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

• Verfasst von: Kölker, Stefan [VerfasserIn]
• Verfasst von: Okun, Jürgen G. [VerfasserIn]
• Verfasst von: Ahlemeyer, Barbara [VerfasserIn]
• Verfasst von: Wyse, Angela T.S. [VerfasserIn]
• Verfasst von: Hörster, Friederike [VerfasserIn]
• Verfasst von: Wajner, Moacir [VerfasserIn]
• Verfasst von: Kohlmüller, Dirk [VerfasserIn]
• Verfasst von: Mayatepek, Ertan [VerfasserIn]
• Verfasst von: Krieglstein, Josef [VerfasserIn]
• Verfasst von: Hoffmann, Georg F. [VerfasserIn]
• Titel: Chronic treatment with glutaric acid induces partial tolerance to excitotoxicity in neuronal cultures from chick embryo telencephalons
• Verf.angabe: Stefan Kölker, Jürgen G. Okun, Barbara Ahlemeyer, Angela T.S. Wyse, Friederike Hörster, Moacir Wajner, Dirk Kohlmüller, Ertan Mayatepek, Josef Krieglstein, Georg F. Hoffmann
• E-Jahr: 2002
• Jahr: 05 April 2002
• Umfang: 7 S.
• Fussnoten: Gesehen am 30.03.2022
• Titel Quelle: Enthalten in: Journal of neuroscience research
• Ort Quelle: New York, NY [u.a.] : Wiley-Liss, 1975
• Jahr Quelle: 2002
• Band/Heft Quelle: 68(2002), 4, Seite 424-431
• ISSN Quelle: 1097-4547
• DOI: doi:10.1002/jnr.10189
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: calcium
• Sach-SW: glutaryl-CoA dehydrogenase
• Sach-SW: Na+/K+-ATPase
• Sach-SW: NMDA receptor
• Sach-SW: reactive oxygen species
• Sach-SW: respiratory chain
• K10plus-PPN: 1797039733

Abstract

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.