Copper Increases Brain Oxidative Stress and Enhances the Ability of 6-Hydroxydopamine to Cause Dopaminergic Degeneration in a Rat Model of Parkinson’s Disease

Abstract

Redox properties enable copper to perform its essential role in many biological processes, but they can also convert it into a potentially hazardous element. Its dyshomeostasis may have serious neurological consequences, and its possible involvement in Parkinson’s disease and other neurodegenerative disorders has been suggested. The in vitro and ex vivo ability of copper to increase oxidative stress has already been demonstrated, and the aim of the present study was to assess in vivo the capacity of copper to cause brain oxidative damage and its ability to increase the dopaminergic degeneration induced by 6-hydroxydopamine. We found that chronic copper administration (10 mg Cu2+/kg/day, IP) causes its accumulation in different brain areas (cortex, striatum, nigra) and was accompanied by an increase in TBARS levels and a decrease in protein free-thiol content in the cortex. A decrease in catalase activity and an increase in glutathione peroxidase activity were also observed in the cortex. The intrastriatal administration of Cu2+ caused an increase in some indices of oxidative stress (TBARS and protein free-thiol content) in striatum and nigra, but was unable to induce dopaminergic degeneration. However, when copper was intrastriatally coadministered with 6-hydroxydopamine, it increased dopaminergic degeneration, a fact that was also accompanied by an increase in the assayed indices of oxidative stress, a decrease in catalase activity, and an augmentation in glutathione activity. Evidently, copper cannot cause neurodegeneration per se, but may potentiate the action of other factors involved in the pathogenesis of Parkinson’s disease through oxidative stress.

This is a preview of subscription content, access via your institution.

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

References

  1. 1.

    Gaier ED, Eipper BA, Mains RE (2013) Copper signaling in the mammalian nervous system: synaptic effects. J Neurosci Res 91:2–19. https://doi.org/10.1002/jnr.23143

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Scheiber IF, Mercer JF, Dringen R (2014) Metabolism and functions of copper in brain. Prog Neurobiol 116:33–57. https://doi.org/10.1016/j.pneurobio.2014.01.002

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Halliwell B, Gutteridge JM (1990) Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 186:1–85

    CAS  Article  Google Scholar 

  4. 4.

    Youdim MB, Fridkin M, Zheng H (2005) Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mech Ageing Dev 126(2):317–326. https://doi.org/10.1016/j.mad.2004.08.023

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Dringen R (2000) Glutathione metabolism and oxidative stress in neurodegeneration. Eur J Biochem 267:4903

    CAS  Article  Google Scholar 

  6. 6.

    Rossi L, Lombardo MF, Ciriolo MR, Rotilio G (2004) Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance. Neurochem Res 29:493–504. https://doi.org/10.1023/B:NERE.0000014820.99232.8a

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658. https://doi.org/10.1111/j.1471-4159.2006.03907.x

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Wittung-Stafshede P (2015) Unresolved questions in human copper pump mechanisms. Q Rev Biophys 48:471–478. https://doi.org/10.1017/S0033583515000128

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Choi B-S, Zheng W (2009) Copper transport to the brain by the blood-brain barrier and blood-CSF barrier. Brain Res 1248:14–21. https://doi.org/10.1016/j.brainres.2008.10.056

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Arciello M, Capo CR, D’Annibale S, Cozzolino M, Ferri A, Carrì MT, Rossi L (2011) Copper depletion increases the mitochondrial-associated SOD1 in neuronal cells. Biometals 24:269–278. https://doi.org/10.1007/s10534-010-9392-3

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Nevitt T, Ohrvik H, Thiele DJ (2012) Charting the travels of copper in eukaryotes from yeast to mammals. Biochim Biophys Acta 1823:1580–1593. https://doi.org/10.1016/j.bbamcr.2012.02.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Rahil-Khazen R, Bolann BJ, Ulvik RJ (2002) Correlations of trace element levels within and between different normal autopsy tissues analyzed by inductively coupled plasma atomic emission spectrometry (ICP-AES). Biometals 15:87–98

    CAS  Article  Google Scholar 

  13. 13.

    Lech T, Sadlik JK (2007) Copper concentration in body tissues and fluids in normal subjects of southern Poland. Biol Trace Elem Res 118:10–15. https://doi.org/10.1007/s12011-007-0014-z

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Davies KM, Bohic S, Carmona A, Ortega R, Cottam V, Hare DJ, Finberg JPM, Reyes S et al (2014) Copper pathology in vulnerable brain regions in Parkinson’s disease. Neurobiol Aging 35:858–866. https://doi.org/10.1016/j.neurobiolaging.2013.09.034

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Davies KM, Hare DJ, Cottam V, Chen N, Hilgers L, Halliday G, Mercer JFB, Double KL (2013) Localization of copper and copper transporters in the human brain. Metallomics 5:43–51. https://doi.org/10.1039/C2MT20151H

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Warren PJ, Earl CJ, Thompson RHS (1960) The distribution of copper in human brain. Brain 83:709–717. https://doi.org/10.1093/brain/83.4.709

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Goldberg WJ, Allen N (1981) Determination of Cu, Mn, Fe, and Ca in six regions of normal human brain, by atomic absorption spectroscopy. Clin Chem 27:562–564

    CAS  PubMed  Google Scholar 

  18. 18.

    Popescu BFG, George MJ, Bergmann U et al (2009) Mapping metals in Parkinson’s and normal brain using rapid-scanning X-ray fluorescence. Phys Med Biol 54:651–663. https://doi.org/10.1088/0031-9155/54/3/012

    Article  PubMed  Google Scholar 

  19. 19.

    Enochs WS, Sarna T, Zecca L, Riley PA, Swartz HM (1994) The roles of neuromelanin, binding of metal ions, and oxidative cytotoxicity in the pathogenesis of Parkinson’s disease: a hypothesis. J Neural Transm 7:83–100

    CAS  Article  Google Scholar 

  20. 20.

    Szerdahelyi P, Kasa P (1986) Histochemical demonstration of copper in normal rat brain and spinal cord. Evidence of localization in glial cells. Histochemistry 85:341–347

    CAS  Article  Google Scholar 

  21. 21.

    Kodama H (1993) Recent developments in Menkes disease. J Inherit Metab Dis 16:791–799. https://doi.org/10.1007/BF00711911

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Becker JS, Salber D (2010) New mass spectrometric tools in brain research. Trends Anal Chem 29:966–979. https://doi.org/10.1016/j.trac.2010.06.009

    CAS  Article  Google Scholar 

  23. 23.

    Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14

    CAS  Article  Google Scholar 

  24. 24.

    de Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535. https://doi.org/10.1016/S1474-4422(06)70471-9

    Article  PubMed  Google Scholar 

  25. 25.

    McNaught KS, Olanow CW (2006) Protein aggregation in the pathogenesis of familial and sporadic Parkinson’s disease. Neurobiol Aging 27:530–545. https://doi.org/10.1016/j.neurobiolaging.2005.08.012

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9:13–24. https://doi.org/10.1038/nrneurol.2012.242

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Sulzer D (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30:244–250. https://doi.org/10.1016/j.tins.2007.03.009

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Antony PM, Diederich NJ, Kruger R, Balling R (2013) The hallmarks of Parkinson’s disease. FEBS J 280:5981–5993. https://doi.org/10.1111/febs.12335

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Pall HS, Williams AC, Blake DR, Lunec J, Gutteridge JM, Hall M, Taylor A (1987) Raised cerebrospinal-fluid copper concentration in Parkinson’s disease. Lancet 2(8553):238–241

    CAS  Article  Google Scholar 

  30. 30.

    Hozumi I, Hasegawa T, Honda A, Ozawa K, Hayashi Y, Hashimoto K, Yamada M, Koumura A et al (2011) Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. J Neurol Sci 303:95–99. https://doi.org/10.1016/j.jns.2011.01.003

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR (2007) Wilson disease: description of 282 patients evaluated over 3 decades. Medicine 86:112–121. https://doi.org/10.1097/MD.0b013e318045a00e

    Article  PubMed  Google Scholar 

  32. 32.

    Paris I, Dagnino-Subiabre A, Marcelain K, Bennett LB, Caviedes P, Caviedes R, Azar CO, Segura-Aguilar J (2001) Copper neurotoxicity is dependent on dopamine-mediated copper uptake and one-electron reduction of aminochrome in a rat substantia nigra neuronal cell line. J Neurochem 77:519–529

    CAS  Article  Google Scholar 

  33. 33.

    Gorell JM, Peterson EL, Rybicki BA, Johnson CC (2004) Multiple risk factors for Parkinson’s disease. J Neurol Sci 217:169–174

    Article  Google Scholar 

  34. 34.

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

    CAS  Article  Google Scholar 

  35. 35.

    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

    CAS  Article  Google Scholar 

  36. 36.

    Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic, London

    Google Scholar 

  37. 37.

    Sánchez-Iglesias S, Rey P, Méndez-Álvarez E, Labandeira-García JL, Soto-Otero R (2007) 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. https://doi.org/10.1007/s11064-006-9232-6

    CAS  Article  PubMed  Google Scholar 

  38. 38.

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

    CAS  Article  Google Scholar 

  39. 39.

    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. https://doi.org/10.1016/j.neuint.2003.11.018

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Flohe L, Gunzler WA (1984) Assays of glutathione peroxidase. Methods Enzymol 105:114–121

    CAS  Article  Google Scholar 

  41. 41.

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

    CAS  Article  Google Scholar 

  42. 42.

    López-Real A, Rey P, Soto-Otero R et al (2005) Angiotensin-converting enzyme inhibition reduces oxidative stress and protects dopaminergic neurons in a 6-hydroxydopamine rat model of parkinsonism. J Neurosci Res 81:865–873. https://doi.org/10.1002/jnr.20598

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Gundersen HJ, Bendtsen TF, Korbo L et al (1988) Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96:379–394

    CAS  Article  Google Scholar 

  44. 44.

    Torres EM, Meldrum A, Kirik D, Dunnett SB (2006) An investigation of the problem of two-layered immunohistochemical staining in paraformaldehyde fixed sections. J Neurosci Methods 158:64–74. https://doi.org/10.1016/j.jneumeth.2006.05.016

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Cruces-Sande A, Méndez-Álvarez E, Soto-Otero R (2017) Copper increases the ability of 6-hydroxydopamine to generate oxidative stress and the ability of ascorbate and glutathione to potentiate this effect: potential implications in Parkinson’s disease. J Neurochem 141:738–749. https://doi.org/10.1111/jnc.14019

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Zheng W, Monnot AD (2012) Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacol Ther 133:177–188. https://doi.org/10.1016/j.pharmthera.2011.10.006

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY (2007) Function and regulation of human copper-transporting ATPases. Physiol Rev 87:1011–1046. https://doi.org/10.1152/physrev.00004.2006

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Pal A, Prasad R (2016) Regional distribution of copper, zinc and iron in brain of Wistar rat model for non-Wilsonian brain copper toxicosis. Indian J Clin Biochem 31:93–98. https://doi.org/10.1007/s12291-015-0503-3

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Sánchez-Iglesias S, Méndez-Álvarez E, Iglesias-González J, Muñoz-Patiño A, Sánchez-Sellero I, Labandeira-García JL, Soto-Otero R (2009) Brain oxidative stress and selective behaviour of aluminium in specific areas of rat brain: potential effects in a 6-OHDA-induced model of Parkinson’s disease. J Neurochem 109:879–888

    Article  Google Scholar 

  50. 50.

    Iglesias-González J, Sánchez-Iglesias S, Méndez-Álvarez E, Rose S, Hikima A, Jenner P, Soto-Otero R (2012) Differential toxicity of 6-hydroxydopamine in SH-SY5Y human neuroblastoma cells and rat brain mitochondria: protective role of catalase and superoxide dismutase. Neurochem Res 37:2150–2160. https://doi.org/10.1007/s11064-012-0838-6

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Iglesias-González J, Sánchez-Iglesias S, Beiras-Iglesias A, Méndez-Álvarez E, Soto-Otero R (2017) Effects of aluminium on rat brain mitochondria bioenergetics: an in vitro and in vivo study. Mol Neurobiol 54:563–570. https://doi.org/10.1007/s12035-015-9650-z

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Yu WR, Jiang H, Wang J, Xie JX (2008) Copper (Cu2+) induces degeneration of dopaminergic neurons in the nigrostriatal system of rats. Neurosci Bull 24:73–78. https://doi.org/10.1007/s12264-008-0073-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was partially supported by the Galician Government (XUGA), Santiago de Compostela, Spain (No. 09CSA005298PR), the Spanish Ministry of Economy and Competitiveness (grant number BFU2015-70523), the Spanish Ministry of Health (CIBERNED), and FEDER (Regional European Development Fund).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ramón Soto-Otero.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cruces-Sande, A., Rodríguez-Pérez, A.I., Herbello-Hermelo, P. et al. Copper Increases Brain Oxidative Stress and Enhances the Ability of 6-Hydroxydopamine to Cause Dopaminergic Degeneration in a Rat Model of Parkinson’s Disease. Mol Neurobiol 56, 2845–2854 (2019). https://doi.org/10.1007/s12035-018-1274-7

Download citation

Keywords

  • Copper
  • 6-Hydroxydopamine
  • Oxidative stress
  • Glutathione peroxidase
  • Catalase
  • Dopaminergic degeneration