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) 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 beta-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.
Kölker
Stefan
S
Division of Metabolic and Endocrine Diseases, University Children's Hospital, Heidelberg, Germany. Stefan_Koelker@med.uni-heidelberg.de
Okun
Jürgen G
JG
Ahlemeyer
Barbara
B
Wyse
Angela T S
AT
Hörster
Friederike
F
Wajner
Moacir
M
Kohlmüller
Dirk
D
Mayatepek
Ertan
E
Krieglstein
Josef
J
Hoffmann
Georg F
GF
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D018929:Cell Culture Techniques; D002642:Chick Embryo; D015536:Down-Regulation / Q000187:drug effects; D004361:Drug Tolerance; D004591:Electrophoresis, Polyacrylamide Gel; D005977:Glutarates / Q000378:metabolism / Q000633:toxicity*; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013687:Telencephalon / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
C108959:3-hydroxyglutaric acid; D005977:Glutarates; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D000254:Sodium-Potassium-Exchanging ATPase; C035736:glutaric acid; D002118:Calcium