4‐Hydroxy‐trans‐2‐nonenoic acid is a γ‐hydroxybutyrate receptor ligand in the cerebral cortex and hippocampus

Elevated production of 4-hydroxy-trans-2-nonenal (HNE) occurs in numerous neurological disorders involving oxidative damage. HNE is metabolized to the non-toxic 4-hydroxy-trans-2-nonenoic acid (HNEAcid) by aldehyde dehydrogenases in the rat cerebral cortex. Based upon the structural similarity of HNEAcid to ligands of the gamma-hydroxybutyrate (GHB) receptor, we hypothesized that HNEAcid is an endogenous ligand for the GHB receptor. HNEAcid displaced the specific binding of the GHB receptor ligand (3)H-NCS382 (30 nm) in membrane preparations of human frontal cerebral cortex and whole rat cerebral cortex with IC(50s) of 3.9 +/- 1.1 and 5.6 +/- 1.2 micro m, respectively. Inhibition was attenuated when the carboxyl group of HNEAcid was replaced with an aldehyde or an alcohol. HNEAcid (300 micro m) did not displace the binding of beta-adrenergic receptor and GABA(B) receptor antagonists, demonstrating the selectivity of HNEAcid for the GHB receptor. HNEAcid is formed in homogenates of human frontal cortical gray matter in an NAD(+)-dependent (V(Max), 0.71 nmol/min/mg) and NADP(+)-dependent (V(Max), 0.12 nmol/min/mg) manner. Lastly, (3)H-NCS382 binding is elevated 2.7-fold with age in the cerebral cortex of rats. Our data demonstrate that an HNE metabolite, formed in rat and human brain, is a signaling molecule analogous to other bioactive lipid peroxidation products.