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1.
Cell Mol Neurobiol ; 33(1): 137-46, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23053545

RESUMEN

Isolated 3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an autosomal recessive disorder of leucine metabolism biochemically characterized by accumulation of 3-methylcrotonylglycine (3MCG), 3-methylcrotonic acid (3MCA) and 3-hydroxyisovaleric acid. A considerable number of affected individuals present neurological symptoms with or without precedent crises of metabolic decompensation and brain abnormalities whose pathogenesis is poorly known. We investigated the in vitro effects of 3MCG and 3MCA on important parameters of oxidative stress in cerebral cortex of young rats. 3MCG and 3MCA significantly increased TBA-RS and carbonyl formation, indicating that these compounds provoke lipid and protein oxidation, respectively. In contrast, nitric oxide production was not affected by 3MCG and 3MCA. Furthermore, 3MCG- and 3MCA-induced elevation of TBA-RS values was fully prevented by melatonin, trolox and reduced glutathione, but not by the nitric oxide inhibitor N(ω)-nitro-L-arginine methyl ester or the combination of catalase plus superoxide dismutase, indicating that reactive oxygen species were involved in the oxidative damage caused by these compounds. We also found that the activity of the antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase and glutathione reductase were not altered in vitro by 3MCG and 3MCA. It is therefore presumed that alterations of the cellular redox homeostasis caused by the major metabolites accumulating in 3MCCD may potentially be involved in the pathophysiology of the neurological dysfunction and structural brain alterations found in patients affected by this disorder.


Asunto(s)
Química Encefálica/fisiología , Ligasas de Carbono-Carbono/deficiencia , Corteza Cerebral/metabolismo , Estrés Oxidativo/fisiología , Factores de Edad , Animales , Corteza Cerebral/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Trastornos Innatos del Ciclo de la Urea/enzimología , Trastornos Innatos del Ciclo de la Urea/fisiopatología
2.
Metab Brain Dis ; 27(4): 479-86, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22699997

RESUMEN

Hyperornithinemia is the biochemical hallmark of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, an inherited metabolic disease clinically characterized by mental retardation whose pathogenesis is still poorly known. In the present work, we produced a chemical animal model of hyperornithinemia induced by a subcutaneous injection of saline-buffered Orn (2-5 µmol/g body weight) to rats. High brain Orn concentrations were achieved, indicating that Orn is permeable to the blood brain barrier. We then investigated the effect of early chronic postnatal administration of Orn on physical development and on the performance of adult rats in the open field, the Morris water maze and in the step down inhibitory avoidance tasks. Chronic Orn treatment had no effect on the appearance of coat, eye opening or upper incisor eruption, nor on the free-fall righting reflex and on the adult rat performance in the Morris water maze and in the inhibitory avoidance tasks, suggesting that physical development, aversive and spatial localization were not changed by Orn. However, Orn-treated rats did not habituate to the open field apparatus, implying a deficit of learning/memory. Motor activity was the same for Orn- and saline- injected animals. We also verified that Orn subcutaneous injections provoked lipid peroxidation in the brain, as determined by a significant increase of thiobarbituric acid-reactive substances levels. Our results indicate that chronic early postnatal hyperornithinemia may impair the central nervous system, causing minor disabilities which result in specific learning deficiencies.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/inducido químicamente , Discapacidades para el Aprendizaje/inducido químicamente , Discapacidades para el Aprendizaje/psicología , Ornitina/toxicidad , Errores Innatos del Metabolismo de los Aminoácidos/psicología , Amoníaco/sangre , Animales , Animales Recién Nacidos , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Citrulina/análogos & derivados , Citrulina/sangre , Cognición/efectos de los fármacos , Cognición/fisiología , Discapacidades del Desarrollo/inducido químicamente , Modelos Animales de Enfermedad , Semivida , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Ornitina/farmacocinética , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
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