RESUMO
Although the precise mechanisms underlying the CNS degeneration of patients with glutaryl-CoA dehydrogenase (GCDH) deficiency are still the subject of intense debate, many studies have highlighted that excitotoxicity plays a fundamental role in the neuropathology of this disease, particularly involving the N-methyl-D-aspartate receptor subtype of ionotropic glutamate receptors. Modulation of the glutamatergic system by these compounds involves an inhibition of glutamate uptake into synaptosomes and synaptic vesicles, and a decrease in glutamate binding. Furthermore, glutaric and 3-hydroxyglutaric acids inhibit glutamate decarboxylase, the key enzyme of GABA synthesis, and striatal GABAergic medium-spiny neurons are highly vulnerable to 3-hydroxyglutaric acid-induced neurotoxicity. In conclusion, glutaric acid and 3-hydroxyglutaric acid induce an imbalance in glutamatergic and GABAergic neurotransmission.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Ácido Glutâmico/fisiologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/deficiência , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Glutaril-CoA Desidrogenase , Humanos , Neurotoxinas/metabolismoRESUMO
Glutaryl-CoA dehydrogenase deficiency is an inherited neurometabolic disease complicated by precipitation of acute encephalopathic crises during a vulnerable period of brain development. These crises result in bilateral striatal damage and subsequently a dystonic dyskinetic movement disorder. In previous in vitro studies neuronal damage in this disease has been linked to an excitotoxic mechanism mediated in particular by one of the accumulating metabolites, 3-hydroxyglutaric acid. However, nothing is known about the in vivo effects of this organic acid. In the present study, we used a stereotaxic intrastriatal injection technique to investigate the behavioral and neurotoxic effects of 3-hydroxyglutaric acid exposure in rats. Here, we report that 3-hydroxyglutaric acid induced an increase in convulsion frequency and duration as determined by open field measurement. Nissl-stained coronal sections from treated rats revealed a pale lesion in the striatum following 3-hydroxyglutaric acid exposure. N-methyl-D-aspartate (NMDA) receptor blockade by MK-801 and stimulation of GABA(A) receptors by muscimol prevented the induction of convulsions and striatal damage by 3-hydroxyglutaric acid, whereas blockade of non-NMDA receptors by 6,7-dinitroquinoxaline-2,3-dione (DNQX) was not protective. We conclude that 3-hydroxyglutaric acid induces convulsions and striatal damage via initiation of an imbalance in the excitatory glutamatergic and the inhibitory GABAergic neurotransmission, resulting in an enhanced excitatory input in striatal neurons. These results support the hypothesis of NMDA receptor-mediated excitotoxic cell damage in glutaryl-CoA dehydrogenase deficiency and represent the basis for the development of new neuroprotective treatment strategies.
Assuntos
Acil Coenzima A/deficiência , Encefalopatias Metabólicas Congênitas/metabolismo , Glutaratos/toxicidade , Neostriado/efeitos dos fármacos , Neurotoxinas/toxicidade , Convulsões/induzido quimicamente , Animais , Encefalopatias Metabólicas Congênitas/patologia , Encefalopatias Metabólicas Congênitas/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Agonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , Ácido Glutâmico/metabolismo , Masculino , Neostriado/patologia , Neostriado/fisiopatologia , Ratos , Ratos Wistar , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/metabolismo , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/patologia , Convulsões/fisiopatologiaRESUMO
A patient with glutaric aciduria type I had an acute encephalopathic crisis despite early treatment. This report indicates that current therapeutic strategies may be insufficient for some high-risk patients and stresses the demand for new approaches in glutaric aciduria type I.
Assuntos
Encefalopatias Metabólicas Congênitas/terapia , Glutaratos/metabolismo , Erros Inatos do Metabolismo/terapia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Oxirredutases/deficiência , Doença Aguda , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/dietoterapia , Glutaril-CoA Desidrogenase , Homozigoto , Humanos , Lactente , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/dietoterapia , Resultado do TratamentoRESUMO
A variety of extracellular matrix (ECM) proteins have been shown to be present in the embryonic heart during the morphogenesis of the valves and membranous septa. It is not known if any specific ECM protein is required for the normal morphogenesis of these tissues, but this is of great interest since there is a high incidence of congenital malformations which affect valvular and septal tissues. Interestingly, the alpha 1 and alpha 2 genes of type VI collagen are located within the region of human chromosome 21 thought to be involved in the congenital heart defect phenotype associated with trisomy 21 (Down's syndrome). In this study we examined the distribution and investigated the function of type VI collagen in the cardiac valves and septa of chicken and mouse embryos during various stages of development. Immunohistochemical and in situ hybridization studies revealed a pattern of cardiac expression of type VI collagen which is present from the earliest stages of valve and septum development through the neonatal period. Results from an in vitro bioassay suggest that type VI collagen may play a role in the formation and migration of specific cells in the forming valves and septa. These data support molecular genetic studies which have indicated that type VI collagen is involved in the heart defect phenotype seen in trisomy 21.