Juliana G. Coelho

In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease

Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of metabolism caused by deficiency of the activity of the mitochondrial enzyme complex branched-chain α-keto acid dehydrogenase (BCKAD) leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine and their corresponding branched-chain α-keto acids. Affected patients present severe brain dysfunction manifested such as ataxia, seizures, coma, psychomotor delay and mental retardation. The mechanisms of brain damage in this disease remain poorly understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. L-Carnitine (L-Car) is considered a potential antioxidant through its action against peroxidation as a scavenger of reactive oxygen species and by its stabilizing effect of damage to cell membranes. In this study we evaluate the possible neuroprotective in vivo effects of L-Car against pro-oxidative effects of BCAA in cerebral cortex of rats. L-Car prevented lipoperoxidation, measured by thiobarbituric acid-reactive substances, protein damage, measured by sulfhydryl and protein carbonyl content and alteration on catalase and glutathione peroxidase activity in rat cortex from a chemically-induced model of MSUD. Our data clearly show that L-Car may be an efficient antioxidant, protecting against the oxidative stress promoted by BCAA. If the present results are confirmed in MSUD patients, this could represent an additional therapeutic approach to the patients affected by this disease.

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.

Pipecolic acid induces oxidative stress in vitro in cerebral cortex of young rats and the protective role of lipoic acid

Pipecolic acid (PA) levels are increased in severe metabolic disorders of the central nervous system such as Zellweger syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy and hyperlysinemia. The affected individuals present progressive neurological dysfunction, hypotonia and growth retardation. The mechanisms of brain damage of these disorders remain poorly understood. Since PA catabolism can produce H2O2 by oxidases, oxidative stress may be a possible mechanism involved in the pathophysiology of these diseases. Lipoic acid (LA) is considered an efficient antioxidant and has been shown to prevent oxidative stress in experimental models of many disorders of the neurologic system. Considering that to our knowledge no study investigated the role of PA on oxidative stress, in the present work we investigated the in vitro effects of PA on some oxidative stress parameters and evaluated the LA efficacy against possible pro-oxidant effects of PA in cerebral cortex of 14-day-old rats. The activities of catalase (CAT), glutathione peroxidase (GPx), glucose 6-phosphate dehydrogenase (G6PD), and glutathione S-transferase (GST) along with reduced glutathione (GSH) content were significantly decreased, while superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBA-RS) were significantly enhanced by PA. LA was able to prevent these effects by improving the activity of antioxidant enzymes, increasing GSH content and reducing TBA-RS. In contrast, glutathione reductase and 6-phosphogluconate dehydrogenase activities and sulfhydryl content were not affected. Taken together, it may be presumed that PA in vitro elicits oxidative stress and LA is able to prevent these effects.

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.