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Chronic treatment with glutaric acid induces partial tolerance to excitotoxicity in neuronal cultures from chick embryo telencephalons
Author(s) -
Kölker Stefan,
Okun Jürgen G.,
Ahlemeyer Barbara,
Wyse Angela T.S.,
Hörster Friederike,
Wajner Moacir,
Kohlmüller Dirk,
Mayatepek Ertan,
Krieglstein Josef,
Hoffmann Georg F.
Publication year - 2002
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10189
Subject(s) - excitotoxicity , nmda receptor , neurotoxicity , glutamate receptor , receptor , downregulation and upregulation , glutathione , chemistry , reactive oxygen species , biochemistry , biology , oxidative stress , microbiology and biotechnology , pharmacology , toxicity , organic chemistry , gene , enzyme
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 Ca 2+ 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.