Inhibition of in vitro CO2 production and lipid synthesis by 2-hydroxybutyric acid in rat brain

2-Hydroxybutyric acid appears at high concentrations in situations related to deficient energy metabolism (e,g., birth asphyxia) and also in inherited metabolic diseases affecting the central nervous system during neonatal de velopment, such as "cerebral" lactic acidosis, glutaric aciduria type II, d ihydrolipoyl dehydrogenase (E-3) deficiency, and propionic acidemia. The pr esent study was carried out to determine the effect of 2-hydroxybutyric aci d at various concentrations (1-10 mM) on CO2 production and lipid synthesis from labeled substrates in cerebral cortex of 30-day-old Wistar rats in vi tro. CO2 production was significantly inhibited (30-70%) by 2-hydroxybutyri c acid in cerebral cortex prisms, in total homogenates and in the mitochond rial fraction. We also demonstrated a significant inhibition of lipid synth esis (20-45%) in cerebral cortex prisms and total homogenates in the presen ce of 2-hydroxybutyric acid. However, no inhibition of lipid synthesis occu rred in homogenates free of nuclei and mitochondria. The results indicate a n impairment of mitochondrial energy metabolism caused by 2-hydroxybutyric acid, a fact that may secondarily lead to reduction of lipid synthesis. It is possible that these findings may be associated with the neuropathophysio logy of the situations where 2-hydroxybutyric acid is accumulated.