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Effect of Leucine Administration on Creatine Kinase Activity in Rat Brain

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Abstract

Maple syrup urine disease (MSUD) is a metabolic disorder biochemically characterized by the accumulation of branched-chain amino acids (BCAA) and their branched-chain keto acids (BCKA) in blood and tissues. Neurological dysfunction is usually present in the patients, but the pathophysiology of brain damage is still obscure. Considering that brain energy metabolism is possibly altered in MSUD, the main objective of this study was to determine creatine kinase activity in the brain of rats subjected to acute and chronic administration of leucine. Chronic hyperleucinemia was induced by subcutaneous administrations of 4.8 μmol leucine/g body weight, twice a day, from the 6th to the 21st postnatal day. For acute hyperleucinemia, 21-day-old rats received three administrations of the amino acid at 3 h interval. Twelve hours after the chronic treatment or 1 h after the acute one, rats were killed and creatine kinase activity measured. The results indicated that acute or chronic administration of leucine altered creatine kinase activity in the brain of leucine-treated rats. Considering the crucial role creatine kinase plays in energy homeostasis in brain, if these effects also occur in the brain of MSUD patients, it is possible that alteration of this enzyme activity may contribute to the brain damage found in this disease.

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References

  • Aksenov, M., AksenovaM., Butterfield, A.D., and Markesbery, W.R. (2000). Oxidative modification of creatine kinase BB in Alzheimer's disease brain. J. Neurochem. 74:2520-2527.

    Google Scholar 

  • Aksenov, M.Y., Aksenova, M.V., Payne, R.M., Smith, C.D., Markesbery, W.R., and Carney, J.M. (1997). The expression of creatine kinase isoenzymes in neocortex of patients with neurodegenerative disorders: Alzheimer's and Pick's disease. Experim. Neurol. 146:458-465.

    Google Scholar 

  • Aksenov, M., Aksenova, M., Payne, R.M., Trojanovski, J.Q., Schmidt, K.L., Carney, J.M., Butterfield, D.A., and Markesbery, W.R. (1999). Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal lobes of neurodegenerative disorders. Dement. Geriatr. Cogn. Disord. 10:158-165.

    Google Scholar 

  • Araujo, P., Wasserman, G.F., Tallini, K., Furlanetto, V., Vargas, C.R., Wannmacher, C.M., Dutra-Filho, C.S., Wyse, A.T.S., and Wajner, M. (2001). Reduction of large neutral amino acids levels in plasma and brain of hyperleucinemic rats. Neurochem. Int. 38:529-537.

    Google Scholar 

  • Brustovetsky, N., Brustovetsky, T., and Dubinsky, J.M. (2001). On the mechanisms of neuroprotection by creatine and phosphocreatine. J. Neurochem. 76:425-434.

    Google Scholar 

  • Chuang, D.T., and Shih, V.E. (2001). Maple syrup urine disease (branched-chain ketoaciduria). In (C.R. Scriver, A.L. Beaudet, W.S. Sly, and D. Valle, eds.), The Metabolic & Molecular Bases of Inherited Diseases, 8th edn., McGraw-Hill, New York, pp. 1667-1724.

    Google Scholar 

  • Coitinho, A.S., de Mello, C.F., Lima, T.T., de Bastiani, J., Fighera, M.R., and Wajner, M. (2001). Pharmacological evidence that alpha-keto isovaleric acid induces convulsions through GABAergic and glutamatergic mechanisms in rats. Brain Res. 894:68-73.

    Google Scholar 

  • Dancis, J., Hutzler, J., and Levitz, M. (1960). Metabolism of the white blood cells in maple syrup urine disease. Biochim. Biophys. Acta 43:342-347.

    Google Scholar 

  • David, S.S., Shoemaker, M., and Haley, B.E. (1998). Abnormal properties of creatine kinase in Alzheimer's disease brain: Correlation of reduced enzyme activity and active site photolabelling with aberrant cytosol-membrane partitioning. Mol. Brain Res. 54:276-287.

    Google Scholar 

  • Fontella, F.U., Gassen, E., Pulrolnik, V., Wannmacher, C.M.D., Klein, A.B., Wajner, M., and Dutra-Filho, C.S. (2002). Stimulation of lipid peroxidation in vitro in rat brain by the metabolites accumulating in maple syrup urine disease. Metab. Brain Dis. 17:47-54.

    Google Scholar 

  • Hensley, K., Hall, N., Subramaniam, R., Cole, P., Harris, M., Aksenova, M.V., Aksenov, M.Y., Gabbita, S.P., Carney, J.M., Lowell, M., Markesbery, W.R., and Butterfield, D.A. (1995). Brain regional correspondence between Alzheimer's disease histopathology biomarkers of protein oxidation. J. Neurochem. 65:2146-2156.

    Google Scholar 

  • Hughes, B.P. (1962). A method for estimation of serum creatine kinase and its use in comparing creatine kinase and aldolase activity in normal and pathological sera. Clin. Chim. Acta 7:597-603.

    Google Scholar 

  • Jouvet, P., Rustin, P., Taylor, D.L., Pocock, J.M., Felderhoff-Mueser, U., Mazarakis, N.D., Sarraf, C., Joashi, U., Kozma, M., Greenwood, K., Edwards, A.D., and Mehemet, A. (2000). Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: Implications for neurological impairment associated with maple syrup urine disease. Mol. Biol. Cell. 11:1919-1932.

    Google Scholar 

  • Kamei, A., Takashima, S., Ctlan, F., and Becker, L.E. (1992). Abnormal dentritic development in maple syrup urine disease. Pediatr. Neurol. 8:145-147.

    Google Scholar 

  • Kiil, R., and Rokkones, T. (1964). Late manifesting variant of branched-chain ketoaciduria (maple syrup urine disease). Acta. Paediatr. 53:356-361.

    Google Scholar 

  • Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randal, R.J. (1951). Protein measurement with a Folin phenol reagent. J. Biol. Chem. 193:265-275.

    Google Scholar 

  • Manos, P., Bryan, G.K., and Edmond, J. (1991). Creatine kinase activity in postnatal rat brain development and in cultured neurons, astrocytes, and oligodendrocytes. J. Neurochem. 56:2101-2107.

    Google Scholar 

  • Mello, C.F., Feksa, L., Brusque, A.M., Wannmacher, C.M.D., and Wajner, M. (1999). Chronic early leucine administration induces behavioral deficits in rats. Life Sciences 65:747-755.

    Google Scholar 

  • Menkes, J.H. (1959). Maple syrup urine disease: Isolation and identification of organic acids in the urine. Pediatrics 23:348-353.

    Google Scholar 

  • Prensky, A.L., and Moser, H.W. (1966). Brain lipids, proteolipids, and free amino acids in maple syrup urine disease. J. Neurochem. 13:863-874.

    Google Scholar 

  • Reis, M., Farage, M., and Wolosker, H. (2000). Chloride-dependent inhibition of vesicular glutamate uptake by by alpha-keto acids accumulated in maple syrup urine disease. Biochim. Biophys. Acta 1475:114-118.

    Google Scholar 

  • Riviello, J.J., Jr., Rezvani, L., Digeorge, A.M., and Foley, C.M. (1991). Cerebral edema causing death in children with maple syrup urine disease. J. Pediatr. 119:42-45.

    Google Scholar 

  • Saks, V.A., Ventura-Clapier, R., and Aliev, M.K. (1996). Metabolic control and metabolic capacity: Two aspects of creatine kinase functioning in the cells. Biochim. Biophys. Acta 1274:81-88.

    Google Scholar 

  • Tavares, R.G., Santos, C.E., Tasca, C.I., 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.

    Google Scholar 

  • Tomimoto, H., Yamamoto, K., Homburger, H.A., and Yanagihara, T. (1993). Immunoelectron microscopic investigation of creatine kinase BB-isoenzyme after cerebral ischemia in gerbils. Acta Neuropathol. 86:447-455.

    Google Scholar 

  • Wallimann, T., Dolder, M., Schlattner, U., Eder, M., Hornemann, T., Kraft, T., and Stolz, M. (1998a). Creatine kinase: An enzyme with a central role in cellular energy metabolism. MAGMA 6:116-119.

    Google Scholar 

  • Wallimann, T., Dolder, M., Schlattner, U., Eder, M., Hornemann, T., O'Gorman, E., Ruck, E., and Brdiczka, D. (1998b). Some new aspects of creatini kinase (CK): Compartmentation, structure, function and regulation for cellular and mitochondrial bioenergetics and physiology. Biofactors 8:229-234.

    Google Scholar 

  • Wallimann, T., Wyss, M., Brdiczka, D., and Nicolay, K. (1992). Intracellular compartmentation, structure and function of creatine kinase in tissues with high and fluctuating energy demands: The ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem. J. 281:21-40.

    Google Scholar 

  • Wyse, A.T.S., Bolognesi, G., Brusque, A.M., Wajner, M., and Wannmacher, C.M.D. (1995). Na+, K+-ATPase activity in the synaptic plasma membrane from the cerebral cortex of rats subjected to chemically induced phenylketonuria. Med. Sci. Res. 23:261-262.

    Google Scholar 

  • Wyss, M., Smeitink, J., Wevers, R.A., and Wallimann, T. (1992). Mitochondrial creatine kinase: A key enzyme of aerobic energy metabolism. Biochim. Biophys. Acta 1102:119-166.

    Google Scholar 

  • Yudkoff, M. (1997). Brain metabolism of branched-chain amino acids. Glia 21:92-98.

    Google Scholar 

  • Zielke, H.R., Huang, Y., Baab, P.J., Collins, R.M. Jr., Zielke, C.L., and Tildon, J.T. (1997). Effects of alpha-ketoisocaproate and leucine on the in vivo oxidation of glutamate and glutamine in the rat brain. Neurochem. Res. 22:1159-1164.

    Google Scholar 

  • Zielke, H.R., Huang, Y., and Tildon, J.T. (1996). Elevation of amino acids in the interstitial space of the rat brain following infusion of a large neutral amino acid and keto acids by microdialysis: Alpha-ketocaproate infusion. Dev. Neurosci. 18:420-425.

    Google Scholar 

  • Zielke, H.R., Zielke, C.L., Baab, P.J., and Collins, R.M. (2002). Large neutral amino acids auto exchange when infused by microdialysis into the rat brain: Implication for maple syrup urine disease and phenylketonuria. Neurochem. Int. 40:347-354.

    Google Scholar 

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil

    Carmen Pilla, Rui Felipe de Oliveira Cardozo, Carlos Severo Dutra-Filho, Angela Terezinha Souza Wyse, Moacir Wajner & Clóvis Milton Duval Wannmacher

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  1. Carmen Pilla
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  2. Rui Felipe de Oliveira Cardozo
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  3. Carlos Severo Dutra-Filho
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  4. Angela Terezinha Souza Wyse
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  5. Moacir Wajner
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  6. Clóvis Milton Duval Wannmacher
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Pilla, C., de Oliveira Cardozo, R.F., Dutra-Filho, C.S. et al. Effect of Leucine Administration on Creatine Kinase Activity in Rat Brain. Metab Brain Dis 18, 17–25 (2003). https://doi.org/10.1023/A:1021974517837

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