Skip to main content
SpringerLink
Log in

Time-Course of Brain Oxidative Damage Caused by Intrastriatal Administration of 6-Hydroxydopamine in a Rat Model of Parkinson’s Disease

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The unilateral and intrastriatal injection of 6-hydroxydopamine is commonly used to provide a partial lesion model of Parkinson’s disease in the investigation of the molecular mechanisms involved in its pathogenesis and to assess new neuroprotective treatments. Its capacity to induce neurodegeneration has been related to its ability to undergo autoxidation in the presence of oxygen and consequently to generate oxidative stress. The aim of the present study was to investigate the time course of brain oxidative damage induced by 6-hydroxydopamine (6 μg in 5 μl of sterile saline containing 0.2% ascorbic acid) injection in the right striatum of the rat. The results of this study show that the indices of both lipid peroxidation (TBARS) and protein oxidation (carbonyl and free thiol contents) increase simultaneously in the ipsilateral striatum and ventral midbrain, reaching a peak value at 48-h post-injection for both TBARS and protein carbonyl content, and at 24 h for protein free thiol content. A lower but significant increase was also observed in the contralateral side (striatum and ventral midbrain). The indices of oxidative stress returned to values close to those found in controls at 7-day post-injection. These data show that the oxidative stress is a possible triggering factor for the neurodegenerative process and the retrograde neurodegeneration observed after 1-week post-injection is a consequence of the cell damage caused during the first days post-injection. The optimal time to assess brain indices of oxidative stress in this model is 48-h post-injection.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909

    Article  PubMed  CAS  Google Scholar 

  2. Aebischer P, Tresco PA, Sagen J et al (1991) Transplantation of microencapsulated bovine chromaffin cells reduces lesion-induced rotational asymmetry in rats. Brain Res 560:43–49

    Article  PubMed  CAS  Google Scholar 

  3. He Y, Appel S, Le W (2001) Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 909:187–193

    Article  PubMed  CAS  Google Scholar 

  4. López-Real A, Rey P, Soto-Otero R et al (2005) Antiotensin-converting enzyme inhibition reduces oxidative stress and protects dopaminergic neurons in a 6-hydroxydopamine rat model of parkinsonism. J Neurosci Res 81:865–873

    Article  PubMed  CAS  Google Scholar 

  5. Muñoz AM, Rey P, Soto-Otero R et al (2004) Systemic administration of N-acetylcysteine protects dopaminergic neurons against 6-hydroxydopamine-induced degeneration. J Neurosci Res 76:551–562

    Article  PubMed  CAS  Google Scholar 

  6. Soto-Otero R, Méndez-Álvarez E, Hermida-Ameijeiras A et al (2002) Effects of (-)-nicotine and (-)-cotinine on 6-hydroxydopamine-induced oxidative stress and neurotoxicity: relevance for Parkinson’s disease. Biochem Pharmacol 64:125–135

    Article  PubMed  CAS  Google Scholar 

  7. Luthman J, Fredriksson A, Sundstorm E et al (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behaviour and monoamine alterations at adult stage. Behav Brain Res 33:267–277

    PubMed  CAS  Google Scholar 

  8. Garver DL, Cedarbaum J, Maas JW (1975) Blood-brain barrier to 6-hydroxydopamine: uptake by heart and brain. Life Sci 17:1081–1084

    Article  PubMed  CAS  Google Scholar 

  9. Javoy F, Sotelo C, Herbert A et al (1976) Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostratal dopamine system. Brain Res 102:210–215

    Article  Google Scholar 

  10. Ungerstdt U (1971) Stereotaxic mapping of the monoamine pathway in the rat brain. Acta Physiol Scand 367(Suppl):1–48

    Google Scholar 

  11. Ichitani I, Okamura H, Matsumoto Y et al (1991) Degeneration of the nigral dopamine neurons after 6-hydroxydopamine injection into the rat striatum. Brain Res 549:330–353

    Article  Google Scholar 

  12. Marti MJ, James CJ, Oo TF et al (1997) Early developmental destruction of terminals in the striatal target induces apoptosis in dopamine neurons of the substantia nigra. J Neurosci 17:2030–2039

    PubMed  CAS  Google Scholar 

  13. Méndez-Álvarez E, Soto-Otero R, Hermida-Ameijeiras A et al (2001) Effect of iron and manganese on hydroxyl radical production by 6-hydroxydopamine: mediation of antioxidants. Free Radical Biol Med 31:986–998

    Article  Google Scholar 

  14. Soto-Otero R, Méndez-Álvarez E, Hermida-Ameijeiras A et al (2000) Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease. J Neurochem 74:1605–1612

    Article  PubMed  CAS  Google Scholar 

  15. Glinka YY, Youdim MBH (1995) Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. Eur J Pharmacol 292:329–332

    PubMed  CAS  Google Scholar 

  16. Glinka Y, Tipton KF, Youdim MBH (1996) Nature of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine. J Neurochem 66(1996) 2004–2010

    PubMed  CAS  Google Scholar 

  17. Glinka Y, Tipton KF, Youdim MBH (1998) Mechanism of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine and its prevention by desferrioxamine. Eur J Pharmacol 351:121–129

    Article  PubMed  CAS  Google Scholar 

  18. Brand MD, Affourtit C, Esteves TC et al (2004) Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radical Biol Med 37:755–767

    Article  CAS  Google Scholar 

  19. Yamamuro A, Yoshioka Y, Ogita K et al (2006) Involvement of endoplasmic reticulum stress on the cell death induced by 6-hydroxydopamine in human neuroblastoma SH-SY5Y cells. Neurochem Res 31:657–664

    Article  PubMed  CAS  Google Scholar 

  20. Jeon BS, Jackson-Lewis V, Burke RE (1995) 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 4:131–137

    Article  PubMed  CAS  Google Scholar 

  21. Jonsson G (1983) Chemical lesioning techniques: monoamine neurotoxins. In: Björklund A, Hökfelt T (eds) Handbook of Chemical Neuroanatomy. Methods in Chemical Neuroanatomy. Elsevier Science Publisher BV, Amsterdam, 463–507

    Google Scholar 

  22. Jiang H, Jackson-Lewis V, Muthane U et al (1993) Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational behaviour in 6-hydroxydopamine-lesioned rats. Brain Res 613:347–351

    Article  PubMed  CAS  Google Scholar 

  23. Björklund LM, Sanchez-Pemaute R, Chung S et al (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99:2344–2349

    Article  PubMed  CAS  Google Scholar 

  24. Markwell MAK, Haas SM, Bieber LL et al (1978) A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem 87:206–210

    Article  PubMed  CAS  Google Scholar 

  25. Hermida-Ameijeiras A, Méndez-Álvarez E, Sánchez-Iglesias S et al (2004) Autoxidation and MAO-mediated metabolism of dopamine as a potential cause of oxidative stress: role of ferrous and ferric ions. Neurochem Int 45:103–116

    Article  PubMed  CAS  Google Scholar 

  26. Méndez-Álvarez E, Soto-Otero R, Hermida-Ameijeiras A et al (2002) Effects of aluminum and zinc on the oxidative stress caused by 6-hydroxydopamine autoxidation: relevance for the pathogenesis of Parkinson’s disease. Biochim Biophys Acta 1586:155–168

    PubMed  Google Scholar 

  27. Przedborski S, Levivier M, Jiang H et al (1995) Dose-dependent lesions of the dopaminergic nigrostriatal pathway induce by intrastriatal injection of 6-hydroxydopamine. Neuroscience 67:631–647

    Article  PubMed  CAS  Google Scholar 

  28. Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401–415

    Article  PubMed  CAS  Google Scholar 

  29. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence. Nat Med 10:S18–S25

    Article  PubMed  Google Scholar 

  30. Przedborski S, Tieu K, Perier et al (2004) MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. J Bioenerg Biomembr 36:375–379

    Article  PubMed  CAS  Google Scholar 

  31. Giasson BI, Lee VM (2000) A new link between pesticides and Parkinson’s disease. Nat Neurosci 3:1227–1228

    Article  PubMed  CAS  Google Scholar 

  32. Giasson BI, Duda JE, Murray IV et al (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration is synucleinopathy lesions. Science 290:985–989

    Article  PubMed  CAS  Google Scholar 

  33. Trojanowski JQ, Lee M-Y (2003) Parkinson’s disease and related α-synucleinopathies are brain amyloidoses. Ann NY Acad Sci 991:107–110

    Article  PubMed  CAS  Google Scholar 

  34. Krantic S, Mechawar N, Reix S et al (2005) Molecular basis of programmed cell death involved in neurodegeneration. Trends Neurosci 28:670–676

    PubMed  CAS  Google Scholar 

  35. Cutillas B, Espejo M, Gil J et al (1999) Caspase inhibition protects nigral neurons against 6-OHDA-induced retrograde degeneration. NeuroReport 10:2605–2608

    Article  PubMed  CAS  Google Scholar 

  36. Przedborski S, Goldman JE (2004) Pathogenic role of glia cells in Parkinson’s disease. In: Hertz L (ed) Non-neuronal cells of the nervous system: function and dysfunction. Elsevier, New York, 967–982

    Google Scholar 

  37. Rodrigues RW, Gomide VC, Chadi G (2001) Astroglial and microglial reaction after a partial nigrostriatal degeneration induced by the striatal injection of different doses of 6-hydroxydopamine. Int J Neurosci 109:91–126

    Article  PubMed  CAS  Google Scholar 

  38. Kamsler A, Segal M (2004) Hydrogen peroxide as a diffusible signal molecule in synaptic plasticity. Mol Neurobiol 29:167–178

    Article  PubMed  CAS  Google Scholar 

  39. Vroegop SM, Decker DE, Buxser SE (1995) Localization of damage induced by reactive oxygen species in cultured cells. Free Radic Biol Med 18:141–151

    Article  PubMed  CAS  Google Scholar 

  40. Lee CS, Sauer H, Björklund A (1996) Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat. Neuroscience 72:641–653

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Grant BFI2003-00493 from the Ministerio de Ciencia y Tecnología with the contribution of the European Regional Development Found (Madrid, Spain) and Grant PGDIT03PXIB20804PR from the Xunta de Galicia (Santiago de Compostela, Spain). The authors are indebted to Dr. J.L. Otero-Cepeda for statistical analysis of the results.

Author information

Authors and Affiliations

  1. Laboratory of Neurochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Santiago de Compostela, San Francisco 1, 15782, Santiago de Compostela, Spain

    Sofía Sánchez-Iglesias, Estefanía Méndez-Álvarez & Ramón Soto-Otero

  2. Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, San Francisco 1, 15782, Santiago de Compostela, Spain

    Pablo Rey & José Luis Labandeira-García

Authors
  1. Sofía Sánchez-Iglesias
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pablo Rey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Estefanía Méndez-Álvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José Luis Labandeira-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ramón Soto-Otero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramón Soto-Otero.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sánchez-Iglesias, S., Rey, P., Méndez-Álvarez, E. et al. Time-Course of Brain Oxidative Damage Caused by Intrastriatal Administration of 6-Hydroxydopamine in a Rat Model of Parkinson’s Disease. Neurochem Res 32, 99–105 (2007). https://doi.org/10.1007/s11064-006-9232-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-006-9232-6

Keywords

Search

Navigation