Abstract
Glutaric acidaemia type I (GA I) may be associated with elevated concentrations of glutaric, 3-hydroxyglutaric and glutaconic acids in blood and urine. Elevated concentrations of glutaric acid (about I mmol/L) (Goodman et al 1977) and 3-hydroxyglutaric acid (Land et al 1992) were also detected in brain tissue. Morphological examinations of the brain reveal atrophy of frontal and temporal lobes, the nucleus caudatus and putamen. The concept of excitotoxicity describes the potential cell damage induced by excitatory amino acids like glutamate (via N-methyl-D-aspartate (NMDA) and non-NMDA receptors). Excessive activation of glutamate receptors can be mediated by either elevated agonist concentrations or cellular energy depletion even in the presence of normal agonist concentrations (Olney 1980). Excitotoxic mechanisms may be suspected to lead to neuronal degeneration in GA I as glutaric acid inhibits glutamate uptake into synaptosomes (Bennett et al 1973) and glutaric, 3-hydroxyglutaric, and glutaconic acids inhibit glutamate decarboxylase, the enzyme which produces γ-aminobutyric acid (GABA) (Stokke et al 1976). In addition, post-synaptic vacuolization, characteristic of excitotoxic neuronal death, has been described in post-mortem examination of brain tissue (cortex and striatum) (Goodman et al 1977). In organotypic slice cultures from rat brain expressing different glutamate receptor subtypes (Gahwiler 1981; Vornov et al 1991), we tested whether glutaric, 3-hydroxyglutaric, or glutaconic acids are neurotoxic (normal and energy deprived conditions) and if this neurotoxicity is related to excitotoxic mechanisms. In addition, the effect of glutaric, 3-hydroxyglutaric and glutaconic acids on glutamate receptor-mediated membrane currents was investigated in frog oocytes expressing different glutamate receptor subtypes (Musshoff et al 1994).
Published Version
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