Document Detail

Maturation-dependent neurotoxicity of 3-hydroxyglutaric and glutaric acids in vitro: a new pathophysiologic approach to glutaryl-CoA dehydrogenase deficiency.
MedLine Citation:
PMID:  10759157     Owner:  NLM     Status:  MEDLINE    
Glutaryl-CoA dehydrogenase deficiency is a neurometabolic disorder with a specific age- and region-dependent neuropathology. Between 6 and 18 mo of age, unspecific illnesses trigger acute encephalopathic crises resulting in acute striatal and cortical necrosis. We hypothesized that acute brain damage in glutaryl-CoA dehydrogenase deficiency is caused by the main pathologic metabolites 3-hydroxyglutaric and glutaric acids through an excitotoxic sequence. Therefore, we investigated the effect of 3-hydroxyglutaric acid and glutaric acid on primary neuronal cultures from chick embryo telencephalons and mixed neuronal and glial cell cultures from neonatal rat hippocampi. Exposure to glutaric acid and 3-hydroxyglutaric acid decreased cell viability in a concentration- and time-dependent fashion. This neurotoxic effect could be totally prevented by preincubation with an N-methyl-D-aspartate receptor subunit 2B (NR2B)-specific antagonist, NR2B antibodies, and an unspecific N-methyl-D-aspartate receptor blocker and was partially blocked with an NR2A-specific antagonist but not with NR2A antibodies or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor and metabotropic glutamate receptor antagonists. Furthermore, metabolite toxicity increased in parallel with the increasing expression of the NR2B subunit on cultured neurons from second to sixth day in vitro. We conclude from these results that 3-hydroxyglutaric acid and glutaric acid act as false neurotransmitters, in particular through NR1/2B, and that the extent of induced neurotoxicity is dependent on the temporal and spatial expression of NR1/2B in the CNS during maturation. Beyond favorable implications for treatment and long-term prognosis, glutaryl-CoA dehydrogenase deficiency is the first neurologic disease in which specific neuropathology could be experimentally linked to ontogenetic expression of a particular neurotransmitter receptor subtype.
S Kölker; B Ahlemeyer; J Krieglstein; G F Hoffmann
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pediatric research     Volume:  47     ISSN:  0031-3998     ISO Abbreviation:  Pediatr. Res.     Publication Date:  2000 Apr 
Date Detail:
Created Date:  2000-06-01     Completed Date:  2000-06-01     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0100714     Medline TA:  Pediatr Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  495-503     Citation Subset:  IM    
Department of Neuropediatrics and Metabolic Diseases, University of Marburg, Federal Republic of Germany.
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MeSH Terms
Antibodies / pharmacology
Brain Diseases, Metabolic, Inborn / enzymology*,  pathology
Cells, Cultured
Chick Embryo
Dizocilpine Maleate / pharmacology
Glutarates / antagonists & inhibitors,  toxicity*
Glutaryl-CoA Dehydrogenase
Neurons / drug effects*
Oxidoreductases / deficiency*
Oxidoreductases Acting on CH-CH Group Donors*
Piperidines / pharmacology
Reg. No./Substance:
0/3-hydroxyglutaric acid; 0/Antibodies; 0/Glutarates; 0/Piperidines; 110-94-1/glutaric acid; 23210-56-2/ifenprodil; 77086-22-7/Dizocilpine Maleate; EC 1.-/Oxidoreductases; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors; EC Dehydrogenase

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