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Chronic treatment with glutaric acid induces partial tolerance to excitotoxicity in neuronal cultures from chick embryo telencephalons

Glutaryl-CoA dehydrogenase deficiency (GDD) is characterized biochemically by an accumulation of glutaric (GA) and 3-hydroxyglutaric (3-OH-GA) acids and clinically by the development of acute striatal degeneration. 3-OH-GA was recently shown to induce neuronal damage via N-methyl-D-aspartate (NMDA)...

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Main Authors: Kölker, Stefan (Author) , Okun, Jürgen G. (Author) , Ahlemeyer, Barbara (Author) , Wyse, Angela T.S. (Author) , Hörster, Friederike (Author) , Wajner, Moacir (Author) , Kohlmüller, Dirk (Author) , Mayatepek, Ertan (Author) , Krieglstein, Josef (Author) , Hoffmann, Georg F. (Author)
Format: Article (Journal)
Language:English
Published: 05 April 2002
In: Journal of neuroscience research
Year: 2002, Volume: 68, Issue: 4, Pages: 424-431
ISSN:1097-4547
DOI:10.1002/jnr.10189
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/jnr.10189
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/jnr.10189
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Author Notes:Stefan Kölker, Jürgen G. Okun, Barbara Ahlemeyer, Angela T.S. Wyse, Friederike Hörster, Moacir Wajner, Dirk Kohlmüller, Ertan Mayatepek, Josef Krieglstein, Georg F. Hoffmann
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Summary:Glutaryl-CoA dehydrogenase deficiency (GDD) is characterized biochemically by an accumulation of glutaric (GA) and 3-hydroxyglutaric (3-OH-GA) acids and clinically by the development of acute striatal degeneration. 3-OH-GA was recently shown to induce neuronal damage via N-methyl-D-aspartate (NMDA) receptors. The pathogenetic role of GA, however, remains unclear. We demonstrate that GA exerts a dual action in cultured chick embryo neurons. Short-term incubation with millimolar concentrations of GA induces a weak neuronal damage, adding to 3-OH-GA neurotoxicity. In contrast, chronic treatment with subtoxic, micromolar concentrations of GA results in partial tolerance to 3-OH-GA- and NMDA-induced cell damage. A downregulation of NMDA receptors, in particular of the NR2B subunit, is critically involved in this GA-induced effect, resulting in a reduced Ca2+ increase and generation of reactive oxygen species after acute exposure to NMDA or 3-OH-GA. Furthermore, GA decreases Na+/K+-ATPase activity, which is prevented by glutathione, suggesting a modulation of NMDA receptor function via resting membrane potential and Na+-dependent glutamate transport. In contrast, GA does not inhibit mitochondrial respiratory chain and β-oxidation of fatty acids, virtually excluding an activation of NMDA receptors secondary to ATP depletion. These results strongly suggest that GA modulates the NMDA receptor-mediated neurotoxicity of 3-OH-GA, providing an explanatory basis for the non-linear relationship between organic acid concentrations and disease progression in GDD patients. Furthermore, GA-induced downregulation of NMDA receptors might be involved in the delayed cerebral maturation of GDD patients, resulting in frontotemporal atrophy and a reduced opercularization, which are common neuroradiological findings in GDD patients. © 2002 Wiley-Liss, Inc.
Item Description:Gesehen am 30.03.2022
Physical Description:Online Resource
ISSN:1097-4547
DOI:10.1002/jnr.10189

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