Skip to main content
SpringerLink
Log in

Role of antioxidant treatment on DNA and lipid damage in the brain of rats subjected to a chemically induced chronic model of tyrosinemia type II

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

Abstract

Tyrosine levels are abnormally elevated in tissues and body fluids of patients with inborn errors of tyrosine metabolism. Tyrosinemia type II, which is caused by tyrosine aminotransferase deficiency, provokes eyes, skin, and central nervous system disturbances in affected patients. However, the mechanisms of brain damage are still poorly known. Considering that studies have demonstrated that oxidative stress may contribute, along with other mechanisms, to the neurological dysfunction characteristic of hypertyrosinemia, in the present study we investigated the effects of antioxidant treatment (NAC and DFX) on DNA damage and oxidative stress markers induced by chronic administration of l-tyrosine in cerebral cortex, hippocampus, and striatum of rats. The results showed elevated levels of DNA migration, and thus DNA damage, after chronic administration of l-tyrosine in all the analyzed brain areas, and that the antioxidant treatment was able to prevent DNA damage in cerebral cortex and hippocampus. However, the co-administration of NAC plus DFX did not prevent the DNA damage in the striatum. Moreover, we found a significant increase in thiobarbituric acid-reactive substances (TBA-RS) and DCFH oxidation in cerebral cortex, as well as an increase in nitrate/nitrite levels in the hippocampus and striatum. Additionally, the antioxidant treatment was able to prevent the increase in TBA-RS levels and in nitrate/nitrite levels, but not the DCFH oxidation. In conclusion, our findings suggest that reactive oxygen and nitrogen species and oxidative stress can play a role in DNA damage in this disorder. Moreover, NAC/DFX supplementation to tyrosinemia type II patients may represent a new therapeutic approach and a possible adjuvant to the current treatment of this disease.

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

Similar content being viewed by others

References

  1. Mitchell GA, Grompe M, Lambert M, Tanguay RM (2001) Hypertyrosinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, vol 8. Mc Graw-Hill, New York, pp 1977–1982

    Google Scholar 

  2. Held PK (2006) Disorders of tyrosine catabolism. Mol Genet Metab 88(2):103–106

    Article  CAS  PubMed  Google Scholar 

  3. Goldsmith LA, Kang E, Bienfang DC, Jimbow K, Gerald P, Baden HP (1973) Tyrosinemia with plantar and palmar keratosis and keratitis. J Pediatr 83(5):798–805

    Article  CAS  PubMed  Google Scholar 

  4. Lemonnier F, Charpentier C, Odievre M, Larregue M, Lemonnier A (1979) Tyrosine aminotransferase isoenzyme deficiency. J Pediatr 94(6):931–932

    Article  CAS  PubMed  Google Scholar 

  5. Thimm E, Herebian D, Assmann B, Klee D, Mayatepek E, Spiekerkoetter U (2011) Increase of CSF tyrosine and impaired serotonin turnover in tyrosinemia type I. Mol Genet Metab 102(2):122–125. doi:10.1016/j.ymgme.2010.11.003

    Article  CAS  PubMed  Google Scholar 

  6. Sener RN (2005) Tyrosinemia: computed tomography, magnetic resonance imaging, diffusion magnetic resonance imaging, and proton spectroscopy findings in the brain. J Comput Assist Tomogr 29(3):323–325

    Article  PubMed  Google Scholar 

  7. De Pra SD, Ferreira GK, Carvalho-Silva M, Vieira JS, Scaini G, Leffa DD, Fagundes GE, Bristot BN, Borges GD, Ferreira GC, Schuck PF, Andrade VM, Streck EL (2014) l-tyrosine induces DNA damage in brain and blood of rats. Neurochem Res 39(1):202–207. doi:10.1007/s11064-013-1207-9

    Article  PubMed  Google Scholar 

  8. Macedo LG, Carvalho-Silva M, Ferreira GK, Vieira JS, Olegario N, Goncalves RC, Vuolo FS, Ferreira GC, Schuck PF, Dal-Pizzol F, Streck EL (2013) Effect of acute administration of l-tyrosine on oxidative stress parameters in brain of young rats. Neurochem Res 38(12):2625–2630. doi:10.1007/s11064-013-1180-3

    Article  CAS  PubMed  Google Scholar 

  9. Sgaravatti AM, Magnusson AS, de Oliveira AS, Rosa AP, Mescka CP, Zanin FR, Pederzolli CD, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS (2009) Tyrosine administration decreases glutathione and stimulates lipid and protein oxidation in rat cerebral cortex. Metab Brain Dis 24(3):415–425. doi:10.1007/s11011-009-9153-6

    Article  CAS  PubMed  Google Scholar 

  10. Sgaravatti AM, Vargas BA, Zandona BR, Deckmann KB, Rockenbach FJ, Moraes TB, Monserrat JM, Sgarbi MB, Pederzolli CD, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS (2008) Tyrosine promotes oxidative stress in cerebral cortex of young rats. Int J Dev Neurosci 26(6):551–559. doi:10.1016/j.ijdevneu.2008.05.007

    Article  CAS  PubMed  Google Scholar 

  11. de Andrade RB, Gemelli T, Rojas DB, Funchal C, Dutra-Filho CS, Wannmacher CM (2011) Tyrosine inhibits creatine kinase activity in cerebral cortex of young rats. Metab Brain Dis 26(3):221–227. doi:10.1007/s11011-011-9255-9

    Article  CAS  PubMed  Google Scholar 

  12. de Andrade RB, Gemelli T, Rojas DB, Funchal C, Dutra-Filho CS, Wannmacher CM (2012) Tyrosine impairs enzymes of energy metabolism in cerebral cortex of rats. Mol Cell Biochem 364(1–2):253–261. doi:10.1007/s11010-012-1225-y

    Article  CAS  PubMed  Google Scholar 

  13. Ferreira GK, Carvalho-Silva M, Gomes LM, Scaini G, Teixeira LJ, Mota IT, Schuck PF, Ferreira GC, Streck EL (2015) The characterization of neuroenergetic effects of chronic l-tyrosine administration in young rats: evidence for striatal susceptibility. Metab Brain Dis 30(1):215–221. doi:10.1007/s11011-014-9615-3

    Article  CAS  PubMed  Google Scholar 

  14. Ferreira GK, Scaini G, Carvalho-Silva M, Gomes LM, Borges LS, Vieira JS, Constantino LS, Ferreira GC, Schuck PF, Streck EL (2013) Effect of l-tyrosine in vitro and in vivo on energy metabolism parameters in brain and liver of young rats. Neurotox Res 23(4):327–335. doi:10.1007/s12640-012-9345-4

    Article  CAS  PubMed  Google Scholar 

  15. Ramos AC, Ferreira GK, Carvalho-Silva M, Furlanetto CB, Goncalves CL, Ferreira GC, Schuck PF, Streck EL (2013) Acute administration of l-tyrosine alters energetic metabolism of hippocampus and striatum of infant rats. Int J Dev Neurosci 31(5):303–307. doi:10.1016/j.ijdevneu.2013.03.005

    Article  CAS  PubMed  Google Scholar 

  16. Ferreira GK, Carvalho-Silva M, Goncalves CL, Vieira JS, Scaini G, Ghedim FV, Deroza PF, Zugno AI, Pereira TC, Oliveira GM, Kist LW, Bogo MR, Schuck PF, Ferreira GC, Streck EL (2012) l-tyrosine administration increases acetylcholinesterase activity in rats. Neurochem Int 61(8):1370–1374. doi:10.1016/j.neuint.2012.09.017

    Article  CAS  PubMed  Google Scholar 

  17. Ferreira GK, Jeremias IC, Scaini G, Carvalho-Silva M, Gomes LM, Furlanetto CB, Morais MO, Schuck PF, Ferreira GC, Streck EL (2013) Effect of acute and chronic administration of l-tyrosine on nerve growth factor levels in rat brain. Neurochem Res 38(8):1742–1746. doi:10.1007/s11064-013-1078-0

    Article  CAS  PubMed  Google Scholar 

  18. Ferreira GK, Scaini G, Jeremias IC, Carvalho-Silva M, Goncalves CL, Pereira TC, Oliveira GM, Kist LW, Bogo MR, Schuck PF, Ferreira GC, Streck EL (2014) An evaluation of the effects of acute and chronic l-tyrosine administration on BDNF levels and BDNF mRNA expression in the rat brain. Mol Neurobiol 49(2):734–740. doi:10.1007/s12035-013-8552-1

    Article  CAS  PubMed  Google Scholar 

  19. Cetinkaya A, Bulbuloglu E, Kurutas EB, Ciralik H, Kantarceken B, Buyukbese MA (2005) Beneficial effects of N-acetylcysteine on acetic acid-induced colitis in rats. Tohoku J Exp Med 206(2):131–139

    Article  CAS  PubMed  Google Scholar 

  20. Bavarsad Shahripour R, Harrigan MR, Alexandrov AV (2014) N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain Behav 4(2):108–122. doi:10.1002/brb3.208

    Article  PubMed  PubMed Central  Google Scholar 

  21. Pinho RA, Silveira PC, Silva LA, Luiz Streck E, Dal-Pizzol F, Moreira JC (2005) N-acetylcysteine and deferoxamine reduce pulmonary oxidative stress and inflammation in rats after coal dust exposure. Environ Res 99(3):355–360. doi:10.1016/j.envres.2005.03.005

    Article  CAS  PubMed  Google Scholar 

  22. De Flora S, Izzotti A, D’Agostini F, Balansky RM (2001) Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. Carcinogenesis 22(7):999–1013

    Article  PubMed  Google Scholar 

  23. De Vries N, De Flora S (1993) N-acetyl-l-cysteine. J Cell Biochem Suppl 17F:270–277

    Article  PubMed  Google Scholar 

  24. Ritter C, Andrades ME, Reinke A, Menna-Barreto S, Moreira JC, Dal-Pizzol F (2004) Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis. Crit Care Med 32(2):342–349. doi:10.1097/01.CCM.0000109454.13145.CA

    Article  CAS  PubMed  Google Scholar 

  25. Di-Pietro PB, Dias ML, Scaini G, Burigo M, Constantino L, Machado RA, Dal-Pizzol F, Streck EL (2008) Inhibition of brain creatine kinase activity after renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration. Neurosci Lett 434(1):139–143. doi:10.1016/j.neulet.2008.01.051

    Article  CAS  PubMed  Google Scholar 

  26. Damiani CR, Benetton CA, Stoffel C, Bardini KC, Cardoso VH, Di Giunta G, Pinho RA, Dal-Pizzol F, Streck EL (2007) Oxidative stress and metabolism in animal model of colitis induced by dextran sulfate sodium. J Gastroenterol Hepatol 22(11):1846–1851. doi:10.1111/j.1440-1746.2007.04890.x

    Article  CAS  PubMed  Google Scholar 

  27. Scaini G, Comim CM, Oliveira GM, Pasquali MA, Quevedo J, Gelain DP, Moreira JC, Schuck PF, Ferreira GC, Bogo MR, Streck EL (2013) Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model. J Inherit Metab Dis 36(5):721–730. doi:10.1007/s10545-012-9549-z

    Article  CAS  PubMed  Google Scholar 

  28. Halliwell B (2011) Free radicals and antioxidants—quo vadis? Trends Pharmacol Sci 32(3):125–130. doi:10.1016/j.tips.2010.12.002

    Article  CAS  PubMed  Google Scholar 

  29. Halliwell B, Lee CY (2010) Using isoprostanes as biomarkers of oxidative stress: some rarely considered issues. Antioxid Redox Signal 13(2):145–156. doi:10.1089/ars.2009.2934

    Article  CAS  PubMed  Google Scholar 

  30. Morre MC, Hefti F, Wurtman RJ (1980) Regional tyrosine levels in rat brain after tyrosine administration. J Neural Transm 49(1–2):45–50

    Article  CAS  PubMed  Google Scholar 

  31. Bongiovanni R, Yamamoto BK, Simpson C, Jaskiw GE (2003) Pharmacokinetics of systemically administered tyrosine: a comparison of serum, brain tissue and in vivo microdialysate levels in the rat. J Neurochem 87(2):310–317

    Article  CAS  PubMed  Google Scholar 

  32. Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175(1):184–191

    Article  CAS  PubMed  Google Scholar 

  33. Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, Miyamae Y, Rojas E, Ryu JC, Sasaki YF (2000) Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35(3):206–221

    Article  CAS  PubMed  Google Scholar 

  34. Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26(3):249–261. doi:10.1385/MB:26:3:249

    Article  CAS  PubMed  Google Scholar 

  35. Esterbauer H, Cheeseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Method Enzymol 186:407–421

    Article  CAS  Google Scholar 

  36. LeBel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5(2):227–231

    Article  CAS  PubMed  Google Scholar 

  37. Miranda KM, Espey MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 5(1):62–71. doi:10.1006/niox.2000.0319

    Article  CAS  PubMed  Google Scholar 

  38. Macsai MS, Schwartz TL, Hinkle D, Hummel MB, Mulhern MG, Rootman D (2001) Tyrosinemia type II: nine cases of ocular signs and symptoms. Am J Ophthalmol 132(4):522–527

    Article  CAS  PubMed  Google Scholar 

  39. Valikhani M, Akhyani M, Jafari AK, Barzegari M, Toosi S (2006) Oculocutaneous tyrosinaemia or tyrosinaemia type 2: a case report. J Eur Acad Dermatol Venereol 20(5):591–594. doi:10.1111/j.1468-3083.2006.01572.x

    Article  CAS  PubMed  Google Scholar 

  40. de Andrade RB, Gemelli T, Rojas DB, Bonorino NF, Costa BM, Funchal C, Dutra-Filho CS, Wannmacher CM (2015) Creatine and pyruvate prevent the alterations caused by tyrosine on parameters of oxidative stress and enzyme activities of phosphoryltransfer network in cerebral cortex of Wistar rats. Mol Neurobiol 51(3):1184–1194. doi:10.1007/s12035-014-8791-9

    Article  PubMed  Google Scholar 

  41. Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362(6422):709–715. doi:10.1038/362709a0

    Article  CAS  PubMed  Google Scholar 

  42. Rao KS (1993) Genomic damage and its repair in young and aging brain. Mol Neurobiol 7(1):23–48

    Article  CAS  PubMed  Google Scholar 

  43. Nakanishi M, Niida H, Murakami H, Shimada M (2009) DNA damage responses in skin biology—implications in tumor prevention and aging acceleration. J Dermatol Sci 56(2):76–81. doi:10.1016/j.jdermsci.2009.09.001

    Article  CAS  PubMed  Google Scholar 

  44. Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9(6):515–540

    Article  CAS  PubMed  Google Scholar 

  45. Stoerner JW, Butler IJ, Morriss FH Jr, Howell RR, Seifert WE Jr, Caprioli RM, Adcock EW 3rd, Denson SE (1980) CSF neurotransmitter studies. An infant with ascorbic acid-responsive tyrosinemia. Am J Dis Child 134(5):492–494

    Article  CAS  PubMed  Google Scholar 

  46. Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8(11):1445–1449. doi:10.1038/nn1578

    Article  CAS  PubMed  Google Scholar 

  47. Knuckey NW, Palm D, Primiano M, Epstein MH, Johanson CE (1995) N-acetylcysteine enhances hippocampal neuronal survival after transient forebrain ischemia in rats. Stroke 26(2):305–310 Discussion 311

    Article  CAS  PubMed  Google Scholar 

  48. Mayer M, Noble M (1994) N-acetyl-l-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro. Proc Natl Acad Sci USA 91(16):7496–7500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Martinez Banaclocha M (2000) N-acetylcysteine elicited increase in complex I activity in synaptic mitochondria from aged mice: implications for treatment of Parkinson’s disease. Brain Res 859(1):173–175

    Article  CAS  PubMed  Google Scholar 

  50. Martinez Banaclocha M, Martinez N (1999) N-acetylcysteine elicited increase in cytochrome c oxidase activity in mice synaptic mitochondria. Brain Res 842(1):249–251

    Article  CAS  PubMed  Google Scholar 

  51. Martinez M, Martinez N, Hernandez AI, Ferrandiz ML (1999) Hypothesis: can N-acetylcysteine be beneficial in Parkinson’s disease? Life Sci 64(15):1253–1257

    Article  CAS  PubMed  Google Scholar 

  52. Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, Morley JE (2003) The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 84(5):1173–1183

    Article  CAS  PubMed  Google Scholar 

  53. Sandhir R, Sood A, Mehrotra A, Kamboj SS (2012) N-Acetylcysteine reverses mitochondrial dysfunctions and behavioral abnormalities in 3-nitropropionic acid-induced Huntington’s disease. Neurodegener Dis 9(3):145–157. doi:10.1159/000334273

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by Grants from Programa de Pós-graduação em Ciências da Saúde—Universidade do Extremo Sul Catarinense (UNESC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Author information

Authors and Affiliations

  1. Laboratório de Bioenergética e Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil

    Emilio L. Streck, Samira D. T. De Prá, Paula Ronsani Ferro, Milena Carvalho-Silva, Lara M. Gomes & Giselli Scaini

  2. Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil

    Emilio L. Streck, Samira D. T. De Prá, Paula Ronsani Ferro, Milena Carvalho-Silva, Lara M. Gomes & Giselli Scaini

  3. Laboratório de Biologia Celular e Molecular, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Adriani Damiani & Vanessa M. Andrade

  4. Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil

    Jotele F. Agostini & Patrícia F. Schuck

  5. Laboratório de Neuroquímica, Instituto de Biofísica Carlos Chagas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Gustavo C. Ferreira

Authors
  1. Emilio L. Streck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samira D. T. De Prá
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paula Ronsani Ferro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Milena Carvalho-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lara M. Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jotele F. Agostini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adriani Damiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vanessa M. Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Patrícia F. Schuck
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gustavo C. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Giselli Scaini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emilio L. Streck.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Streck, E.L., De Prá, S.D.T., Ferro, P.R. et al. Role of antioxidant treatment on DNA and lipid damage in the brain of rats subjected to a chemically induced chronic model of tyrosinemia type II. Mol Cell Biochem 435, 207–214 (2017). https://doi.org/10.1007/s11010-017-3070-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-3070-5

Keywords

Search

Navigation