2.1.1 Ketones as key mediators of seizure control

The most conspicuous metabolic change induced by a ketogenic diet is elevated blood ketone levels [7]. While it is well-documented that ketones enhance neuron energetics, accumulating evidence suggests they may also play direct and indirect roles in reducing neuron excitability, exerting direct antiseizure effects, and decreasing generation of reactive oxygen species and inflammatory mediators [7, 8, 11]. Thus, there are multiple avenues by which ketones may contribute to improved seizure control; they are not just "energy molecules" [11].

Ketones enhance intracellular adenosine triphosphate (ATP) levels and bioenergetic capacity by increasing mitochondrial oxidative phosphorylation [12]. The oxidation of acetoacetate and BHB feeds acetyl-CoA directly into the Krebs cycle


ATP = adenosine triphosphate; GABA = γ-aminobutyric acid.

Table 1.

Mechanisms through which ketogenic diets may stabilize synaptic function.

2. Ketogenic diets

Epilepsy - Advances in Diagnosis and Therapy

pH) [10].

2.1 Mechanisms of ketogenic diets in epilepsy

2.1.1 Ketones as key mediators of seizure control

ATP = adenosine triphosphate; GABA = γ-aminobutyric acid.

Mechanisms through which ketogenic diets may stabilize synaptic function.

Table 1.

148

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

Ketogenic diets appear to improve seizure control through a variety of mechanisms that collectively stabilize neuron synaptic function (Table 1) [7, 8]. It is not known whether the key mediators of improved seizure control are the ketones

The most conspicuous metabolic change induced by a ketogenic diet is elevated blood ketone levels [7]. While it is well-documented that ketones enhance neuron energetics, accumulating evidence suggests they may also play direct and indirect roles in reducing neuron excitability, exerting direct antiseizure effects, and decreasing generation of reactive oxygen species and inflammatory mediators [7, 8, 11]. Thus, there are multiple avenues by which ketones may contribute to

Ketones enhance intracellular adenosine triphosphate (ATP) levels and bioener-

getic capacity by increasing mitochondrial oxidative phosphorylation [12]. The oxidation of acetoacetate and BHB feeds acetyl-CoA directly into the Krebs cycle

Enhanced neuron energetics Enhanced neuron ATP production

Reduced neuron excitability Hyperpolarized potassium channels

Direct antiseizure effects Ketone-mediated antiseizure effects

Other mechanisms Reduced oxidative stress

Stimulated mitochondrial biogenesis

Altered glutamate to GABA ratio Increased extracellular adenosine

Raised medium-chain fatty acids Reduced glucose metabolism

Reduced inflammation

themselves, or additional metabolic changes induced by the diets [11].

improved seizure control; they are not just "energy molecules" [11].

General mechanism Specific mechanism

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 used to enhance ATP production [12].

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 reduces neuron excitability.

Studies dating back to the 1930s also support the direct antiseizure effects of 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 previously missed for methodological reasons [11].

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 mediators [18].
