title: Cerebral organic acid disorders induce neuronal damage via excitotoxic organic acids in vitro.
abstract: Glutaryl-CoA dehydrogenase deficiency (GDD), which is one of the most frequent organic acid disorders, is characterized by a specific age- and regional-dependent neuropathology. We hypothesized that the distinct brain damage in GDD could be caused by the main pathologic metabolites, the organic acids glutaric (GA) and 3-hydroxyglutaric (3-OH-GA) acids, through an excitotoxic sequence. Therefore, we investigated the effects of 3-OH-GA and GA on primary neuronal cultures from chick embryonic telencephalons. Here we report that 3-OH-GA and GA decreased cell viability concentration- and time-dependently, which could be only totally prevented by preincubation with MK-801, ifenprodil and NR2B antibodies. Furthermore, cell viability decreased in parallel with the increasing expression of NR2B subunit on cultured neurons from 2nd to 6th DIV. We conclude that GA and 3-OH-GA act as excitotoxic organic acids (EOA) specifically through NR1/NR2B and that the extent of induced neurotoxicity is dependent on NR1/NR2B expression during maturation.
authors.affiliation: Department of Neuropediatrics and Metabolic Disorders, University Children's Hospital, Marburg, Federal Republic of Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kölker
authors.forename: B
authors.initials: B
authors.lastname: Ahlemeyer
authors.forename: J
authors.initials: J
authors.lastname: Krieglstein
authors.forename: G F
authors.initials: GF
authors.lastname: Hoffmann
mesh_terms: D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D018846:Excitatory Amino Acids / Q000378:metabolism*; D005977:Glutarates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D050770:Glutaryl-CoA Dehydrogenase; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000172:deficiency*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D013687:Telencephalon / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: C108959:3-hydroxyglutaric acid; D018846:Excitatory Amino Acids; D005977:Glutarates; D010088:Oxidoreductases; D007770:L-Lactate Dehydrogenase; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050770:Glutaryl-CoA Dehydrogenase; C035736:glutaric acid