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Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease

Nature Medicine volume 1, pages 226–231 (1995)Cite this article

Abstract

A high survival rate of grafted dopamine neurons is crucial for reversing neurological deficits following brain tissue transplantation in Parkinson's disease. For unknown reasons the survival rate of transplanted dopamine neurons is only around 10% in experimental animals. The hypothesis that oxidative stress causes the loss of transplanted neurons was tested by grafting neurons from transgenic mice that overexpress Cu/Zn superoxide dismutase. Compared with the survival of those taken from non-transgenic littermates, the survival was 4 times higher for the transgenic dopamine neurons with a concomitant more extensive functional recovery. The results provide direct support for the free radical hypothesis of dopaminergic neuron death in brain tissue grafting.

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References

  1. Lindvall, O. Neural transplantation in Parkinson's disease. in Functional Neural Transplantation (eds. Dunnett, S.B & Bj¨rklund, A.) 103–137 (Raven Press, New York, 1994).

    Google Scholar 

  2. Sauer, H. & Brundin, P. Effects of cool storage on survival and function of in-trastriatal ventral mesencephalic grafts. Restor. Neurol. Neurosci. 2, 123–135 (1991).

    CAS  PubMed  Google Scholar 

  3. Brundin, P. et al. Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release. Exp. Brain Res. 70, 192–208 (1988).

    CAS  PubMed  Google Scholar 

  4. Frodl, E.M., Duan, W.-M., Sauer, H., Kupsch, A. & Brundin, P. Human embryonic dopamine neurons xenografted to the rat: Effects of cryopreservation and varying regional source of donor cells on transplant survival, morphology and function. Brain Res. 647, 286–298 (1994).

    Article  CAS  Google Scholar 

  5. Nakao, N., Frodl, E.M., Duan, W.-M., Widner, H. & Brundin, P. Lazaroids improve the survival of grafted rat embryonic dopaminergic neurons. Proc. natn. Acad. Sci. U.S.A. 91, 12408–12412 (1994).

    Article  CAS  Google Scholar 

  6. Duan, W.-M., Widner, H. & Brundin, P. Temporal pattern of host response against intrastriatal grafts of syngeneic, allogeneic or xenogeneic embryonic neuronal tissue in rats. Exp. Brain Res., in the press.

  7. Hall, E.D. & Braughler, J.M. Central nervous system trauma and stroke: II. Physiological and pharmacological evidence for the involvement of oxygen radicals and lipid peroxidation. Free Rad. Biol. Med. 6, 303–313 (1989).

    Article  CAS  Google Scholar 

  8. Siesjö, B.K., Aghardh, C.-D. & Bengtsson, F. Free radicals and brain damage. Cereb. Brain Metab. Rev. 1, 165–211 (1989).

    Google Scholar 

  9. Olanow, C.W. A radical hypothesis for neurodegeneration. Trends Neurosci. 16, 439–444 (1994).

    Article  Google Scholar 

  10. Coyle, J.T. & Puttfarcken, P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 262, 689–694 (1993).

    Article  CAS  Google Scholar 

  11. Epstein, C.J. et al. Transgenic mice with increased CuZn-superoxide dismutase activity: an animal model of dosage effects in Down syndrome. Proc. natn. Acad. Sci. U.S.A. 84, 8044–8048 (1987).

    Article  CAS  Google Scholar 

  12. Fridovich, I. Superoxide dismutases. Adv. Enzym. 58, 61–97 (1986).

    CAS  Google Scholar 

  13. Przedborski, S. et al. Superoxide dismutase, catalase, and glutathione peroxidase activities in copper/zinc-superoxide dismutase transgenic mice. J. Neurochem. 58, 1760–1767 (1992).

    Article  CAS  Google Scholar 

  14. Cadet, J.L. et al. Attenuation of methamphetamine-induced neurotoxicity in copper/zinc superoxide dismutase transgenic mice. J. Neurochem. 62, 380–383 (1994).

    Article  CAS  Google Scholar 

  15. Kinouchi, H. et al. Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn Superoxide dismutase. Proc. natn. Acad. Sci. U.S.A. 88, 11158–11162 (1992).

    Article  Google Scholar 

  16. Przedborski, S. et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. J. Neurosci. 12, 1658–1667 (1992).

    Article  CAS  Google Scholar 

  17. Baker, H., Joh, T.H. & Reis, D.J. Genetic control of number of midbrain dopaminergic neurons in inbred strains of mice: Relationship to size and neuronal density of the striatum. Proc. natn. Acad. Sci. U.S.A. 77, 4369–4373 (1980).

    Article  CAS  Google Scholar 

  18. German, D.C., Schlusselberg, D.S. & Woodward, D.J. Three-dimensional computer reconstruction of midbrain dopaminergic neuronal populations: From mouse to man. J. Neural Transm. 57, 243–254 (1983).

    Article  CAS  Google Scholar 

  19. Triarhou, L.C., Norton, J. & Ghetti, B. Mesencephalic dopamine cell deficit involves areas A8, A9 and A10 in weaver mutant mice. Exp. Brain Res. 70, 256–265 (1988).

    Article  CAS  Google Scholar 

  20. Chadi, G. et al. Protective actions of human recombinant basic fibroblast growth factor on MPTP-lesioned nigrostriatal dopamine neurons after intraventricular infusion. Exp. Brain Res. 97, 145–158 (1993).

    Article  CAS  Google Scholar 

  21. Dexter, D.T. et al. Nigral dopaminergic cell loss in vitamin E deficient rats. NeuroReport 5, 1773–1776 (1994).

    Article  CAS  Google Scholar 

  22. Dexter, D.T. et al. Nigrostriatal function in vitamin E deficiency: Clinical, experimental, and positron emission tomographic studies. Ann. Neurol. 35, 298–303 (1994).

    Article  CAS  Google Scholar 

  23. Oppenheim, R.W. Cell death during development of the nervous system. Annu. Rev. Neurosci. 14, 453–501 (1991).

    Article  CAS  Google Scholar 

  24. Mahalik, T.J., Hahn, W.E., Clayton, G.H. & Owens, G.P. Programmed cell death in developing grafts of fetal substantia nigra. Exp. Neurol. 129, 27–36 (1994).

    Article  CAS  Google Scholar 

  25. Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A. & Freeman, B.A. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. natn. Acad. Sci. U.S.A. 87, 1620–1624 (1990).

    Article  CAS  Google Scholar 

  26. Lipton, S.A. et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632 (1993).

    Article  CAS  Google Scholar 

  27. Huang, Z. et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265, 1883–1885 (1994).

    Article  CAS  Google Scholar 

  28. Rosen, D.R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familiar amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

    Article  CAS  Google Scholar 

  29. Deng, H.-X. et al. Amyotrophic lateral sclerosis and structural defects in CuZn superoxide dismutase. Science 261, 1047–1051 (1993).

    Article  CAS  Google Scholar 

  30. Gurney, M.E. et al. Motor neuron degeneration in mice that express a human CuZn superoxide dismutase mutation. Science 264, 1772–1775 (1994).

    Article  CAS  Google Scholar 

  31. Sofic, E., Paulus, W., Jellinger, K., Riederer, P. & Youdium, M.B.H. Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J. Neurochem. 56, 978–982 (1991).

    Article  CAS  Google Scholar 

  32. Dexter, D.T. et al. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J. Neurochem. 52, 1830–1836 (1989).

    Article  CAS  Google Scholar 

  33. Riederer, P. et al. Transition metals, ferritin, glutathione, ascorbic acid in parkinsonian brains. J. Neurochem. 52, 515–520 (1989).

    Article  CAS  Google Scholar 

  34. Sian, J. et al. Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol. 36, 348–355 (1994).

    Article  CAS  Google Scholar 

  35. Dexter, D.T. et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J. Neurochem. 52, 381–389 (1989).

    Article  CAS  Google Scholar 

  36. Lieman-Hurwitz, J., Dafni, N., Lavie, V. & Groner, Y. Human cytoplasmic superoxide dismutase cDNA clone: A probe for studying the molecular biology of Down syndrome. Proc. natn. Acad. Sci. U.S.A. 79, 2808–2811 (1982).

    Article  CAS  Google Scholar 

  37. Brundin, P., Isacson, O. & Björklund, A. Monitoring of cell viability in suspension of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res. 331, 251–259 (1985).

    Article  CAS  Google Scholar 

  38. Ungerstedt, U. & Arbuthnott, G.W. Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system. Brain Res. 24, 486–493 (1970).

    Article  Google Scholar 

  39. Schmidt, R.H., Björklund, A., Stenevi, U., Dunnett, S.B. & Gage, F.H. Intracerebral grafting of neuronal cell suspensions. III. Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism. Acta. physiol. scand. Suppl. 522, 19–28 (1983).

    CAS  PubMed  Google Scholar 

  40. Abercrombie, M. Estimation of nuclear population from microtome sections. Anat. Rec. 94, 239–247 (1946).

    Article  CAS  Google Scholar 

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Author notes

  1. Faye A. Eggerding

    Present address: Applied Biosystems Division, Perkin-Elmer Corporation, Foster City, California, 94404, USA

Authors and Affiliations

  1. Section for Neuronal Survival, Department of Medical Cell Research, University of Lund, Sweden

    Naoyuki Nakao, Eva M. Frodl, Håkan Widner & Patrik Brundin

  2. Department of Neurological Surgery, Wakayama Medical College, Wakayama City, Japan

    Naoyuki Nakao

  3. Department of Pediatrics, University of California, San Francisco, California, 94143, USA

    Elaine Carlson, Faye A. Eggerding & Charles J. Epstein

Authors
  1. Naoyuki Nakao
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  2. Eva M. Frodl
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  3. Håkan Widner
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  4. Elaine Carlson
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  5. Faye A. Eggerding
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  6. Charles J. Epstein
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  7. Patrik Brundin
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Nakao, N., Frodl, E., Widner, H. et al. Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease. Nat Med 1, 226–231 (1995). https://doi.org/10.1038/nm0395-226

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