title: Glutaric aciduria I: creatine supplementation restores creatinephosphate levels in mixed cortex cells from rat incubated with 3-hydroxyglutarate.
abstract: The pathogenesis of neurological sequelae in glutaric aciduria I (GA I) is still unclear. Some evidence exists for compromised energy generation in the brain of patients with GA I resulting in 'slow-onset' excitotoxicity. Previously, we have shown a reduced activity of the mitochondrial ATPsynthase in cultured mixed cortex cells from neonatal rats incubated with 2-4mM 3-hydroxyglutarate (3-OH glut) for 24h. In the present study we measured cellular contents of high energy phosphate compounds (creatinephosphate CP, ATP, and ADP) in this model after a 24h incubation period with 2-4mM glutarate (glut) or 3-OH glut. 3-OH glut specifically led to a reduction of CP content in a dose-dependent manner, whereas concentrations of ATP, ADP, and AMP remained unchanged. The drop in CP-concentration could be prevented by preincubation with the non-competitive NMDA-receptor antagonist MK 801 or coincubation with 1mM creatine. NMDA-receptor associated ion channels may be opened due to a lack of energy inside the neurons caused by a reduction of CP. This is followed by membrane depolarization which could impair electrogenic creatine transport into the cell.
authors.affiliation: Department of Pediatrics, Hanover Medical School, Hannover, Germany. das.anibh@mh-hannover.de
authors.forename: A M
authors.initials: AM
authors.lastname: Das
authors.forename: T
authors.initials: T
authors.lastname: Lücke
authors.forename: K
authors.initials: K
authors.lastname: Ullrich
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D003401:Creatine / Q000008:administration & dosage / Q000627:therapeutic use*; D005977:Glutarates / Q000008:administration & dosage* / Q000652:urine*; D008661:Metabolism, Inborn Errors / Q000188:drug therapy* / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism*; D051381:Rats
chemical_list: C108959:3-hydroxyglutaric acid; D000227:Adenine Nucleotides; D005977:Glutarates; D010725:Phosphocreatine; C035736:glutaric acid; D003401:Creatine