Ketone bodies in epilepsy

Abstract

Seizures that are resistant to standard medications remain a major clinical problem. One underutilized option for patients with medication-resistant seizures is the high-fat, low-carbohydrate ketogenic diet. The diet received its name based on the observation that patients consuming this diet produce ketone bodies (e.g., acetoacetate, β-hydroxybutyrate, and acetone). Although the exact mechanisms of the diet are unknown, ketone bodies have been hypothesized to contribute to the anticonvulsant and antiepileptic effects. In this review, anticonvulsant properties of ketone bodies and the ketogenic diet are discussed (including GABAergic and glutamatergic effects). Because of the importance of ketone body metabolism in the early stages of life, the effects of ketone bodies on developing neurons in vitro also are discussed. Understanding how ketone bodies exert their effects will help optimize their use in treating epilepsy and other neurological disorders.

© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Figures

Figure 1

A high-fat, low-carbohydrate ketogenic diet causes a shift in the metabolic activity of hepatocytes. Under these conditions, the Krebs cycle can not utilize the high levels of acetyl-CoA generated from fat. Remaining acetyl-CoA is converted to the ketone body acetoacetate. The two additional ketone bodies, acetone and β-hydroxybutyrate, are derived from acetoacetate by spontaneous degradation and enzymatic conversion with β-hydroxybutyrate dehydrogenase, respectively. The three ketone bodies are then released from the hepatocyte, cross the blood brain barrier, and may exert their effects in the brain. Abbreviations: CAT, carnitine-acylcarnitine translocase; ACA, acetoacetate; BHB, β-hydroxybutyrate; BBB, blood brain barrier.

Figure 2

Possible anticonvulsant effects of ketone bodies on the brain. (1) Increased GABA synthesis through alteration of glutamate cycling in glutamate-glutamine cycle or altered neuronal responsiveness to GABA at GABAA receptors. (2) Decreased glutamate release by competitive inhibition of vesicular glutamate transporters. (3) Other neurotransmitters, including norepinephrine and adenosine. (4) Increased membrane potential hyperpolarization via KATP channels possibly mediated by GABAB receptor signaling. (5) Decreased reactive oxygen species production from glutamate exposure. (6) Electron transport chain subunit transcription. Abbreviations: A1R, adenosine receptor; Cl, chloride; GLN, glutamine; GLU, glutamate; GABA, γ-aminobutyric acid ; GABABR, γ-aminobutyric acid beta receptor; GABAAR, γ-aminobutyric acid alpha receptor; VGLUT, vesicular glutamate transporter; ROS, reactive oxygen species.