrate diet that forces the body to burn fats—not carbohydrates—as the primary energy source [7, 8]. During this process, the liver converts fats into ketone bodies, or "ketones" (organic molecules that readily serve as energy substrates for non-hepatic organs, particularly brain, heart, and skeletal muscle) [9]. The three endogenous ketones are acetone, acetoacetate, and beta-hydroxybutyrate (BHB) [7]; BHB is the primary blood ketone. During a sustained ketogenic diet, the blood BHB level is elevated, and lies within the range of 0.5–8 mmol/L, constituting a state of "physiological ketosis" (in contrast to pathological ketoacidosis, which is associated with a blood BHB level of 15–20 mmol/L or higher, and a concomitant lowering of blood pH) [10].

through anaplerosis (the replenishing of depleted metabolic cycle intermediates) [7], which increases the turnover of the Krebs cycle, generating additional protons and electrons that are channeled to the electron transport chain where they may be

Ketones may also inhibit neuronal excitability. ATP-dependent potassium channels, which hyperpolarize the cell membrane, are activated by ketones, decreasing spontaneous cell firing rates [13]. Moreover, acetoacetate concentrations well within the range produced by a ketogenic diet inhibit vesicle loading of the excitatory neurotransmitter glutamate, resulting in reduced glutamate release into the synapse and enhanced synthesis of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) [14]. It is thought that the ensuing altered glutamate to GABA ratio

Studies dating back to the 1930s also support the direct antiseizure effects of

Lastly, ketones may influence seizure control by lowering cell oxidative stress and inflammation [11]. BHB inhibits histone deacetylases (enzymes that remove acetyl groups from lysine residues on histones, allowing DNA to wrap tightly and preventing gene expression), resulting in upregulated anti-oxidant genes and reduced oxidative stress in kidney cells [17]. Moreover, BHB inhibits the assembly of the immune sensor nucleotide oligomerization domain (NOD)-like receptor protein 3, a multi-protein complex that controls the release of various inflammatory

Emerging evidence suggests that a number of additional metabolic changes induced by ketogenic diets may also contribute to enhanced neuron energetics, reduced neuron excitability, and direct antiseizure effects, improving seizure

Ketogenic diets can improve seizure control in patients with mitochondrial disorders [19]. This observation may be partly explained by the action of the medium-chain fatty acid, decanoic acid, on peroxisomal proliferator-activated receptor γ, which stimulates neuronal mitochondrial biogenesis [19]. The increased mitochondrial biomass enhances neuron ATP production capacity and cell energy

Ketogenic diets may also alter brain levels of the neurotransmitter adenosine. The disruption of adenosine signaling induces seizures; this effect is reversible by a ketogenic diet [20]. This observation suggests that the diet increases extracellular adenosine levels, activating inhibitory adenosine A1 receptors and reducing neuron

Lastly, ketogenic diets may exert direct antiseizure effects by raising mediumchain fatty acid levels and decreasing glucose metabolism [7, 8]. The medium-chain fatty acid, decanoic acid, blocks seizure-like activity in animals [21]. Moreover, since the antiseizure effects of ketogenic diets can be rapidly reversed by glucose infusions, decreased glucose metabolism is thought to contribute to seizure control. The mechanism for this effect could be partially explained by the observation that ketogenic diets induce a reduction in glycolysis, subsequently repressing the expression of brain-derived neurotrophic factor, a known pro-convulsant [7].

ketones [15, 16]. In mice, acetone and acetoacetate raise seizure thresholds, resulting in fewer seizures [15, 16]. Although BHB did not appear to contribute to antiseizure effects in these earlier studies, more recent studies indicate that BHB probably does play a direct antiseizure role, and that its effects may have been

used to enhance ATP production [12].

DOI: http://dx.doi.org/10.5772/intechopen.83711

Ketogenic Diet Therapies in Children and Adults with Epilepsy

previously missed for methodological reasons [11].

2.1.2 Additional metabolic changes that may mediate seizure control

reduces neuron excitability.

mediators [18].

control [7, 8].

reserves.

149

hyperexcitability [7].
