Assuntos
Alantoína/metabolismo , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Estresse Oxidativo/fisiologia , Ácido Úrico/metabolismo , Adulto , Alantoína/sangue , Alantoína/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidianoRESUMO
Among various hypothetical mechanisms for the in vivo production of reactive oxygen species, transition metal-catalyzed reactions in cooperation with a biologic reducing agent like ascorbic acid or superoxide may be some of the most important. In the present study, we retrospectively examined the existence of non-protein-bound metal ions, an essentially hazardous pro-oxidant form of various transition metals, and the occurrence of metal-catalyzed reactive oxygen species production in cerebrospinal fluid (CSF) of 10 infants with hypoxic ischemic encephalopathy (HIE) subsequent to perinatal asphyxia and 12 control infants within 72 h of birth. Non-protein-bound iron was detected in eight out of 10 CSF samples from the HIE infants and its level was significantly correlated with Sarnat's clinical stage, whereas none of the control infants had detectable non-protein-bound iron levels. Non-protein-bound copper was below the detection limit in all CSF samples from both groups. Ascorbic acid was significantly increased in the CSF of HIE infants when compared with that of controls (means, 664.9 versus 449.4 microM, p = 0.008). ortho-Tyrosine and meta-tyrosine, which are highly specific and sensitive markers of protein oxidation induced by hydroxyl radicals, were significantly higher in HIE infants than in controls when evaluated by the ratio relative to their source amino acid, phenylalanine [means, 110.5 versus 75.4, p = 0.018 for ortho-tyrosine/phenylalanine; 104.6 versus 67.7 (nM/microM x 10(2)), p = 0.048 for meta-tyrosine/phenylalanine]. Both ratios were significantly correlated with non-protein-bound iron, but not with ascorbic acid. Our preliminary observations provide direct evidence that hydroxyl radicals are generated in the CNS during asphyxiation. Iron chelation therapy could be worth developing as a neuroprotective strategy for perinatal asphyxia.
Assuntos
Cobre/líquido cefalorraquidiano , Hipóxia-Isquemia Encefálica/líquido cefalorraquidiano , Ferro/líquido cefalorraquidiano , Alantoína/líquido cefalorraquidiano , Ácido Ascórbico/líquido cefalorraquidiano , Biomarcadores , Ácido Desidroascórbico/líquido cefalorraquidiano , Feminino , Humanos , Radical Hidroxila/líquido cefalorraquidiano , Recém-Nascido , Masculino , Estresse Oxidativo , Ligação Proteica , Espécies Reativas de Oxigênio/líquido cefalorraquidianoAssuntos
Encéfalo/fisiopatologia , Líquido Cefalorraquidiano/química , Meningites Bacterianas/fisiopatologia , Supuração , Alantoína/líquido cefalorraquidiano , Animais , Ácido Ascórbico/líquido cefalorraquidiano , Ácido Ascórbico/uso terapêutico , Encéfalo/patologia , Líquido Cefalorraquidiano/citologia , Sequestradores de Radicais Livres/uso terapêutico , Humanos , Meningites Bacterianas/complicações , Meningites Bacterianas/diagnóstico , Meningites Bacterianas/tratamento farmacológico , Prognóstico , Resultado do Tratamento , Tirosina/metabolismo , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidiano , Ácido Úrico/uso terapêuticoRESUMO
OBJECTIVE: To study reactive nitrogen species-mediated oxidative brain damage and antioxidant defenses in patients with acute bacterial meningitis. METHODS: Nitrotyrosine (a widely used marker for the formation of reactive nitrogen species, such as peroxynitrite) and the lipid peroxidation product 4-hydroxynonenal were detected by immunohistochemistry in brain specimens obtained at autopsy. CSF concentrations of nitrotyrosine were quantified by ELISA. CSF and serum concentrations of ascorbic acid, uric acid, and its oxidation product allantoin were determined by high-pressure liquid chromatography. RESULTS: Tyrosine nitration was strongly increased during meningitis. It was most evident in inflammatory cells and blood vessels in the subarachnoid space. The same cell types stained positive for the lipid peroxidation marker 4-hydroxynonenal, suggesting that reactive nitrogen species contribute to oxidative brain damage during meningitis. High CSF nitrotyrosine concentrations were associated with an unfavorable outcome according to the Glasgow Outcome Score. In the CSF, the increase of nitrotyrosine was accompanied by a depletion of the antioxidant ascorbic acid and an increased oxidation of the natural peroxynitrite scavenger uric acid to allantoin. CONCLUSION: These findings indicate that oxidative stress due to reactive nitrogen species and altered antioxidant defenses are involved in the pathophysiology of bacterial meningitis in humans.