Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency.
J Neurochem
; 97(3): 899-910, 2006 May.
Article
em En
| MEDLINE
| ID: mdl-16573641
ABSTRACT
Glutaric acid (GA) and 3-hydroxyglutaric acids (3-OH-GA) are key metabolites in glutaryl co-enzyme A dehydrogenase (GCDH) deficiency and are both considered to be potential neurotoxins. As cerebral concentrations of GA and 3-OH-GA have not yet been studied systematically, we investigated the tissue-specific distribution of these organic acids and glutarylcarnitine in brain, liver, skeletal and heart muscle of Gcdh-deficient mice as well as in hepatic Gcdh-/- mice and in C57Bl/6 mice following intraperitoneal loading. Furthermore, we determined the flux of GA and 3-OH-GA across the blood-brain barrier (BBB) using porcine brain microvessel endothelial cells. Concentrations of GA, 3-OH-GA and glutarylcarnitine were significantly elevated in all tissues of Gcdh-/- mice. Strikingly, cerebral concentrations of GA and 3-OH-GA were unexpectedly high, reaching similar concentrations as those found in liver. In contrast, cerebral concentrations of these organic acids remained low in hepatic Gcdh-/- mice and after intraperitoneal injection of GA and 3-OH-GA. These results suggest limited flux of GA and 3-OH-GA across the BBB, which was supported in cultured porcine brain capillary endothelial cells. In conclusion, we propose that an intracerebral de novo synthesis and subsequent trapping of GA and 3-OH-GA should be considered as a biochemical risk factor for neurodegeneration in GCDH deficiency.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
/
Barreira Hematoencefálica
/
Doenças Neurodegenerativas
/
Glutaril-CoA Desidrogenase
/
Glutaratos
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article