Formation of gamma-hydroxybutyrate in brain.

Abstract

Abstract— Gamma‐hydroxybutyric acid is a neuroactive compound which has been found to be a normal constituent of mammalian brain. The present report characterized enzymatic activity in brain forming gamma‐hydroxybutyrate (GHB) from succinic semialdehyde (SSA). When NADPH served as cofactor, whole brain homogenate was capable of forming nearly 300 nmol GHB/min/g brain when enzyme activity was measured at 37°C. GHB production was significantly less (50%) when NADH was the cofactor. A regional localization of these activities indicated that the cerebellum and septal area contained the highest capacity to form GHB in the presence of NADPH; intermediate to high activity was found in the cortex, medulla, superior colliculus and corpus striatum; low activity was present in the inferior colliculus, thalamus, pons, hippocampus, substantia nigra and hypothalamus. Activity in the presence of NADH was rather evenly distributed with the exceptions of the cerebellum and inferior colliculus, which contained high and low activity respectively. Both NADPH‐ and NADH‐dependent activities were found primarily in the cytosol. Pentobarbital inhibited enzyme activity and enzyme activity was differentiated from lactic dehydrogenase and alcohol dehydrogenase by use of specific inhibitors. In addition, mixed substrate experiments and kinetic analysis provided evidence for the presence of two reversible NADPH‐dependent enzymes capable of producing GHB from SSA.