title: 3-Hydroxyglutaric acid fails to affect the viability of primary neuronal rat cells.
abstract: Glutaric aciduria type I (GA I) is an autosomal recessive inherited metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCD) resulting in the accumulation of 3-hydroxyglutaric acid (3OHG), glutaric acid and glutaconic acid in body fluids. GA I is characterized by a specific age- and brain region-dependent neuropathology. Previous studies using organotypic slice cultures of rats and primary chick embryo telencephalon cell cultures indicated that death of neurons is a consequence of an excitotoxic mechanism induced by 3OHG. We used primary neuronal cells of neonatal rats as a model system to test cell viability after treatment with 3OHG. Western blot analysis was used to prove the expression of functional N-methyl-D-aspartate (NMDA) receptors revealing no alteration in the expression of NMDA-2a and -2b receptor subtypes in response to 3OHG. When neuronal cells cultured for 10 or 20 days were treated with 1 mM glutamate, the viability of cells was reduced by 40%. This effect could be prevented by coincubation with the NMDA receptor antagonist MK801. In contrast, incubation of cells with 3OHG for up to 24 h in concentrations of 4-8 mM did not cause increased cell death as compared with untreated control cultures. These results indicate that 3OHG is not excitotoxic in this model of neuronal rat cell cultures despite the presence of functional NMDA receptors. Therefore, alternative or additional pathomechanisms than excitotoxicity may be relevant for neurodegeneration in GA I.
authors.affiliation: University Children's Hospital Hamburg-Eppendorf, D-20246 Hamburg, Germany. ffreudenberg@rics.bwh.harvard.edu
authors.forename: F
authors.initials: F
authors.lastname: Freudenberg
authors.forename: Z
authors.initials: Z
authors.lastname: Lukacs
authors.forename: K
authors.initials: K
authors.lastname: Ullrich
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005977:Glutarates / Q000494:pharmacology*; D050770:Glutaryl-CoA Dehydrogenase; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: C108959:3-hydroxyglutaric acid; D000143:Acids; D005977:Glutarates; D016194:Receptors, N-Methyl-D-Aspartate; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050770:Glutaryl-CoA Dehydrogenase