Isovaleric, methylmalonic, and propionic acid decrease anesthetic EC50 in tadpoles, modulate glycine receptor function, and interact with the lipid 1,2-dipalmitoyl-Sn-glycero-3-phosphocholine.

Abstract

Elevated concentrations of isovaleric (IVA), methylmalonic (MMA), and propionic acid are associated with impaired consciousness in genetic diseases (organic acidemias). We conjectured that part of the central nervous system depression observed in these disorders was due to anesthetic effects of these metabolites. We tested three hypotheses. First, that these metabolites would have anesthetic-sparing effects, possibly being anesthetics by themselves. Second, that these compounds would modulate glycine and gamma-aminobutyric acid (GABA(A)) receptor function, increasing chloride currents through these channels as potent clinical inhaled anesthetics do. Third, that these compounds would affect physical properties of lipids. Anesthetic EC(50)s were measured in Xenopus laevis tadpoles. Glycine and GABA(A) receptors were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. Pressure-area isotherms of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) monolayers were measured with and without added organic acids. IVA acid was an anesthetic in tadpoles, whereas MMA and propionic acid decreased isoflurane's EC(50) by half. All three organic acids concentration-dependently increased current through alpha(1) glycine receptors. There were minimal effects on alpha(1)beta(2)gamma(2s) GABA(A) receptors. The organic acids increased total lateral pressure (surface pressure) of DPPC monolayers, including at mean molecular areas typical of bilayers. IVA, MMA, and propionic acid have anesthetic effects in tadpoles, positively modulate glycine receptor function and affect physical properties of DPPC monolayers.