Skip to main content
SpringerLink
Log in

NMDA-receptors are involved in Cu2+/paraquat-induced death of cultured cerebellar granule neurons

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Rat cultured cerebellar granule neurons (CGNs) were not sensitive to CuCl2 (1-10 µM, 24 h), whereas paraquat (150 µM) decreased neuronal survival to 79 ± 3% of control level. Simultaneous treatment of CGNs with paraquat and CuCl2 (2, 5, or 10 µM Cu2+/paraquat) caused significant copper dose-dependent death, lowering their survival to 56 ± 4, 37 ± 3, or 16 ± 2%, respectively, and stimulating elevated production of free radicals in CGNs. Introduction of vitamin E, a non-competitive antagonist of NMDA subtype of glutamate receptors (MK-801), and also removal of glutamine from the incubation medium decreased toxicity of Cu2+/paraquat mixture. However, addition of Cu2+ into the incubation medium did not affect CGNs death caused by glutamate. These data emphasize that excessive copper in the brain may trigger oxidative stress, which in turn results in release of glutamate, overstimulation of glutamate receptors, and neuronal death.

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

Similar content being viewed by others

References

  1. Stelmashook, E. V., Isaev, N. K., Genrikhs, E. E., Amelkina, G. A., Khaspekov, L. G., Skrebitsky, V. G., and Illarioshkin, S. N. (2014) Role of zinc and copper ions in the pathogenetic mechanisms of Alzheimer’s and Parkinson’s diseases, Biochemistry (Moscow), 79, 391–396.

    Article  CAS  Google Scholar 

  2. Gaier, E. D., Eipper, B. A., and Mains, R. E. (2013) Copper signaling in the mammalian nervous system: synaptic effects, J. Neurosci. Res., 91, 2–19.

    CAS  PubMed  Google Scholar 

  3. Kardos, J., Kovacs, I., Hajos, F., Kalman, M., and Simonyi, M. (1989) Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability, Neurosci. Lett., 103, 139–144.

    Article  CAS  PubMed  Google Scholar 

  4. Jomova, K., Vondrakova, D., Lawson, M., and Valko, M. (2010) Metals, oxidative stress and neurodegenerative disorders, Mol. Cell. Biochem., 345, 91–104.

    Article  CAS  PubMed  Google Scholar 

  5. Cartwright, G. E., and Wintrobe, M. M. (1964) Copper metabolism in normal subjects, Am. J. Clin. Nutr., 14, 224–232.

    CAS  PubMed  Google Scholar 

  6. Linder, M. C. (1991) Biochemistry of Copper, Plenum Press, New York.

    Book  Google Scholar 

  7. Isaev, N. K., Stelmashook, E. V., Dirnagl, U., Plotnikov, E. Yu., Kuvshinova, E. A., and Zorov, D. B. (2008) Mitochondrial free radical production induced by glucose deprivation in cerebellar granule neurons, Biochemistry (Moscow), 73, 149–155.

    Article  CAS  Google Scholar 

  8. Eagle, H. (1959) Amino acid metabolism in mammalian cell cultures, Science, 130, 432–437.

    Article  CAS  PubMed  Google Scholar 

  9. Gallo, V., Ciotti, M. T., Aloisi, F., and Levi, G. (1982) Selective release of glutamate from cerebellar granule cells differen tiating in culture, Proc. Natl. Acad. Sci. USA, 79, 7919–7923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McCaslin, P. P., and Morgan, W. W. (1987) Cultured cerebellar cells as an in vitro model of excitatory amino acid receptor function, Brain Res., 417, 380–384.

    Article  CAS  PubMed  Google Scholar 

  11. Stelmashook, E. V., Novikova, S. V., and Isaev, N. K. (2010) Glutamine effect on cultured granule neuron death induced by glucose deprivation and chemical hypoxia, Biochemistry (Moscow), 75, 1039–1044.

    Article  CAS  Google Scholar 

  12. Gonzalez-Polo, R. A., Rodriguez-Martin, A., Moran, J. M., Niso, M., Soler, G., and Fuentes, J. M. (2004) Paraquat-induced apoptotic cell death in cerebellar granule cells, Brain Res., 1011, 170–176.

    Article  CAS  PubMed  Google Scholar 

  13. Cristovao, A. C., Choi, D. H., Baltazar, G., Beal, M. F., and Kim, Y. S. (2009) The role of NADPH oxidase 1derived reactive oxygen species in paraquat-mediated dopaminergic cell death, Antioxid. Redox Signal., 11, 2105-2018.

  14. Stelmashook, E. V., Isaev, N. K., Plotnikov, E. Y., Uzbekov, R. E., Alieva, I. B., Arbeille, B., and Zorov, D. B. (2009) Effect of transitory glucose deprivation on mitochondrial structure and functions in cultured cerebellar granule neurons, Neurosci. Lett., 461, 140–144.

    Article  CAS  PubMed  Google Scholar 

  15. Liu, Y., Lu, L., Hettinger, C. L., Dong, G., Zhang, D., Rezvani, K., Wang, X., and Wang, H. (2014) Ubiquilin-1 protects cells from oxidative stress and ischemic stroke caused tissue injury in mice, J. Neurosci., 34, 2813–2821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stelmashook, E. V., Isaev, N. K., and Zorov, D. B. (2007) Paraquat potentiates glutamate toxicity in immature cultures of cerebellar granule neurons, Toxicol. Lett., 174, 82–88.

    Article  CAS  PubMed  Google Scholar 

  17. Isaev, N. K., Genrikhs, E. E., Aleksandrova, O. P., Zelenova, E. A., and Stelmashook, E. V. (2016) Glucose deprivation stimulates Cu2+ toxicity in cultured cerebellar granule neurons and Cu2+-dependent zinc release, Toxicol. Lett., 250/251, 29–34.

    Article  Google Scholar 

  18. Su, X. Y., Wu, W. H., Huang, Z. P., Hu, J., Lei, P., Yu, C. H., Zhao, Y. F., and Li, Y. M. (2007) Hydrogen peroxide can be generated by tau in the presence of Cu(II), Biochem. Biophys. Res. Commun., 358, 661–665.

    Article  CAS  PubMed  Google Scholar 

  19. Samuele, A., Mangiagalli, A., Armentero, M. T., Fancellu, R., Bazzini, E., Vairetti, M., Ferrigno, A., Richelmi, P., Nappi, G., and Blandini, F. (2005) Oxidative stress and pro-apoptotic conditions in a rodent model of Wilson’s disease, Biochim. Biophys. Acta, 1741, 325–330.

    Article  CAS  PubMed  Google Scholar 

  20. Kumar, V., Kalita, J., Misra, U. K., and Bora, H. K. (2015) A study of dose response and organ usceptibility of copper toxicity in a rat model, J. Trace Elem. Med. Biol., 29, 269–274.

    Article  CAS  PubMed  Google Scholar 

  21. Gaetke, L. M., Chow-Johnson, H. S., and Chow, C. K. (2014) Copper: toxicological relevance and mechanisms, Arch. Toxicol., 88, 1929–1938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Isaev, N. K., Stelmashook, E. V., Ruscher, K., Andreeva, N. A., and Zorov, D. B. (2004) Menadione reduces rotenone-induced cell death in cerebellar granule neurons, Neuroreport, 15, 2227–2231.

    Article  CAS  PubMed  Google Scholar 

  23. Rodriguez-Rocha, H., Garcia-Garcia, A., Pickett, C., Li, S., Jones, J., Chen, H., Webb, B., Choi, J., Zhou, Y., Zimmerman, M. C., and Franco, R. (2013) Compartmentalized oxidative stress in dopaminergic cell death induced by pesticides and complex I inhibitors: distinct roles of superoxide anion and superoxide dismutases, Free Radic. Biol. Med., 61, 370–383.

    Article  CAS  PubMed  Google Scholar 

  24. Stelmashook, E. V., Lozier, E. R., Goryacheva, E. S., Mergenthaler, P., Novikova, S. V., Zorov, D. B., and Isaev, N. K. (2010) Glutamine-mediated protection from neuronal cell death depends on mitochondrial activity, Neurosci. Lett., 482, 151–155.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neurology Research Center, 125367, Moscow, Russia

    E. V. Stelmashook, E. E. Genrikhs, O. P. Aleksandrova, E. A. Zelenova & N. K. Isaev

  2. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    G. A. Amelkina, E. A. Zelenova & N. K. Isaev

Authors
  1. E. V. Stelmashook
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. E. Genrikhs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O. P. Aleksandrova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. A. Amelkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. A. Zelenova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. K. Isaev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to E. V. Stelmashook or N. K. Isaev.

Additional information

Original Russian Text © E. V. Stelmashook, E. E. Genrikhs, O. P. Aleksandrova, G. A. Amelkina, E. A. Zelenova, N. K. Isaev, 2016, published in Biokhimiya, 2016, Vol. 81, No. 8, pp. 1137-1144.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stelmashook, E.V., Genrikhs, E.E., Aleksandrova, O.P. et al. NMDA-receptors are involved in Cu2+/paraquat-induced death of cultured cerebellar granule neurons. Biochemistry Moscow 81, 899–905 (2016). https://doi.org/10.1134/S0006297916080113

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297916080113

Keywords

Search

Navigation