3-Hydroxyglutaric and glutaric acids are neurotoxic through NMDA receptors in vitro.

Abstract

Glutaryl-CoA dehydrogenase deficiency (GDD; McKusick 231670) causes an accumulation of 3-hydroxyglutaric (30H-GA) and glutaric (GA) acids in body fluids as well as brain tissue (Baric et al 1998; Goodman et al 1977). Typically between the 6th and 18th months of age, intercurrent illness or even a routine immunization can trigger an acute encephalitis-like encephalopathic crisis that leads to an irreversible bilateral striatal destruction and consequently to a severe dystonic-dyskinetic disorder with loss of previously acquired motor skills (Hoffmann et al 1991, 1996). Although the biochemical and clinical features of GDD are well described, the mechanism of age- and regional-specific neuronal damage remains unclear. Substantial evidence points to an excitotoxic sequence in GDD: GA and 30H-GA exhibit structural similarities to the excitotoxic amino acid glutamate, and post-mortem examination of brain tissue of GDD patients revealed postsynaptic vacuolation in striatum and cortex similar to that of glutamate-mediated damage (Goodman et al 1977). A previous study using organotypic rat brain slice cultures showed a neurotoxic effect of 30H-GA, though at high concentrations (> 1.5 mmol/L), but not for GA, suggesting that 30H-GA is the main excitotoxin in GDD (Flott-Rahmel et al 1997). We hypothesized that the age- and regional specific brain damage in GDD could be caused by overstimulation of NMDA receptors and subsequent excitotoxic cell death. We therefore investigated the effects of the main pathological metabolites GA and 30H-GA on neuronal cultures and whether neurotoxic effects could be prevented by NMDA and non-NMDA receptor antagonists.