RESUMO
This study was aimed at investigating the anticonvulsant activity of lipoic acid (LA) against pilocarpine-induced seizures as well as the effects of this metabolic antioxidant on the hippocampal extracellular concentrations of amino acid neurotransmitters glutamate, aspartate, glycine and glutamate and γ-aminobutyric acid (GABA). In vivo microdialysis demonstrated that an intraperitoneal administration of pilocarpine induced a pronounced increment of hippocampal glutamate and aspartate concentrations, whereas no significant change was observed in the levels of glycine or GABA. LA (10, 20 or 30 mg/kg) pretreatment completely blocked pilocarpine-evoked increases in extracellular glutamate and aspartate concentrations. Significant reductions in hippocampal GABA and glycine concentrations were also observed although not as pronounced as those shown by glutamate and aspartate. Based on the finding that LA protected rats against pilocarpine-induced seizures, it could be suggested that the reduction in inhibitory amino acid neurotransmitters levels was comparatively minor and offset by a more pronounced reduction in glutamate and aspartate extracellular concentrations. Therefore, the fact that LA could drastically reduce pilocarpine-induced increases in glutamate and aspartate should account, at least partly, for its anticonvulsant activity observed in pilocarpine-induced seizure in rats.
Assuntos
Aminoácidos Excitatórios/líquido cefalorraquidiano , Hipocampo/metabolismo , Pilocarpina/farmacologia , Convulsões/metabolismo , Ácido Tióctico/farmacologia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Ácido Aspártico/líquido cefalorraquidiano , Diálise/métodos , Ácido Glutâmico/líquido cefalorraquidiano , Glicina/líquido cefalorraquidiano , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/mortalidade , Convulsões/fisiopatologia , Convulsões/prevenção & controle , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/mortalidade , Estado Epiléptico/fisiopatologia , Estado Epiléptico/prevenção & controle , Análise de Sobrevida , Ácido Tióctico/uso terapêutico , Ácido gama-Aminobutírico/líquido cefalorraquidianoRESUMO
A hiperglicemia näo-cetótica é uma doença genética, de herança autossômica recessiva, que causa distúrbios graves em recém-nascidos, podem levar à morte. Níveis aumentados de glicina no cérebro produzem lesäo neurológica irreversível. O diagnóstico clínico é confirmado por cromatografia líquida (HPLC), comparando-se os níveis de glicina em plasma e líquido cefalorraquidiano - uma relaçäo LCR/plasma maior do que 0,09 fecha o diagnóstico. O presente estudo relata dois casos de hiperglicemia neonatal com quadro clínico e evoluçäo neurológica semelhantes. Nos dois casos, os sintomas começaram nas primeiras 48 horas de vida, e näo havia antecedentes familiares, pré-natais ou perinatais. Os dois recém-nascidos apresentaram boas condiçöes ao nascimento. Além disso, em ambos os casos, o daignóstico laboratorial (HPLC) foi bastante tardio: as amostras de sangue total e liquor foram colhidas 55§ e no 17§ dia, respectivamente. As concentraçöes de glicina em LCR e plasma, e a relaçäo LCR/plasma, foram (em mg/dl), para as crianças número 1 e número 2, repectivamente: 2,8 e 3,3 (R=0,85); 2,4 e 8 (r=0,3). Muito embora os recém-nascidos tenham permanecido em unidade de terapia intensiva e suporte ventilatório e tenham sido medicados com benzoato de sódio e diazepam, o diagnóstico tardio da hiperglicinemia acarretou lesöes neurológicas graves e irreversíveis nas duas crianças. No entanto, a importância do diagnóstico laboratorial para o aconselhamento genético dos dois casais é inquestionável
Assuntos
Humanos , Recém-Nascido , Convulsões/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Glicina/metabolismo , Deficiência Intelectual/etiologia , Cromatografia Líquida , Glicina/sangue , Glicina/líquido cefalorraquidiano , Recém-NascidoRESUMO
BACKGROUND: Excitotoxicity is an important mechanism in secondary neuronal injury after traumatic brain injury (TBI). Excitatory amino acids (EAAs) are increased in cerebrospinal fluid (CSF) in adults after TBI; however, studies in pediatric head trauma are lacking. We hypothesized that CSF glutamate, aspartate, and glycine would be increased after TBI in children and that these increases would be associated with age, child abuse, poor outcome, and cerebral ischemia. METHODS: EAAs were measured in 66 CSF samples from 18 children after severe TBI. Control samples were obtained from 19 children who received lumbar punctures to rule out meningitis. RESULTS: Peak and mean CSF glycine and peak CSF glutamate levels were increased versus control values. Subgroups of patients with TBI were compared by using univariate regression analysis. Massive increases in CSF glutamate were found in children <4 years old and in child abuse victims. Increased CSF glutamate and glycine were associated with poor outcome. A trend toward an association between high glutamate concentration and ischemic blood flow was observed. CONCLUSIONS: CSF EAAs are increased in infants and children with severe TBI. Young age and child abuse were associated with extremely high CSF glutamate concentrations after TBI. A possible role for excitotoxicity after pediatric TBI is supported.
Assuntos
Ácido Aspártico/líquido cefalorraquidiano , Lesões Encefálicas/líquido cefalorraquidiano , Lesões Encefálicas/etiologia , Ventrículos Cerebrais , Maus-Tratos Infantis , Aminoácidos Excitatórios/líquido cefalorraquidiano , Ácido Glutâmico/líquido cefalorraquidiano , Glicina/líquido cefalorraquidiano , Adolescente , Fatores Etários , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/mortalidade , Isquemia Encefálica/etiologia , Estudos de Casos e Controles , Criança , Maus-Tratos Infantis/estatística & dados numéricos , Pré-Escolar , Pessoas com Deficiência/estatística & dados numéricos , Escala de Coma de Glasgow , Escala de Resultado de Glasgow , Humanos , Lactente , Prognóstico , Análise de Sobrevida , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
A 16-year-old boy had intermittent chorea, delirium, and vertical gaze palsy precipitated by febrile illness. Nonketotic hyperglycinemia was confirmed by measurement of liver and lymphoblast glycine cleavage enzyme activity. Deficient but residual enzyme activity was demonstrated in both tissues, possibly accounting for the mild phenotype. Confirmation of an atypical variant of nonketotic hyperglycinemia with residual glycine cleavage enzyme activity has important implications for diagnosis and treatment.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Glicina/sangue , Glicina/líquido cefalorraquidiano , Adolescente , Humanos , Cariotipagem , Fígado/enzimologia , Masculino , FenótipoRESUMO
A 13-year-old girl with early-onset, mild, slowly progressive mental retardation caused by nonketotic hyperglycinemia is described. The plasma and cerebrospinal fluid glycine concentrations were elevated, but the cerebrospinal fluid/plasma glycine ratio was only mildly elevated. The diagnosis was confirmed by demonstration of a defect in the activity of the glycine cleavage system in cultured lymphoblasts.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Glicina/sangue , Linfócitos/metabolismo , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/líquido cefalorraquidiano , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Células Cultivadas/metabolismo , Feminino , Glicina/líquido cefalorraquidiano , Humanos , Deficiência Intelectual/sangue , Deficiência Intelectual/diagnósticoRESUMO
To test the hypothesis that nonketotic hyperglycinemia causes overstimulation of the excitatory N-methyl-D-aspartate receptor by allosteric glycine activation, and that reduction of glycine and blocking of the cation channel coupled to the receptor would be beneficial, we administered benzoate and dextromethorphan, a blocker of the N-methyl-D-aspartate channel to an infant with nonketotic hyperglycinemia. Therapy with benzoate, 500 mg/kg per day, was started on day 5, and the dosage was increased to 750 mg/kg per day on day 8, with prompt normalization of the neurologic and electroencephalographic findings. The glycine concentrations in both plasma and cerebrospinal fluid were substantially reduced. Dextromethorphan was added to the regimen on day 12. The electroencephalogram remained normal until the infant was 8 months of age, when diffuse slowing became apparent. Serial brain magnetic resonance imaging showed delayed myelination. At 12 months of age, physical examination findings and growth were normal except for hypotonia. The developmental quotient was approximately 60, and the child was free of seizures. This outcome, although not ideal, is better than that typical for nonketotic hyperglycinemia. Our results suggest that trials with additional patients and other N-methyl-D-aspartate cation channel blockers are warranted.
Assuntos
Benzoatos/uso terapêutico , Dextrometorfano/uso terapêutico , Glicina/sangue , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Benzoatos/sangue , Ácido Benzoico , Dextrometorfano/administração & dosagem , Eletroencefalografia/efeitos dos fármacos , Glicina/líquido cefalorraquidiano , Humanos , Lactente , Recém-Nascido , Cetose , Masculino , Erros Inatos do Metabolismo/tratamento farmacológico , Exame Neurológico , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
The molecular nature of the glycine cleavage system was investigated in eight patients with typical (neonatal) and two patients with atypical (late onset) nonketotic hyperglycinemia (NKH). The overall activity of the glycine cleavage system was found to be decreased in all of the liver and brain tissue studied, but it was undetectable or extremely low in typical NKH, whereas there was some residual activity in atypical NKH. Six patients with typical NKH had a specific defect in the P protein, and one a defect in the T protein; the activity of the T protein was defective in one patient with atypical NKH.