Anesthetic properties of the ketone bodies β-hydroxybutyric acid and acetone

BACKGROUND: We tested the hypothesis that two metabolites that are elevated in ketosis (β-hydroxybutyric acid, and acetone) modulate ion channels in a manner similar to anesthetics and produce anesthesia in animals. METHODS: α1β2γ2sγ-aminobutyric acid type A (GABAA), α1 glycine, NR1/NR2A N-methyl-d-aspartate, and two pore domain TRESK channels were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. The effect of β hydroxybutyric acid and acetone on channel function was measured. The anesthetic effects of these drugs were measured in X. laevis tadpoles. RESULTS: Both β hydroxybutyric acid and acetone enhanced glycine receptor function in the concentration range that is obtained in ketoacidosis in humans. Beta hydroxybutyric acid also enhanced GABAA receptor function at these concentrations. Both acetone and β-hydroxybutyric acid anesthetized tadpoles, with an EC50 for acetone of 264 ± 2 mM (mean ± se) and for β-hydroxybutyric acid of 151 ± 11 mM at pH 7.0. Acetone enhanced GABAA receptors at concentrations of 50 mM and above. Inhibition of TRESK channel function was seen with 100 mM acetone or larger concentration. N-methyl-D-aspartate receptor function was inhibited at concentrations of acetone of 200 mM and larger. CONCLUSIONS: Beta hydroxybutyric acid and acetone are anesthetics. Both ketone bodies enhance inhibitory glycine receptors at concentrations observed clinically in ketoacidosis. In addition, β-hydroxybutyric acid enhances GABAA receptor function at these concentrations. Subanesthetic concentrations of these drugs may contribute to the lethargy and impairment of consciousness seen in ketoacidosis.