Abstract
In this study we investigated the in vitro effects of the metabolites accumulating in maple syrup urine disease on lipid peroxidation in brain of young rats. Chemiluminescence and thiobarbituric acid-reactive substances were measured in brain homogenates from 7- and 30-day-old rats in the presence of 10 mM of the branched-chain amino acids L-leucine, L-isoleucine, or L-valine; their keto acids L-2-ketoisocaproic acid, L-2-keto-3-methylvaleric acid, or L-2-ketoisovaleric acid; or the hydroxy derivatives L-2-hydroxyisocaproic acid, L-2-hydroxy-3-methylvaleric acid, or L-2-hydroxyisovaleric acid separately added to the incubation medium. We observed that all amino acids, keto acids, and hydroxy acids accumulating in this disease stimulate to a variable degree the in vitro parameters of lipid peroxidation tested in homogenates of rat brain. The results indicate a possible participation of oxidative stress in the neuropathology of maple syrup urine disease patients, especially during a crisis, when the metabolites are highly increased, and point to the use of antioxidant drugs as a possible adjuvant therapy in such situations to improve the neurological status of the patients and to prevent sequelae.
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REFERENCES
Bremer, H.J., Duran, M., Kamerling, J.P., Przyrembel, H., and Wadman, S.K. (1981). Disturbances of amino acid metabolism: Clinical Chemistry and Diagnosis, Urban & Schaqarzenberg, Baltimore, Munich, pp. 359-363.
Buege, J.A., and Aust, S.D. (1978). Microssomal lipid peroxidation. Methods Enzymol. 52:302-309.
Chuang, D.T. and Shih, V.E. (1995). Disorders of branched chain amino acid and keto acid metabolism. In (C.R. Scriver, A.L. Beaudet, W.L. Sly, and D. Valle, eds.), The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, pp. 1239-1277.
Cini, M., Fariello, R.G., Bianchetti, A., and Moretti, A. (1994). Studies on lipid peroxidation in the rat brain. Neurochem. Res. 19:283-288.
Danner, D.J. and Elsas, L.J. II. (1989). Disorders of branched chain amino acid and keto acid metabolism. In (C.R. Scriver, A.L. Beaudet, W.L. Sly, and D.Valle, eds.), The Metabolic Basis of Inherited Disease, McGraw-Hill, New York, pp. 671-692.
Gonzalez-Flecha, B., Llesuy, S., and Boveris, A. (1991). Hydroperoxide-initiated chemiluminescence: An assay for oxidative stress in biopsies of heart, liver, and muscle. Free Radc. Biol. Med. 10:93-100.
Halestrap, A.P., Brand, M.D., and Denton, R.M. (1974). Inhibition of mitochondrial puruvate transport by phenylpyruvate and ?-ketoisocaproate. Biochem. Biophys. Acta 367:102-108.
Halliwell, B. (1996). Free radicals, protein and DNA: Oxidative damage versus redox regulation. Biochem. Soc. Trans. 24:1023-1027.
Halliwell, B. and Gutteridge, J.M.C. (1985). Oxygen radicals and nervous system. Trends Neurosci. 8:22-26.
Halliwell, B. and Gutteridge, J.M.C. (1999). Free Radicals in Biology and Medicine, Oxford University Press, Oxford.
Halliwell, B., Gutteridge, J.M.C., and Cross, C.E. (1992). Free radicals, antioxidants, and human disease: Where are we now? J. Lab. Clin. Med. 119:598-620.
Howell, R.K. and Lee, M. (1963). Influence of alpha-ketoacids on the respiration of brain in vitro. Proc. Soc. Exp. Biol. Med. 113:660-663.
Huang, Y., Zielke, H.R., Tildon, J.T., Zielke, C.L., and Baab, P.J. (1996). Elevation of amino acids in the interstitial space of the rat brain following infusion of large neutral amino and keto acids by microdialysis: Leucine infusion. Dev. Neurosci. 18:415-419.
Land, J.M., Mowbray, J., and Clark, J.B. (1976). Control of pyruvate and ?-hydroxybutyrate utilization in rat brain mitochondria and its relevance to phenylketonuria and maple syrup urine disease. J. Neurochem. 26:823-830.
Lowry, O.H., Rosenrough, R.L., Farr, R.L., and Randall, R.J. (1951). Protein measurement with the Folin Phenol Reagent. J. Biol. Chem. 193:265-275.
Nyhan, W.L. (1984). Abnormalities in Amino Acid Metabolism in Clinical Medicine, Appleton-Century-Crofts, Norwalk, pp. 21-35.
Peinemann, F. and Danner, D.J. (1994). Maple syrup urine disease 1954 to 1993. J. Inherit. Metab. Dis. 17:3-15.
Reznick, A.Z. and Packer,L. (1993). Free radicals and antioxidants in muscular neurological diseases and disorders. In (G. Poli, E. Albano, and M.U. Dianzani, eds.), Free Radicals: From Basic Science to Medicine, Birkhäuser, Basel, pp. 425-437.
Saudubray, J.M., Ogier, H., Billette de Vilmeur, T., Bonnefont, J.P., Lyonnet, S., Herve, F., Munnich, A., Rabier, D., Coude, M., and Charpentier, C. (1991). Inborns errors of the metabolism of branched-chain amino acids. In (J. Schuab, F. Van Hoof, and H.L. Vis, eds.), Inborn Errors of Metabolism, Raven Press, New York, pp. 137-153.
Snyderman, S.E., Goldstein, F., Sansaricq, C., and Norton, P.M. (1984). The relationship between the branched chain amino acids and their ?-ketoacids in maple syrup urine disease. Pediatr. Res. 18:851-853.
Snyderman, S.E., Norton, P.M., and Roitman, E. (1964). Maple syrup urine disease, with particular reference to dietotherapy. Pediatrics 34:454-472.
Taketomi, T., Kunishita, T., Hara, A., and Mizushima, S. (1983). Abnormal protein and lipid compositions of the cerebral myelin of a patient with maple syrup urine disease. Jpn. J. Exp. Med. 53:109-116.
Tashian, R.E. (1961). Inhibition of brain glutamic acid decarboxylase by phenylalanine, valine, and leucine derivatives:Asuggestion concerning the etiology of the neurological defect in phenylketonuria and branchedchain ketonuria. Metabolism 10:393-402.
Tavares, R.G., Santos, C.E.S., Tasca, C., Wajner, M., Souza, D.O., and Dutra-Filho, C.S. (2000). Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease. J. Neurol. Sci. 181:44-49.
Treacy, E., Clow, C.L., Reade, T.R., Chitayat, D., Mamer, O.A., and Scriver, C.R. (1992). Maple syrup urine disease: Interrelationship between branched chain amino-, oxo-, and hydroxyacids; implications for treatment; association with CNS dysmelination. J. Inherit. Metab. Dis. 15:121-135.
Tribble, D. and Shapira, R. (1983). Myelin proteins: Degradation in rat brain initiated by metabolites causative of maple syrup urine disease. Biochem. Biophys. Res. Commun. 114:440-446.
Yeman, S.J. (1986). The mammalian 2-oxoacid dehydrogenase: A complex family. Trends Biochem. Sci. 11:293-296.
Yuwiler, A. and Geller, E. (1965). Serotonin depletion by dietary leucine. Nature 208:83-84.
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Fontella, F.U., Gassen, E., Pulrolnik, V. et al. Stimulation of Lipid Peroxidation in Vitro in Rat Brain by the Metabolites Accumulating in Maple Syrup Urine Disease. Metab Brain Dis 17, 47–54 (2002). https://doi.org/10.1023/A:1014004414733
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DOI: https://doi.org/10.1023/A:1014004414733