Skip to main content

Advertisement

SpringerLink
Log in

Creatine and pyruvate prevent behavioral and oxidative stress alterations caused by hypertryptophanemia in rats

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

It is known that the accumulation of tryptophan and its metabolites is related to brain damage associated with both hypertryptophanemia and neurodegenerative diseases. In this study, we investigated the effect of tryptophan administration on various parameters of behavior in the open-field task and oxidative stress, and the effects of creatine and pyruvate, on the effect of tryptophan. Forty, 60-day-old male Wistar rats, were randomly divided into four groups: saline, tryptophan, pyruvate + creatine, tryptophan + pyruvate + creatine. Animals received three subcutaneous injections of tryptophan (2 μmol/g body weight each one at 3 h of intervals) and/or pyruvate (200 μg/g body weight 1 h before tryptophan), and/or creatine (400 μg/g body weight twice a day for 5 days before tryptophan twice a day for 5 days before training); controls received saline solution (NaCl 0.85%) at the same volumes (30 μl/g body weight) than the other substances. Results showed that tryptophan increased the activity of the animals, suggesting a reduction in the ability of habituation to the environment. Tryptophan induced increase of TBA-RS and total sulfhydryls. The effects of tryptophan in the open field, and in oxidative stress were fully prevented by the combination of creatine plus pyruvate. In case these findings also occur in humans affected by hypertryptophanemia or other neurodegenerative disease in which tryptophan accumulates, it is feasible that oxidative stress may be involved in the mechanisms leading to the brain injury, suggesting that creatine and pyruvate supplementation could benefit patients affected by these disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Levy HL (2001) Hartnup disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited diseases, 8th edn. McGraw-Hill, New York, pp 1667–1724

    Google Scholar 

  2. Okuda S, Nishiyama N, Saito H, Katsuki H (1996) Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proc Natl Acad Sci USA 93:12553–12558

    Article  PubMed  CAS  Google Scholar 

  3. Heyes MP (1996) The kynurenine pathway and neurological disease. Therapeutic strategies. Adv Exp Med Biol 398:125–129

    Article  PubMed  CAS  Google Scholar 

  4. Stone TW (2001) Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Progr Neurobiol 64:185–218

    Article  CAS  Google Scholar 

  5. Sardar AM, Bell JE, Reynolds GP (1995) Increased concentrations of the neurotoxin 3-hydroxykynurenine in the frontal cortex of HIV-1-positive patients. J Neurochem 64:932–935

    Article  PubMed  CAS  Google Scholar 

  6. Pearson SJ, Reynolds GP (1991) Determination of 3-hydroxykynurenine in human brain and plasma by high-performance liquid chromatography with electrochemical detection. Increased concentrations in hepatic encephalopathy. J Chromatogr 565:436–440

    Article  PubMed  CAS  Google Scholar 

  7. Cornelio AR, Rodrigues-Junior Vda S, Rech VC, de Souza Wyse AT, Dutra-Filho CS, Wajner M, Wannmacher CM (2006) Inhibition of creatine kinase activity from rat cerebral cortex by 3-hydroxykynurenine. Brain Res 1124(1):188–196

    Article  PubMed  CAS  Google Scholar 

  8. Guillemin GJ, Brew BJ (2002) Implications of the kynurenine pathway and quinolinic acid in Alzheimer’s disease. Redox Rep 7:1–8

    Article  Google Scholar 

  9. Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs D (1999) Degradation of tryptophan in neurodegenerative disorders. Adv Exp Med Biol 467:133–138

    Article  PubMed  CAS  Google Scholar 

  10. Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs D (2000) Tryptophan degradation and immune activation in Alzheimer’s disease. J Neural Transm 107:343–353

    Article  PubMed  CAS  Google Scholar 

  11. Baran H, Jellinger K, Deecke L (1999) Kynurenine metabolism in Alzheimer’s disease. J Neural Transm 106:165–181

    Article  PubMed  CAS  Google Scholar 

  12. Heyes MP, Saito K, Crowley JS (1992) Quinolinic acid and kynurenine pathway metabolism in inflammatory and noninflammatory neurological disease. Brain 115:1249–1273

    Article  PubMed  Google Scholar 

  13. Pearson SJ, Reynolds GP (1992) Increased brain concentration of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neurosci Lett 144:199–201

    Article  PubMed  CAS  Google Scholar 

  14. Guidetti P, Reddy H, Tagle DA, Schwarcz R (2000) Early kynurenergic impairment in Huntington’s disease and in a transgenic animal model. Neurosci Lett 282:233–235

    Article  Google Scholar 

  15. Maurizi CP (1990) The therapeutic potential for tryptophan and melatonin: possible roles in depression, sleep, Alzheimer’s disease and abnormal aging. Med Hypotheses 31:233–242

    Article  PubMed  CAS  Google Scholar 

  16. Widner B, Ledochowski M, Fuchs D (2000) Sleep disturbances and tryptophan in patients with Alzheimer’s disease. Lancet 355:755–756

    Article  PubMed  CAS  Google Scholar 

  17. Porter RJ, Lunn BS, Walker LL, Gray JM, Ballard CG, O’Brien JT (2000) Cognitive deficit induced by acute tryptophan depletion in patients with Alzheimer’s disease. Am J Psychiatry 157:38–640

    Article  Google Scholar 

  18. Snedden W, Mellor CS, Martin JR (1983) Familial hypertryptophanemia, tryptophanuria and indolketonuria. Clin Chim Acta 131:247–256

    Article  PubMed  CAS  Google Scholar 

  19. Tada K, Ito H, Wada Y, Arakawa T (1963) Congenital tryptophanuria with dwarfism (“H” disease-like clinical features without indicanuria and generalized aminoaciduria): a probably new inborn error of tryptophan metabolism. Tohoku J Exp Med 80:118–134

    Article  PubMed  CAS  Google Scholar 

  20. Martin IR, Mellor CS, Fraser FC (1995) Familial hypertryptophanemia in two siblings. Clin Gen 47:180–183

    Article  CAS  Google Scholar 

  21. Feksa LR, Cornelio A, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM (2005) The effects of the interactions between amino acids on pyruvate kinase activity from the brain cortex of young rats. Int J Dev Neurosci 23(6):509–514

    Article  PubMed  CAS  Google Scholar 

  22. Cornelio AR, Rodrigues V Jr, de Souza Wyse AT, Dutra-Filho CS, Wajner M, Wannmacher CM (2004) Tryptophan reduces creatine kinase activity in the brain cortex of rats. Int J Dev Neurosci 22(2):95–101

    Article  PubMed  CAS  Google Scholar 

  23. Feksa LR, Latini A, Rech VC, Feksa PB, Koch GD, Amaral MF, Leipnitz G, Dutra-Filho CS, Wajner M, Wannmacher CM (2008) Tryptophan administration induces oxidative stress in brain cortex of rats. Metab Brain Dis 23(2):221–233

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  25. David SS, Shoemaker M, Haley BE (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

    Article  PubMed  CAS  Google Scholar 

  26. Aksenov M, Aksenova M, Butterfield AD, Markesbery WR (2000) Oxidative modification of creatine kinase BB in Alzheimer’s disease brain. J Neurochem 74:2520–2527

    Article  PubMed  CAS  Google Scholar 

  27. Gualano B, Artioli GG, Poortmans JR, Lancha AH (2010) Exploring the therapeutic role of creatine supplementation. Amino Acids 38:31–44

    Article  PubMed  CAS  Google Scholar 

  28. Guimbal C, Kilimann MW (1993) A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney CDNA cloning and functional expression. J Biol Chem 268:8418–8421

    PubMed  CAS  Google Scholar 

  29. Schloss P, Mayser W, Betz H (1994) The putative rat choline transporter CHOT1 transports creatine and is highly expressed in neural and muscle-rich tissues. Biochem Biophys Res Commun 198:637–645

    Article  PubMed  CAS  Google Scholar 

  30. Happe HK, Murrin LC (1995) In situ hybridization analysis of CHOT1, a creatine transporter, in the rat central nervous system. J Comp Neurol 351:94–103

    Article  PubMed  CAS  Google Scholar 

  31. Hemmer W, Wallimann T (1993) Functional aspects of creatine kinase in brain. Dev Neurosci 15:249–260

    Article  PubMed  CAS  Google Scholar 

  32. Saltarelli MD, Bauman AL, Moore KR, Bradley CC, Blakely RD (1996) Expression of the rat brain creatine transporter in situ and in transfected HeLa cells. Dev Neurosci 18:524–534

    Article  PubMed  CAS  Google Scholar 

  33. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213

    PubMed  CAS  Google Scholar 

  34. Hemmer W, Zanolla E, Furter-Graves EM, Eppenberger HM, Wallimann T (1994) Creatine kinase isoenzymes in chicken cerebellum: specific localization of brain-type creatine kinase in Bergmann glial cells and muscle-type creatine kinase in Purkinje neurons. Eur J Neurosci 6:538–549

    Article  PubMed  CAS  Google Scholar 

  35. Beal MF, Palomo T, Kostrzewa RM, Archer T (2000) Neuroprotective and neurorestorative strategies for neuronal injury. Neurotoxic Res 2(2–3):71–84

    Article  CAS  Google Scholar 

  36. Chaturvedi RK, Beal MF (2008) Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 1147:395–412 Review

    Article  PubMed  CAS  Google Scholar 

  37. Brand K (1997) Aerobic glycolysis by proliferating cells: protection against oxidative stress at the expense of energy yield. J Bioenerg Biomembr 29:355–364

    Article  PubMed  CAS  Google Scholar 

  38. Brand KA, Hermfisse U (1997) Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J 11:388–395

    PubMed  CAS  Google Scholar 

  39. Andrae U, Singh J, Ziegler-Skylakakis K (1985) Pyruvate and related a-ketoacids protect mammalian cells in culture against hydrogen peroxide-induced cytotoxicity. Toxicol Lett 28:93–98

    Article  PubMed  CAS  Google Scholar 

  40. Clement MV, Ponton A, Pervaiz S (1998) Apoptosis induced by hydrogen peroxide is mediated by decreased superoxide anion concentration and reduction of intracellular milieu. FEBS Lett 440:13–18

    Article  PubMed  CAS  Google Scholar 

  41. Kitamura Y, Ota T, Matsuoka Y, Tooyama I, Kimura H, Shimohama S, Normura Y, Gebicke-Haerter PJ, Taniguchi T (1999) Hydrogen peroxide induced apoptosis mediated by p53 protein in glial cells. Glia 25:154–164

    Article  PubMed  CAS  Google Scholar 

  42. Palomba L, Sestili P, Columbaro M, Falcieri E, Cantoni O (1999) Apoptosis and necrosis following exposure of U937 cells to increasing concentrations of hydrogen peroxide: the effect of the poly (ADP-ribose) polymerase inhibitor 3-aminobenzamide. Biochem Pharmacol 58:1743–1750

    Article  PubMed  CAS  Google Scholar 

  43. Mazzio EA, Soliman KF (2003) Cytoprotection of pyruvic acid and reduced beta-nicotinamide adenine dinucleotide against hydrogen peroxide toxicity in neuroblastoma cells. Neurochem Res 28(5):733–741

    Article  PubMed  CAS  Google Scholar 

  44. Reznick AZ, Witt EH, Silbermann M, Packer L (1993) The threshold of age in exercise and antioxidants action. EXS 62:423–427 Review

    Google Scholar 

  45. Méndez-Alvarez E, Soto-Otero R, Hermida-Ameijeiras A, López-Martín ME, Labandeira-Garcia JL (2001) Effect of iron and manganese on hydroxyl radical production by 6-hydroxydopamine: mediation of antioxidants. Free Radic Biol Med 31(8):986–998

    Article  PubMed  Google Scholar 

  46. Karelson E, Bogdanovic N, Garlind A, Winbland B, Zilmer K, Kullisaar T, Vihalemm T, Kairane C, Zilmer M (2001) The cerebrocortical areas in normal brain aging and in Alzheimer’s disease: noticeable differences in the lipid peroxidation level and in antioxidant defense. Neurochem Res 26(4):353–361

    Article  PubMed  CAS  Google Scholar 

  47. Feksa LR, Cornelio A, Vargas CR, de Souza Wyse AT, Wajner M, Wannmacher CM (2003) Alanine prevents the inhibition of pyruvate kinase activity caused by tryptophan in cerebral cortex of rats. Met Brain Dis 18(2):129–137

    Article  CAS  Google Scholar 

  48. Ryu JK, Choi HB, Mclarnon JB (2006) Combined minocycline plus pyruvate treatment enhances effects of each agent to inhibit inflammation, oxidative damage, and neuronal loss in an excitotoxic animal model of Huntington’s disease. Neuroscience 141:1835–1848

    Article  PubMed  CAS  Google Scholar 

  49. Stöckler S, Holzbach U, Hanenfeld F, Marquardt I, Helms G, Requart M, Hänicke W, Frahm J (1994) Creatine deficiency in the brain: a new, treatable Inborn Error of Metabolism. Pediatr Res 36:409–413

    Article  PubMed  Google Scholar 

  50. Eilam David (2002) Open-Field behavior withstands drastics changes in arena size. Behav Brain Res 142:53–62

    Article  Google Scholar 

  51. Walsh RN, Cummins RA (1976) The open-field test: a critical review. Psychol Bull 83:482–504

    Article  PubMed  CAS  Google Scholar 

  52. Archer J (1973) The influence of testosterone on chick behavior in novel environments. Behav Biol 8(1):93–108

    Article  PubMed  CAS  Google Scholar 

  53. Elias JW, Bell RW (1975) Open fields interpretation: social status and social vs. spatial stimulation as factors. J Gen Psychol 92(2d Half):293–294

    Article  PubMed  CAS  Google Scholar 

  54. Llesuy SF, Milei J, Molina H, Boveris A, Milei S (1985) Comparisons of lipid peroxidation and myocardial damage induced by adriamycin and 4′-epiadriamycin in mice. Tumori 71:241–249

    PubMed  CAS  Google Scholar 

  55. González-Flecha B, Llesuy S, Boveris A (1991) Hydroperoxide-initiated chemiluminescence: an assay for oxidative stress in biopsies of heart, liver and muscle. Free Radical Biol Med 10:93–100

    Article  Google Scholar 

  56. Kehrer JP (2000) Cause-effect of oxidative stress and apoptosis. Teratology 62(4):235–236 Review

    Article  PubMed  CAS  Google Scholar 

  57. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358

    Article  PubMed  CAS  Google Scholar 

  58. Aksenov MY, Aksenova MV, Butterfield DA, Geddes JW, Markesbery WR (2001) Protein oxidation in the brain in Alzheimer’s disease. Neuroscience 103(2):373–383

    Article  PubMed  CAS  Google Scholar 

  59. Denenberg VH (1969) Open-field behavior in the rat: what does it mean? Ann N Y Acad Sci 159(3):852–859

    Article  PubMed  CAS  Google Scholar 

  60. Halliwell B, Gutteridge JMC (1996) Oxygen radicals and nervous system. Trends Neurosci 8:22–26

    Article  Google Scholar 

  61. Halliwell B, Gutteridge JMC (eds) (1999) Free radical in biological and medicine. Oxford University Press, Oxford, pp 188–276

  62. Maus M, Marin P, Israël M, Glowinski J, Prémont J (1999) Pyruvate and lactate protect striatal neurons against n-methyl-d-aspartate-induced neurotoxicity. Eur J Neurosci 11(9):3215–3224

    Article  PubMed  CAS  Google Scholar 

  63. Lawler JM, Barnes WS, Wu G, Song W, Demaree S (2002) Direct antioxidant properties of creatine. Biochem Biophys Res Commun 290(1):47–52

    Article  PubMed  CAS  Google Scholar 

  64. Hahn KA, Salomons GS, Tackels-Horne D, Wood TC, Taylor HA, Schroer RJ, Lubs HA, Jakobs C, Olson RL, Holden KR, Stevenson RE, Schwartz CE (2002) X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28Am. J Hum Genet 70(5):1349–1356

    Article  CAS  Google Scholar 

  65. Nasrallah F, Feki M, Kaabachi N (2010) Creatine and creatine deficiency syndromes: biochemical and clinical aspects. Pediatr Neurol 42(3):163–171 Review

    Article  PubMed  Google Scholar 

  66. Forrest CM, Mackay GM, Stoy N, Egerton M, Christofides J, Stone TW, Darlington LG (2004) Tryptophan loading induces oxidative stress. Free Radical Res 38:1167–1171

    Article  CAS  Google Scholar 

  67. Feksa LR, Latini A, Rech VC, Wajner M, Dutra-Filho CS, de Souza Wyse AT, Wannmacher CM (2006) Promotion of oxidative stress by L-tryptophan in cerebral cortex of rats. Neurochem Int 49(1):87–93

    Article  PubMed  CAS  Google Scholar 

  68. Beal MF (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illness? Ann Neurol 31:119–130

    Article  PubMed  CAS  Google Scholar 

  69. Beal MF, Hyman BT, Koroshetz W (1993) Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci 16:125–131

    Article  PubMed  CAS  Google Scholar 

  70. Beal MF (1995) Aging, energy and oxidative stress in neurodegenerative diseases. Ann Neurol 38:357–366

    Article  PubMed  CAS  Google Scholar 

  71. Hodgkins PS, Schwarcz R (1998) Interference with cellular energy metabolism reduces kynurenic acid formation in rat brain slices: reversal by lactate and pyruvate. Eur J Neurosci 10:1986–1994

    Article  PubMed  CAS  Google Scholar 

  72. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695

    Article  PubMed  CAS  Google Scholar 

  73. Nakagami Y, Saito H, Katsuki H (1996) 3-Hydroxykynurenine toxicity on the rat striatum in vivo. Jpn J Pharmacol 71:183–186

    Article  PubMed  CAS  Google Scholar 

  74. Dzeja PP, Redfield MM, Burnett JC, Terzic A (2000) Failing energetics in failing hearts. Curr Cardiol Rep 2:212–217

    Article  PubMed  CAS  Google Scholar 

  75. Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Dauok R, Beal MF (1998) Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci 18:156–163

    PubMed  CAS  Google Scholar 

  76. Strong MJ, Pattee GL (2000) Creatine and coenzyme Q10 in the treatment of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 1:17–20

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful for the financial support of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and FINEP Rede Instituto Brasileiro de Neurociência (IBN-Net).

Author information

Authors and Affiliations

  1. Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 anexo, Porto Alegre, RS, 90035-003, Brazil

    Vivian Strassburger Andrade, Denise Bertin Rojas, Lenise Oliveira, Mychely Lopes Nunes, Fernanda Luz de Castro, Cristina Garcia, Tanise Gemelli, Rodrigo Binkowski de Andrade & Clóvis Milton Duval Wannmacher

Authors
  1. Vivian Strassburger Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Denise Bertin Rojas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lenise Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mychely Lopes Nunes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fernanda Luz de Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cristina Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tanise Gemelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rodrigo Binkowski de Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Clóvis Milton Duval Wannmacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clóvis Milton Duval Wannmacher.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Andrade, V.S., Rojas, D.B., Oliveira, L. et al. Creatine and pyruvate prevent behavioral and oxidative stress alterations caused by hypertryptophanemia in rats. Mol Cell Biochem 362, 225–232 (2012). https://doi.org/10.1007/s11010-011-1147-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-1147-0

Keywords

Search

Navigation