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Considering that pyruvate kinase activity, a crucial enzyme for glucose metabolism and energy liberation in brain, may be regulated by some amino acids, it is possible that diminution of this enzyme activity may contribute to the brain damage caused by amino acids accumulated in metabolic diseases, such as phenylalanine, tryptophan and cystine. Therefore, the present study was undertaken to investigate the effect of these amino acids on pyruvate kinase activity in the brain cortex of rats. We also investigated the effect of serine and alanine on pyruvate kinase activity in the same tissue. The results suggested that phenylalanine, tryptophan, cystine, alanine, and serine act at the same site on the enzyme, phenylalanine, tryptophan, and cystine causing inhibition, and alanine and serine preventing this effect. Cystine also inhibited the enzyme activity through a different mechanism, possibly acting on the enzyme thiol groups. Considering that this enzyme is a target for amino acids accumulated in some metabolic diseases of amino acid metabolism, it is possible that its inhibition may contribute to the brain damage found in these diseases.

In the present study were evaluated the in vivo effects of arginine administration on creatine kinase (CK) activity in cerebellum of rats. We also tested the influence of antioxidants, namely alpha-tocopherol and ascorbic acid and the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), on the effects elicited by Arg in order to investigate the possible participation of nitric oxide (NO) and/or its derivatives peroxynitrite (ONOO(-)) and other/or free radicals on the effects of arginine on CK activity. Sixty-day-old rats were treated with a single i.p. injection of saline (control, group I), arginine (0.8 g/kg) (group II), L-NAME (2.0 mg/kg or 20.0 mg/kg) (group III) or Arg (0.8 g/kg) plus L-NAME (2.0 mg/kg or 20.0 mg/kg) (group IV) and were killed 1 h later. In another set of experiments, the animals were pretreated for 1 week with daily i.p. administration of saline (control) or alpha-tocopherol (40 mg/kg) and ascorbic acid (100 mg/kg). Twelve hours after the last injection of the antioxidants, the rats received one i.p. injection of arginine (0.8 g/kg) or saline and were killed 1 h later. Results showed that total and cytosolic CK activities were significantly inhibited by arginine administration in cerebellum of rats, in contrast to mitochondrial CK activity which was not affected by this amino acid. Furthermore, simultaneous injection of L-NAME (20.0 mg/kg) and treatment with alpha-tocopherol and ascorbic acid prevented these effects. The data indicate that the reduction of CK activity in cerebellum of rats caused by arginine was probably mediated by NO and/or its derivatives ONOO(-)and other free radicals. Considering the importance of CK for the maintenance of energy homeostasis in the brain, if this enzyme inhibition also occurs in hyperargininemic patients, it is possible that CK inhibition may be one of the mechanisms by which arginine is neurotoxic in hyperargininemia.

Hypertryptophanemia is a rare inherited metabolic disorder probably caused by a blockage in the conversion of tryptophan to kynurenine, accumulating tryptophan and some of its metabolites in plasma and tissues of affected patients. The patients present mild to moderate mental retardation with exaggerated affective responses, periodic mood swings, and apparent hypersexual behavior. Pyruvate kinase catalyses a critical step in the glycolysis pathway, the main route that provides energy to brain functioning. The main objective of the present study was to determine pyruvate kinase activity in brain cortex of rats subjected to acute chemically induced hypertryptophanemia. The effect of alanine administration to the treated rats on the enzyme activity was also investigated. We also studied the in vitro effect of the two amino acids on pyruvate kinase activity in the brain cortex of nontreated rats. The results indicated that tryptophan inhibits pyruvate kinase in vitro and in vivo and that alanine prevents this inhibitory effect on the enzyme activity. Considering the crucial role pyruvate kinase plays in glucose metabolism in brain, it is possible that inhibition of this enzyme activity may contribute to the brain damage characteristic of this disease. Further studies will be necessary to evaluate possible benefits of alanine administration to the patients affected by hypertryptophanemia.

Hypertryptophanemia is a rare inherited metabolic disorder probably caused by a blockage in the conversion of tryptophan to kynurenine, resulting in the accumulation of tryptophan and some of its metabolites in plasma and tissues of affected patients. The patients present mild-to-moderate mental retardation with exaggerated affective responses, periodic mood swings, and apparent hypersexual behavior. Creatine kinase plays a key role in energy metabolism of tissues with intermittently high and fluctuating energy requirements, such as nervous tissue. The main objective of the present study was to investigate the effect of acute administration of tryptophan on creatine kinase activity in brain cortex of Wistar rats. We also studied the in vitro effect of this amino acid on creatine kinase activity in the brain cortex of non-treated rats. The results indicated that tryptophan inhibits creatine kinase in vitro and in vivo. We also observed that the in vitro inhibition was fully prevented but not reversed by pre-incubation with reduced glutathione, suggesting that the inhibitory effect of tryptophan on CK activity is possibly mediated by oxidation of essential thiol groups of the enzyme and/or long-lasting adduct formation. Considering the importance of creatine kinase for the maintenance of energy homeostasis in the brain, it is conceivable that an inhibition of this enzyme activity in the brain may be one of the mechanisms by which tryptophan might be neurotoxic.

The mechanisms by which phenylalanine is toxic to the brain in phenylketonuria are not fully understood. Considering that brain glucose metabolism is reduced in these patients, our main objective was to determine pyruvate kinase activity in brain cortex of rats subjected to acute and chronic chemically induced hyperphenylalaninemia. The effect of alanine administration on the enzyme activity in the treated rats was also investigated. We also studied the in vitro effect of the two amino acids on pyruvate kinase activity in brain cortex of nontreated rats. The results indicated that phenylalanine inhibits pyruvate kinase in vitro and in vivo and that alanine prevents the inhibitory effect of phenylalanine on the enzyme activity. Considering the crucial role pyruvate kinase plays in glucose metabolism in brain, it is possible that inhibition of this enzyme activity may contribute to the brain damage characteristic of this disease.

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