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Acute administration of 5-oxoproline induces oxidative damage to lipids and proteins and impairs antioxidant defenses in cerebral cortex and cerebellum of young rats

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Abstract

5-Oxoproline accumulates in glutathione synthetase deficiency, an autossomic recessive inherited disorder clinically characterized by hemolytic anemia, metabolic acidosis, and severe neurological symptoms whose mechanisms are poorly known. In the present study we investigated the effects of acute subcutaneous administration of 5-oxoproline to verify whether oxidative stress is elicited by this metabolite in vivo in cerebral cortex and cerebellum of 14-day-old rats. Our results showed that the acute administration of 5-oxoproline is able to promote both lipid and protein oxidation, to impair brain antioxidant defenses, to alter SH/SS ratio and to enhance hydrogen peroxide content, thus promoting oxidative stress in vivo, a mechanism that may be involved in the neuropathology of gluthatione synthetase deficiency.

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References

  • Aebi H (1984) Catalase in vitro. Meth Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  • Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA (2006) Melatonin as an antioxidant, geroprotector and anticarcinogen. Biochim Biophys Acta 1757:573–589

    Article  CAS  PubMed  Google Scholar 

  • Barone D, Spignoli G (1990) Investigations on the binding properties of the nootropic agent pyroglutamic acid. Drugs Exp Clin Res 16:85–99

    CAS  PubMed  Google Scholar 

  • Beard JL, Connor JR, Jones BC (1993) Iron in the brain. Nutr Rev 51:157–170

    Article  CAS  PubMed  Google Scholar 

  • Bennet JP Jr, Logan WJ, Snyder SH (1973) Amino acids as central nervous transmitters: the influence of ions, amino acid analogues, and ontogeny on transport systems for L-glutamic and aspartic acids and glycine into central nervous synaptosomes. J Neurochem 2:1533–1550

    Article  Google Scholar 

  • Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Meth Enzymol 108:347–352

    CAS  Google Scholar 

  • Caccia S, Garattini G, Ghezzi P, Zanini MG (1982) Plasma and brain levels of glutamate and pyroglutamate after oral monosodium glutamate to rats. Toxicol Lett 10:169–175

    Article  CAS  PubMed  Google Scholar 

  • Caccia S, Ghezzi P, Garattini S, Salmona M, Takasaki Y, Torii K (1983) Pyroglutamate kinetics and neurotoxicity studies in mice. Toxicol Lett 16:225–22

    Article  CAS  PubMed  Google Scholar 

  • Campese VM, Sindhu RK, Ye S, Bay Y, Vaziri ND, Jabbari B (2007) Regional expression of NO synthase, NAD(P)H oxidase and superoxide dismutase in the rat brain. Brain Res 1134:27–32

    Article  CAS  PubMed  Google Scholar 

  • Dahl N, Pigg M, Ristoff E, Gali R, Carlsson B, Mannervik B, Larsson A, Board P (1997) Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction. Hum Mol Genet 6:1147–1152

    Article  CAS  PubMed  Google Scholar 

  • Dusticier N, Kerkerian L, Errami M, Nieoullon A (1985) Effects of pyroglutamic acid on corticostriatal glutamatergic transmission. Neuropharmacology 24:903–908

    Article  CAS  PubMed  Google Scholar 

  • Escobedo M, Cravioto J (1973) Studies on the malabsorption syndromes. Inhibition of Na+-K+-ATPase of small intestine microvilli by pyrrolidone carboxylic acid. Clin Chim Acta 49:147–151

    Article  CAS  PubMed  Google Scholar 

  • Evelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi EA (2001) Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols. Arch Biochem Biophys 388:261–266

    Article  CAS  PubMed  Google Scholar 

  • Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658

    Article  CAS  PubMed  Google Scholar 

  • Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press Inc., New York

    Google Scholar 

  • Hashida K, Sakakura Y, Makino N (2002) Kinetic studies on the hydrogen peroxide elimination by cultured PC12 cells. Biochim Biophys Acta 1572:85–90

    CAS  PubMed  Google Scholar 

  • Hazel AS (2007) Excitotoxic mechanisms in stroke: an update of concepts and treatment strategies. Neurochem Int 50:941–953

    Article  CAS  Google Scholar 

  • Hoffmann GF, Meier-Augenstein W, Stöckler S, Surtees R, Rating D, Nyhan WL (1993) Physiology and pathophysiology of organic acids in cerebrospinal fluid. J Inherit Metab Dis 16:648–669

    Article  CAS  PubMed  Google Scholar 

  • Hussain S, Slikker W Jr, Ali SF (1995) Age-related changes in antioxidant enzymes, superoxide dismutase, catalase, glutathione peroxidase and glutathione in different regions of mouse brain. Int J Devl Neurosci 13:811–817

    Article  CAS  Google Scholar 

  • Jain A, Buist NRM, Kennaway NG, Powell BR, Auld PA, Martensson J (1994) Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency. J Pediatr 124:229–233

    Article  CAS  PubMed  Google Scholar 

  • Jellum E, Kluge T, Borrensen HC, Stokke O, Eldjarn L (1970) Pyroglutamic aciduria: a new inborn error of metabolism. Scand J Clin Lab Invest 26:327–335

    Article  CAS  PubMed  Google Scholar 

  • Kletzien RF, Harris PKW, Foellmi LA (1994) Glucose 6-phosphate dehydrogenase: a “housekeeping” enzyme subject to tissue-specific regulation by hormones, nutrients and oxidant stress. FASEB J 8:174–181

    CAS  PubMed  Google Scholar 

  • Larsson A, Wachtmeister L, von Wendt L, Anderson R, Hagenfeldt L, Herrin KM (1985) Ophtalmological, psychometric and therapeutic investigation in two sisters with hereditary glutathione synthetase deficiency (5-oxoprolinuria). Neuropediatrics 16:131–136

    Article  CAS  PubMed  Google Scholar 

  • Larsson A, Anderson ME (2001) Glutathione synthetase deficiency and other disorders of the γ-glutamyl cycle. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 2205–2216

    Google Scholar 

  • Lees GJ (1993) Contributory mechanisms in the causation of neurodegenerative disorders. Neuroscience 54:287–322

    Article  CAS  PubMed  Google Scholar 

  • Leong SF, Clark JB (1984) Regional enzyme development in rat brain. Enzymes associated with glucose utilization. Biochem J 218:131–138

    CAS  PubMed  Google Scholar 

  • Lissi E, Caceres T, Videla LA (1986) Visible chemiluminescence from rat brain homogenates undergoing autoxidation. I. Effect of additives and products accumulation. Free Radic Biol Med 2:63–69

    CAS  Google Scholar 

  • Lissi E, Pascual C, Del Castillo MD (1992) Luminol luminescence induced by 2, 2′-azo-bis-(2-amidinopropane) thermolysis. Free Radic Res Commun 17:299–311

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Lewis-Farr A, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Marklund SL (1985) Pyrogallol autoxidation. In: Greenwald RA (ed) CRC handbook of methods for oxygen radical research. CRC, Boca Raton, pp 243–247

    Google Scholar 

  • Marstein S, Jellum E, Nesbakken R, Perry TL (1981) Biochemical investigations of biopsied brain tissue and autopsied organs from a patient with pyroglutamic acidemia (5-oxoprolinemia). Clin Chim Acta 111:219–228

    Article  CAS  PubMed  Google Scholar 

  • Meister A (1974) The γ-glutamyl cycle. Diseases associated with specific deficiencies. Annals Intern Med 81:247–253

    CAS  Google Scholar 

  • Moriarty-Craige SE, Jones DP (2004) Extracellular thiols and thiol/disulfide redox in metabolism. Ann Rev Nutr 24:481–509

    Article  CAS  Google Scholar 

  • Nicholls DG, Budd SL (1998) Mitochondria and neuronal glutamate excitotoxicity. Biochim Biophys Acta 1366:97–112

    Article  CAS  PubMed  Google Scholar 

  • Ninfali P, Ditroilo M, Capellacci S, Biagioti E (2001) Rabbit brain glucose-6-phosphate dehydrogenase: biochemical properties and inactivation by free radicals and 4-hydroxy-2-nonenal. Neuroreport 12:4149–4153

    Article  CAS  PubMed  Google Scholar 

  • Njalsson R (2005) Glutathione synthetase deficiency. Cell Mol Life Sci 62:1938–1945

    Article  CAS  PubMed  Google Scholar 

  • Njalsson R, Norgren S (2005) Physiological and pathological aspects of GSH metabolism. Acta Paediatr 94:132–137

    Article  PubMed  Google Scholar 

  • Nygren J, Ristoff E, Carlsson K, Möller L, Larsson A (2005) Oxidative DNA damage in cultured fibroblasts from patients with hereditary glutathione synthethase deficiency. Free Radic Res 39:595–601

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Omaye ST, Turnbull JD, Sauberlich HE (1979) Selected methods for the determination of ascorbic acid in animal cells, tissues and fluids. Meth Enzymol 62:3–11

    Article  CAS  PubMed  Google Scholar 

  • Pederzolli CD, Sgaravatti AM, Braum CA, Prestes CC, Zorzi GK, Wannmacher CMD, Wajner M, Wyse ATS, Dutra Filho CS (2007) 5-oxoproline reduces non-enzymatic antioxidant defenses in vitro in rat brain. Metab Brain Dis 22:51–65

    Article  CAS  PubMed  Google Scholar 

  • Pick E, Keisari Y (1980) A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J Immunol Methods 38:161–170

    Article  CAS  PubMed  Google Scholar 

  • Reznick AZ, Packer L (1994) Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Meth Enzymol 233:357–363

    Article  CAS  PubMed  Google Scholar 

  • Rieke GK, Scarfe AD, Hunter JF (1984) L-pyroglutamate: an alternate neurotoxin for a rodent model of Huntington’s Disease. Brain Res Bull 13:443–456

    Article  CAS  PubMed  Google Scholar 

  • Rieke GK, Smith J, Idusuyi OB, Semenya J, Howard R, Williams S (1989) Chronic intrastriatal L-pyroglutamate: neuropathology and neuron sparing like Huntington’s Disease. Exp Neurol 104:147–154

    Article  CAS  PubMed  Google Scholar 

  • Ristoff E, Mayatepek E, Larsson A (2001) Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr 139:79–84

    Article  CAS  PubMed  Google Scholar 

  • Ristoff E, Larsson A (2007) Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis 2:16

    Article  PubMed  Google Scholar 

  • Rothstein JD, Jin L, Dykes-Hoberg M, Kuncl RW (1993) Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc Natl Acad Sci USA 90:6591–6595

    Article  CAS  PubMed  Google Scholar 

  • Silva AR, Silva CG, Ruschel C, Helegda C, Wyse ATS, Wannmacher CMD, Wajner M, Dutra Filho CS (2001) L-Pyroglutamic acid inhibits energy production and lipid synthesis in cerebral cortex of young rats in vitro. Neurochem Res 26:1277–1283

    Article  CAS  PubMed  Google Scholar 

  • Skullerud K, Marstein S, Schrader H, Brundelet PJ (1980) The cerebral lesions in a patient with generalized glutathione deficiency and pyroglutamic aciduria (5-oxoprolinuria). Acta Neuropathol 52:235–238

    Article  CAS  PubMed  Google Scholar 

  • Stadtman ER (1990) Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. Free Radic Biol Med 9:315–325

    Article  CAS  PubMed  Google Scholar 

  • Stadtman ER, Levine RL (2003) Free-radical mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids 25:207–218

    Article  CAS  PubMed  Google Scholar 

  • Sultana R, Piroddi M, Galli F, Butterfield DA (2008) Protein levels and activities of some antioxidant enzymes in hippocampus of subjects with amnestic mild cognitive impairment. Neurochem Res 33:2540–2546

    Article  CAS  PubMed  Google Scholar 

  • Sweetman L (1991) Organic acid analysis. In: Hommes FA (ed) Techniques in diagnostic human biochemical genetics: a laboratory manual. Wiley-Liss, New York, pp 143–176

    Google Scholar 

  • Wendel A (1981) Glutathione peroxidase. Meth Enzymol 77:325–332

    Article  CAS  PubMed  Google Scholar 

  • Williams AC, Ford WCL (2004) Functional significance of the pentose phosphate pathway and glutathione reductase in the antioxidant defenses in human sperm. Biol Reprod 71:1309–1316

    Article  CAS  PubMed  Google Scholar 

  • Yang MS, Chan HW, Yu LC (2006) Glutathione peroxidase and glutathione reductase activities are partially responsible for determining the susceptibility of cells to oxidative stress. Toxicology 226:126–130

    Article  CAS  PubMed  Google Scholar 

  • Zahler WL, Cleland WW (1968) A specific and sensitive assay for disulfides. J Biol Chem 243:716–719

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the research grants from Programa de Núcleos de Excelência (PRONEX), 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 #01.06.0842-00).

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil

    Carolina Didonet Pederzolli, Caroline Paula Mescka, Bernardo Remuzzi Zandoná, Ângela Malysz Sgaravatti, Mirian Bonaldi Sgarbi, Angela Terezinha de Souza Wyse, Clóvis Milton Duval Wannmacher, Moacir Wajner & Carlos Severo Dutra-Filho

  2. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Carolina Didonet Pederzolli, Ângela Malysz Sgaravatti, Angela Terezinha de Souza Wyse, Clóvis Milton Duval Wannmacher, Moacir Wajner & Carlos Severo Dutra-Filho

  3. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil

    Daniella de Moura Coelho, Moacir Wajner & Carmen Regla Vargas

  4. Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Carmen Regla Vargas

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  1. Carolina Didonet Pederzolli
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  2. Caroline Paula Mescka
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  3. Bernardo Remuzzi Zandoná
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  4. Daniella de Moura Coelho
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  5. Ângela Malysz Sgaravatti
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  6. Mirian Bonaldi Sgarbi
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  7. Angela Terezinha de Souza Wyse
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  8. Clóvis Milton Duval Wannmacher
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  9. Moacir Wajner
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  10. Carmen Regla Vargas
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  11. Carlos Severo Dutra-Filho
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Correspondence to Carlos Severo Dutra-Filho.

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Pederzolli, C.D., Mescka, C.P., Zandoná, B.R. et al. Acute administration of 5-oxoproline induces oxidative damage to lipids and proteins and impairs antioxidant defenses in cerebral cortex and cerebellum of young rats. Metab Brain Dis 25, 145–154 (2010). https://doi.org/10.1007/s11011-010-9190-1

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