Fernanda Rech Zanin

Lipoic acid prevents oxidative stress in vitro and in vivo by an acute hyperphenylalaninemia chemically-induced in rat brain

Phenylketonuria (PKU) is a recessive autosomal disorder caused by a severe deficiency of phenylalanine-4-hydroxilase activity which leads to the accumulation of L-phenylalanine (Phe) in the tissues and plasma of patients. The main clinical features are retarded development and intellectual impairment. Recent studies have shown that oxidative stress may be involved in neuropathology of hyperphenylalaninemia. Lipoic acid (LA) is considered a potent antioxidant which is well absorbed from diet and can easily cross the blood-brain barrier. We investigated the neuroprotective effects of lipoic acid against oxidative stress caused by Phe in vivo and in vitro. Lipoic acid prevented the inhibition provoked by Phe on the activities of catalase, superoxide dismutase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase. It also prevented Phe alterations on total radical-trapping antioxidant potential, thiobarbituric acid-reactive substances, glutathione concentration and on production of reactive species. It is concluded that lipoic acid may be an efficient antioxidant in the CNS against oxidative stress induced by hyperphenylalaninemia. If the present results are confirmed in PKU patients, it is possible that supplementation of lipoic acid may contribute to the treatment of PKU as an adjuvant therapeutic approach to Phe-restricted dietary treatment and amino acid mixture.

Intracerebroventricular administration of N-acetylaspartic acid impairs antioxidant defenses and promotes protein oxidation in cerebral cortex of rats

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.

Exercício aeróbico agudo restaura a concentração de triptofano em cérebro de ratos com hiperfenilalaninemia

INTRODUCAO: A fenilcetonuria (PKU) e caracterizada pela deficiencia da enzima fenilalanina hidroxilase, causando acumulo de fenilalanina. O diagnostico precoce e a subordinacao a dieta pobre em fenilalanina sao importantes para prevenir os efeitos prejudiciais da hiperfenilalaninemia. Nao aderir estritamente a dieta provoca, entre outros efeitos, um desequilibrio entre os aminoacidos neutros que usam o mesmo transportador da fenilalanina na barreira hematoencefalica, causando, entao, a diminuicao da entrada de triptofano, o precursor de serotonina no cerebro. Esse neurotransmissor tem sido implicado na regulacao dos estados de humor, sendo sua alta producao ligada a fadiga central em individuos submetidos a exercicio prolongado. O exercicio fisico aumenta os niveis de triptofano livre no sangue, o que facilita seu influxo no cerebro, podendo, portanto, ser util nos estados hiperfenilalaninemicos. OBJETIVO: Avaliar se o exercicio aerobico e capaz de normalizar as concentracoes de triptofano no cerebro de ratos com hiperfenilalaninemia. METODOS: Trinta e dois ratos foram separados nos grupos sedentario (Sed) e exercicio (Exe), e cada um deles subdividido em controle (SAL) e hiperfenilalaninemia (PKU). A hiperfenilalaninemia foi induzida pela administracao de alfa-metilfenilalanina e fenilalanina durante tres dias, enquanto os grupos SAL receberam salina. Os grupos Exe realizaram uma sessao de exercicio aerobico com duracao de 60min e velocidade de 12m.min-1. RESULTADOS: A concentracao de triptofano no cerebro nos grupos PKU foi significativamente menor que nos grupos SAL, tanto Sed como Exe, compativel com a condicao hiperfenilalaninemica. O exercicio aumentou a concentracao cerebral de triptofano comparada aos animais sedentarios. O achado mais interessante foi que a concentracao cerebral de triptofano no grupo ExePKU nao foi diferente do SedSAL. CONCLUSAO: Os resultados indicam um importante papel do exercicio aerobico para restaurar a concentracao de triptofano no cerebro em ratos hiperfenilalaninemicos.