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. 1994 Dec 20;91(26):12408–12412. doi: 10.1073/pnas.91.26.12408

Lazaroids improve the survival of grafted rat embryonic dopamine neurons.

N Nakao 1, E M Frodl 1, W M Duan 1, H Widner 1, P Brundin 1
PMCID: PMC45447  PMID: 7809050

Abstract

In rodent models of Parkinson disease in which transplants of dissociated rodent and human embryonic mesencephalic tissue, rich in dopamine neurons, have been studied, only 5-20% of the dopamine neurons survive the implantation procedure. We have investigated the effects of inhibiting free radical generation with two lazaroids, U-74389G and U-83836E, on the survival of embryonic rat dopamine neurons. U-74389G is a 21-aminosteroid, and U-83836E combines the piperazinyl pyrimidine portion of 21-aminosteroids with the antioxidant ring of alpha-tocopherol. In an initial study, we found that the lazaroids markedly prolonged the period after tissue dissociation that an embryonic mesencephalic cell suspension exhibits high cell viability in vitro, as assessed by using a dye exclusion method. In a second series of experiments, addition of lazaroids to dissociated mesencephalic graft tissue increased the yield of surviving rat dopamine neurons 2.6-fold after implantation in the dopamine-denervated rat striatum. The improved survival correlated with an earlier onset of graft-induced functional effects in the amphetamine-induced rotation test. Thus, inhibition of free radical generation can significantly increase the yield of grafted embryonic dopamine neurons. Addition of lazaroids to the graft preparation is a relatively simple modification of the transplantation protocol and could readily be applied in a clinical setting. Moreover, since iron-dependent lipid peroxidation has been suggested to play a role in the death of nigral dopamine neurons in Parkinson disease and lazaroids are particularly potent inhibitors of such processes, the findings may have implications for the pathogenesis of this disease.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Björklund A., Dunnett S. B., Stenevi U., Lewis M. E., Iversen S. D. Reinnervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res. 1980 Oct 20;199(2):307–333. doi: 10.1016/0006-8993(80)90692-7. [DOI] [PubMed] [Google Scholar]
  2. Brundin P., Barbin G., Strecker R. E., Isacson O., Prochiantz A., Björklund A. Survival and function of dissociated rat dopamine neurones grafted at different developmental stages or after being cultured in vitro. Brain Res. 1988 Apr 1;467(2):233–243. doi: 10.1016/0165-3806(88)90027-2. [DOI] [PubMed] [Google Scholar]
  3. Brundin P., Isacson O., Björklund A. Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res. 1985 Apr 8;331(2):251–259. doi: 10.1016/0006-8993(85)91550-1. [DOI] [PubMed] [Google Scholar]
  4. Brundin P., Isacson O., Gage F. H., Björklund A. Intrastriatal grafting of dopamine-containing neuronal cell suspensions: effects of mixing with target or non-target cells. Brain Res. 1986 Jan;389(1-2):77–84. doi: 10.1016/0165-3806(86)90174-4. [DOI] [PubMed] [Google Scholar]
  5. Brundin P., Strecker R. E., Widner H., Clarke D. J., Nilsson O. G., Astedt B., Lindvall O., Björklund A. 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. 1988;70(1):192–208. doi: 10.1007/BF00271860. [DOI] [PubMed] [Google Scholar]
  6. Coyle J. T., Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993 Oct 29;262(5134):689–695. doi: 10.1126/science.7901908. [DOI] [PubMed] [Google Scholar]
  7. Dexter D. T., Wells F. R., Lees A. J., Agid F., Agid Y., Jenner P., Marsden C. D. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J Neurochem. 1989 Jun;52(6):1830–1836. doi: 10.1111/j.1471-4159.1989.tb07264.x. [DOI] [PubMed] [Google Scholar]
  8. Fleishaker J. C., Peters G. R., Cathcart K. S., Steenwyk R. C. Evaluation of the pharmacokinetics and tolerability of tirilazad mesylate, a 21-aminosteroid free radical scavenger: II. Multiple-dose administration. J Clin Pharmacol. 1993 Feb;33(2):182–190. doi: 10.1002/j.1552-4604.1993.tb03941.x. [DOI] [PubMed] [Google Scholar]
  9. Freed W. J. GM1 ganglioside does not stimulate reinnervation of the striatum by substantia nigra grafts. Brain Res Bull. 1985 Jan;14(1):91–95. doi: 10.1016/0361-9230(85)90180-7. [DOI] [PubMed] [Google Scholar]
  10. 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. 1994 Jun 6;647(2):286–298. doi: 10.1016/0006-8993(94)91328-5. [DOI] [PubMed] [Google Scholar]
  11. Hall E. D., Braughler J. M. Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radic Biol Med. 1989;6(3):303–313. doi: 10.1016/0891-5849(89)90057-9. [DOI] [PubMed] [Google Scholar]
  12. Hall E. D., Braughler J. M., Yonkers P. A., Smith S. L., Linseman K. L., Means E. D., Scherch H. M., Von Voigtlander P. F., Lahti R. A., Jacobsen E. J. U-78517F: a potent inhibitor of lipid peroxidation with activity in experimental brain injury and ischemia. J Pharmacol Exp Ther. 1991 Aug;258(2):688–694. [PubMed] [Google Scholar]
  13. Jacobsen E. J., McCall J. M., Ayer D. E., Van Doornik F. J., Palmer J. R., Belonga K. L., Braughler J. M., Hall E. D., Houser D. J., Krook M. A. Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma. J Med Chem. 1990 Apr;33(4):1145–1151. doi: 10.1021/jm00166a010. [DOI] [PubMed] [Google Scholar]
  14. Mayer E., Fawcett J. W., Dunnett S. B. Basic fibroblast growth factor promotes the survival of embryonic ventral mesencephalic dopaminergic neurons--II. Effects on nigral transplants in vivo. Neuroscience. 1993 Sep;56(2):389–398. doi: 10.1016/0306-4522(93)90340-l. [DOI] [PubMed] [Google Scholar]
  15. Nishino H., Hashitani T., Isobe Y., Furuyama F., Sato H., Kumazaki M., Horikomi K., Awaya A. tGS ganglioside induces peculiar morphological features in grafted dopaminergic cells and promotes motor recovery in rats with unilateral lesions in the nigrostriatal dopamine pathway. Brain Res. 1990 Nov 26;534(1-2):73–82. doi: 10.1016/0006-8993(90)90114-q. [DOI] [PubMed] [Google Scholar]
  16. Olanow C. W. A radical hypothesis for neurodegeneration. Trends Neurosci. 1993 Nov;16(11):439–444. doi: 10.1016/0166-2236(93)90070-3. [DOI] [PubMed] [Google Scholar]
  17. Rioux L., Gaudin D. P., Bui L. K., Grégoire L., DiPaolo T., Bédard P. J. Correlation of functional recovery after a 6-hydroxydopamine lesion with survival of grafted fetal neurons and release of dopamine in the striatum of the rat. Neuroscience. 1991;40(1):123–131. doi: 10.1016/0306-4522(91)90179-r. [DOI] [PubMed] [Google Scholar]
  18. Rioux L., Gaudin D. P., Gagnon C., Di Paolo T., Bédard P. J. Decrease of behavioral and biochemical denervation supersensitivity of rat striatum by nigral transplants. Neuroscience. 1991;44(1):75–83. doi: 10.1016/0306-4522(91)90251-i. [DOI] [PubMed] [Google Scholar]
  19. Rosen D. R., Siddique T., Patterson D., Figlewicz D. A., Sapp P., Hentati A., Donaldson D., Goto J., O'Regan J. P., Deng H. X. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59–62. doi: 10.1038/362059a0. [DOI] [PubMed] [Google Scholar]
  20. Sauer H., Fischer W., Nikkhah G., Wiegand S. J., Brundin P., Lindsay R. M., Björklund A. Brain-derived neurotrophic factor enhances function rather than survival of intrastriatal dopamine cell-rich grafts. Brain Res. 1993 Oct 29;626(1-2):37–44. doi: 10.1016/0006-8993(93)90560-a. [DOI] [PubMed] [Google Scholar]
  21. Sauer H., Frodl E. M., Kupsch A., ten Bruggencate G., Oertel W. H. Cryopreservation, survival and function of intrastriatal fetal mesencephalic grafts in a rat model of Parkinson's disease. Exp Brain Res. 1992;90(1):54–62. doi: 10.1007/BF00229256. [DOI] [PubMed] [Google Scholar]
  22. 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. 1983;522:19–28. [PubMed] [Google Scholar]
  23. Ungerstedt U., Arbuthnott G. W. Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res. 1970 Dec 18;24(3):485–493. doi: 10.1016/0006-8993(70)90187-3. [DOI] [PubMed] [Google Scholar]
  24. Youdim M. B., Ben-Shachar D., Riederer P. Is Parkinson's disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration? Acta Neurol Scand Suppl. 1989;126:47–54. doi: 10.1111/j.1600-0404.1989.tb01782.x. [DOI] [PubMed] [Google Scholar]
  25. Yurek D. M., Collier T. J., Sladek J. R., Jr Embryonic mesencephalic and striatal co-grafts: development of grafted dopamine neurons and functional recovery. Exp Neurol. 1990 Aug;109(2):191–199. doi: 10.1016/0014-4886(90)90073-2. [DOI] [PubMed] [Google Scholar]
  26. Zuddas Alessandro, Corsini Giovanni U., Barker Jeffery L., Kopin Irwin J., Di Porzio Umberto. Specific Reinnervation of Lesioned Mouse Striatum by Grafted Mesencephalic Dopaminergic Neurons. Eur J Neurosci. 1991 Oct;3(1):72–85. doi: 10.1111/j.1460-9568.1991.tb00813.x. [DOI] [PubMed] [Google Scholar]

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