title: Contribution of reactive oxygen species to 3-hydroxyglutarate neurotoxicity in primary neuronal cultures from chick embryo telencephalons.
abstract: Glutaryl-CoA dehydrogenase deficiency is an autosomal recessively inherited neurometabolic disorder with a distinct neuropathology characterized by acute encephalopathic crises during a vulnerable period of brain development. 3-Hydroxyglutarate (3-OH-GA), which accumulates in affected patients, has been identified as an endogenous neurotoxin mediating excitotoxicity via N-methyl-D-aspartate receptors. As increased generation of reactive oxygen species (ROS) and nitric oxide (NO) plays an important role in excitotoxic neuronal damage, we investigated whether ROS and NO contribute to 3-OH-GA neurotoxicity. 3-OH-GA increased mitochondrial ROS generation in primary neuronal cultures from chick embryo telencephalons, which could be prevented by MK-801, confirming the central role of N-methyl-D-aspartate receptor stimulation in 3-OH-GA toxicity. ROS increase was reduced by alpha-tocopherol and--less effectively-by melatonin. alpha-Tocopherol revealed a wider time frame for neuroprotection than melatonin. Creatine also reduced neuronal damage and ROS formation but only if it was administered >or=6 h before 3-OH-GA. NO production revealed only a slight increase after 3-OH-GA incubation. NO synthase inhibitor N(omega)-nitro-L-arginine prevented NO increase but did not protect neurons against 3-OH-GA. The NO donor S-nitroso-N-acetylpenicillamine revealed no effect on 3-OH-GA toxicity at low concentrations (0.5-5 microM), whereas it potentiated neuronal damage at high concentrations (50-500 microM), suggesting that weak endogenous NO production elicited by 3-OH-GA did not affect neuronal viability. We conclude from our results that ROS generation contributes to 3-OH-GA neurotoxicity in vitro and that radical scavenging and stabilization of brain energy metabolism by creatine are hopeful new strategies in glutaryl-CoA dehydrogenase deficiency.
authors: Division of Metabolic and Endocrine Diseases, University Children's Hospital Heidelberg, DE-69120 Heidelberg, Germany. Stefan_Koelker@med.uni-heidelberg.de
authors: S
authors: S
authors: Kölker
authors: B
authors: B
authors: Ahlemeyer
authors: J
authors: J
authors: Krieglstein
authors: G F
authors: GF
authors: Hoffmann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D003401:Creatine / Q000494:pharmacology; D005977:Glutarates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D017382:Reactive Oxygen Species; D013687:Telencephalon / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D014810:Vitamin E / Q000494:pharmacology
chemical_list: C108959:3-hydroxyglutaric acid; D005977:Glutarates; D017382:Reactive Oxygen Species; D014810:Vitamin E; D009569:Nitric Oxide; D003401:Creatine