RESUMEN
INTRODUÇÃO: A fenilcetonúria (PKU) é caracterizada pela deficiência da enzima fenilalanina hidroxilase, causando acúmulo de fenilalanina. O diagnóstico precoce e a subordinação à dieta pobre em fenilalanina são importantes para prevenir os efeitos prejudiciais da hiperfenilalaninemia. Não aderir estritamente à dieta provoca, entre outros efeitos, um desequilíbrio entre os aminoácidos neutros que usam o mesmo transportador da fenilalanina na barreira hematoencefálica, causando, então, a diminuição da entrada de triptofano, o precursor de serotonina no cérebro. Esse neurotransmissor tem sido implicado na regulação dos estados de humor, sendo sua alta produção ligada à fadiga central em indivíduos submetidos a exercício prolongado. O exercício físico aumenta os níveis de triptofano livre no sangue, o que facilita seu influxo no cérebro, podendo, portanto, ser útil nos estados hiperfenilalaninêmicos. OBJETIVO: Avaliar se o exercício aeróbico é capaz de normalizar as concentrações de triptofano no cérebro de ratos com hiperfenilalaninemia. MÉTODOS: Trinta e dois ratos foram separados nos grupos sedentário (Sed) e exercício (Exe), e cada um deles subdividido em controle (SAL) e hiperfenilalaninemia (PKU). A hiperfenilalaninemia foi induzida pela administração de alfa-metilfenilalanina e fenilalanina durante três dias, enquanto os grupos SAL receberam salina. Os grupos Exe realizaram uma sessão de exercício aeróbico com duração de 60min e velocidade de 12m.min-1. RESULTADOS: A concentração de triptofano no cérebro nos grupos PKU foi significativamente menor que nos grupos SAL, tanto Sed como Exe, compatível com a condição hiperfenilalaninêmica. O exercício aumentou a concentração cerebral de triptofano comparada aos animais sedentários. O achado mais interessante foi que a concentração cerebral de triptofano no grupo ExePKU não foi diferente do SedSAL. CONCLUSÃO: Os resultados indicam um importante papel do exercício aeróbico para restaurar a concentração de triptofano no cérebro em ratos hiperfenilalaninêmicos.
INTRODUCTION: Phenylketonuria (PKU) is characterized by deficiency of the enzyme phenylalanine hydroxylase, leading to accumulation of phenylalanine. Early diagnosis and subordination to low-phenylalanine diet are important to prevent the harmful effects of hyperphenylalaninemia. In case the diet is not strictly followed, some possible effects are imbalance in the neutral amino acids that use the same carrier of phenylalanine to cross the blood-brain barrier, causing hence reduction in tryptophan entry, the precursor of serotonin in the brain. This neurotransmitter has been implicated in the regulation of mood states, and its high production is linked to central fatigue in individuals subjected to prolonged exercise. Physical exercise increases free tryptophan levels in the blood, which facilitates its influx in the brain, and therefore, may be useful in hyperphenylalaninemia states. OBJECTIVE: To assess whether aerobic exercise is able to normalize the concentrations of tryptophan in the brain of rats with hyperphenylalaninemia. METHODS: 32 rats were randomly assigned to sedentary (Sed) and exercise (Exe) groups, and then divided into control (HEA) and hyperphenylalaninemia (PKU). Hyperphenylalaninemia was induced by administration of alpha-metylphenylalanine and phenylalanine for three days, while the HEA groups received saline. Exe groups held a session of aerobic exercise lasting 60 minutes and speed of 12 m.min-1. RESULTS: The concentration of tryptophan in the brain of PKU groups was significantly lower than HEA groups (both in Sed and Exe groups), compatible with the condition of hyperphenylalaninemia. The exercise increased brain tryptophan levels comparing to sedentary animals. The most interesting finding was that the brain tryptophan levels of ExePKU group were not different from SedHEA group. CONCLUSION: The results indicate an important role of aerobic exercise to restore the concentration of tryptophan in the brain in hyperphenylalaninemic rats.
RESUMEN
N-Acetylaspartic acid (NAA) accumulates in Canavan disease, a severe inherited neurometabolic disorder clinically characterized by mental retardation, hypotonia, macrocephaly, and seizures. The mechanisms of brain damage in this disease remain poorly understood. Recent studies developed by our research group showed that NAA induces oxidative stress in vitro and in vivo in cerebral cortex of rats. Lipoic acid is considered as an efficient antioxidant which can easily cross the blood-brain barrier. Considering the absence of specific treatment to Canavan disease, this study evaluates the possible prevention of the oxidative stress promoted by NAA in vivo by the antioxidant lipoic acid to preliminarily evaluate lipoic acid efficacy against pro-oxidative effects of NAA. Fourteen-day-old Wistar rats received an acute administration of 0.6 mmol NAA/g body weight with or without lipoic acid (40 mg/kg body weight). Catalase (CAT), glutathione peroxidase (GPx), and glucose 6-phosphate dehydrogenase activities, hydrogen peroxide content, thiobarbituric acid-reactive substances (TBA-RS), spontaneous chemiluminescence, protein carbonyl content, total antioxidant potential, and DNA-protein cross-links were assayed in the cerebral cortex of rats. CAT, GPx activities, and total antioxidant potential were significantly reduced, while hydrogen peroxide content, TBA-RS, spontaneous chemiluminescence, and protein carbonyl content were significantly enhanced by acute administration of NAA. Those effects were all prevented by lipoic acid pretreatment. Our results clearly show that lipoic acid may protect against the oxidative stress promoted by NAA. This could represent a new therapeutic approach to the patients affected by Canavan disease.
Asunto(s)
Ácido Aspártico/análogos & derivados , Fármacos Neuroprotectores/farmacología , Ácido Tióctico/farmacología , Animales , Ácido Aspártico/toxicidad , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
5-Oxoproline accumulates in glutathione synthetase deficiency, an autossomic recessive inherited disorder clinically characterized by hemolytic anemia, metabolic acidosis, and severe neurological symptoms whose mechanisms are poorly known. In the present study we investigated the effects of acute subcutaneous administration of 5-oxoproline to verify whether oxidative stress is elicited by this metabolite in vivo in cerebral cortex and cerebellum of 14-day-old rats. Our results showed that the acute administration of 5-oxoproline is able to promote both lipid and protein oxidation, to impair brain antioxidant defenses, to alter SH/SS ratio and to enhance hydrogen peroxide content, thus promoting oxidative stress in vivo, a mechanism that may be involved in the neuropathology of gluthatione synthetase deficiency.
Asunto(s)
Antioxidantes/metabolismo , Encefalopatías Metabólicas Innatas/inducido químicamente , Cerebelo/efectos de los fármacos , Cerebro/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácido Pirrolidona Carboxílico/toxicidad , Factores de Edad , Animales , Antioxidantes/fisiología , Encefalopatías Metabólicas Innatas/metabolismo , Cerebelo/metabolismo , Cerebro/metabolismo , Modelos Animales de Enfermedad , Glutatión Sintasa/deficiencia , Peroxidación de Lípido/fisiología , Proteínas del Tejido Nervioso/fisiología , Estrés Oxidativo/fisiología , Ácido Pirrolidona Carboxílico/metabolismo , Ratas , Ratas WistarRESUMEN
N-Acetylaspartic acid accumulates in Canavan Disease, a severe inherited neurometabolic disease clinically characterized by severe mental retardation, hypotonia, macrocephaly and generalized tonic and clonic type seizures. Considering that the mechanisms of brain damage in this disease remain poorly understood, in the present study we investigated the in vitro and in vivo effects of N-acetylaspartic acid on the activities of catalase, superoxide dismutase and glutathione peroxidase, as well as on hydrogen peroxide concentration in cerebral cortex of 14-day-old rats. Catalase and glutathione peroxidase activities were significantly inhibited, while hydrogen peroxide concentration was significantly enhanced by N-acetylaspartic acid both in vitro and in vivo. In contrast, superoxide dismutase activity was not altered by N-acetylaspartic acid. Our results clearly show that N-acetylaspartic acid impairs the enzymatic antioxidant defenses in rat brain. This could be involved in the pathophysiological mechanisms responsible for the brain damage observed in patients affected by Canavan Disease.
Asunto(s)
Antioxidantes/metabolismo , Ácido Aspártico/análogos & derivados , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Peróxido de Hidrógeno/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Ácido Aspártico/metabolismo , Ácido Aspártico/toxicidad , Ácido Aspártico/orina , Encéfalo/enzimología , Enfermedad de Canavan/metabolismo , Enfermedad de Canavan/fisiopatología , Catalasa/efectos de los fármacos , Esquema de Medicación , Femenino , Glutatión Peroxidasa/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Superóxido Dismutasa/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
N-acetylaspartic acid (NAA) is the biochemical hallmark of Canavan Disease, an inherited metabolic disease caused by deficiency of aspartoacylase activity. NAA is an immediate precursor for the enzyme-mediated biosynthesis of N-acetylaspartylglutamic acid (NAAG), whose concentration is also increased in urine and cerebrospinal fluid of patients affected by CD. This neurodegenerative disorder is clinically characterized by severe mental retardation, hypotonia and macrocephaly, and generalized tonic and clonic type seizures. Considering that the mechanisms of brain damage in this disease remain not fully understood, in the present study we investigated whether intracerebroventricular administration of NAA or NAAG elicits oxidative stress in cerebral cortex of 30-day-old rats. NAA significantly reduced total radical-trapping antioxidant potential, catalase and glucose 6-phosphate dehydrogenase activities, whereas protein carbonyl content and superoxide dismutase activity were significantly enhanced. Lipid peroxidation indices and glutathione peroxidase activity were not affected by NAA. In contrast, NAAG did not alter any of the oxidative stress parameters tested. Our results indicate that intracerebroventricular administration of NAA impairs antioxidant defenses and induces oxidative damage to proteins, which could be involved in the neurotoxicity of NAA accumulation in CD patients.
Asunto(s)
Ácido Aspártico/análogos & derivados , Enfermedad de Canavan/metabolismo , Corteza Cerebral/metabolismo , Neurotoxinas/toxicidad , Estrés Oxidativo/fisiología , Animales , Antioxidantes/metabolismo , Ácido Aspártico/administración & dosificación , Ácido Aspártico/metabolismo , Ácido Aspártico/toxicidad , Daño Encefálico Crónico/etiología , Daño Encefálico Crónico/metabolismo , Enfermedad de Canavan/complicaciones , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Corteza Cerebral/efectos de los fármacos , Dipéptidos/administración & dosificación , Dipéptidos/metabolismo , Dipéptidos/toxicidad , Modelos Animales de Enfermedad , Glucosafosfato Deshidrogenasa/efectos de los fármacos , Glucosafosfato Deshidrogenasa/metabolismo , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Inyecciones Intraventriculares , Peroxidación de Lípido , Masculino , Neuropéptidos/administración & dosificación , Neuropéptidos/metabolismo , Neuropéptidos/toxicidad , Neurotoxinas/administración & dosificación , Neurotoxinas/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
This study investigated the effects of glutaric acid, which predominantly accumulates in glutaric acidemia type I, on some in vitro parameters of oxidative stress in brain of young rats. We evaluated chemiluminescence, total radical-antioxidant potential (TRAP) and the activities of the antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase in brain tissue homogenates in the presence of glutaric acid at concentrations ranging from 0.05 to 2.0 mM. The acid significantly increased chemiluminescence (up to 65%) and reduced total radical-antioxidant potential (up to 28%) and glutathione peroxidase activity (up to 46%), without affecting catalase and superoxide dismutase activities. The results provide evidence that glutaric acid induces oxidative stress in vitro in rat brain. If these findings also occur in humans, it is possible that they may contribute to the neuropathology of patients affected by glutaric acidemia type I.