Effects of Fetal Mesencephalic Cell Grafts on the Intrastriatal 6-hydroxydoapmine Lesioned Rats

  • Joo, Wan Seok (Department of Pharmacology, College of Medicine and Neuroscience Research Institute of Medical Research Center, Seoul National University) ;
  • Nam, Eun-Joo (Department of Pharmacology, College of Medicine and Neuroscience Research Institute of Medical Research Center, Seoul National University) ;
  • Im, Heh-ln (Department of Pharmacology, College of Medicine and Neuroscience Research Institute of Medical Research Center, Seoul National University) ;
  • Jung, Jin-Ah (Department of Pharmacology, College of Medicine and Neuroscience Research Institute of Medical Research Center, Seoul National University) ;
  • Lee, Eun-Sun (Department of Pharmacology, College of Medicine and Neuroscience Research Institute of Medical Research Center, Seoul National University) ;
  • Hwang, Yu-Jin (Department of Pharmacology, College of Medicine and Neuroscience Research Institute of Medical Research Center, Seoul National University) ;
  • Kim, Yong-Sik (Department of Pharmacology, College of Medicine and Neuroscience Research Institute of Medical Research Center, Seoul National University)
  • 발행 : 2004.10.21

초록

The effects of fetal mesencephalic cell grafts on the restoration of nigrostriatal dopaminergic function were studied in the intrastriatal 6-hydroxydopamine-lesioned rats. Four weeks after lesioning, transplantation of ventral mesencephalic cells from embryonic day 14 fetuses showed the number of tyrosine hydroxylase (TH) positive cells and fiber outgrowth in the grafted striatum, and significantly ameliorated symptomatic motor behavior of the animals, as determined by apomorphine-induced rotation. Furthermore, in substantia nigra pars compacta (SNc), the numbers of TH + cells and fibers were markedly restored. Dopamine content of ipsilateral SNc was close to that of contralateral SNc $(91.9{\pm}9.8%)$ in the transplanted animals, while the ratio was approximately 32% in sham-grafted animals. These results indicate that grafted cells restored the activity for the dopaminergic neurons located in SNc, although they were transplanted into striatum. In addition, we showed that the implanted fetal cells expressed high level of glial cell line-derived neurotrophic factor (GDNF), suggesting that the transplanted fetal cells might serve as a dopamine producer and a reservoir of neurotrophic factors. These results may be helpful in consideration of the therapeutic transplantation at early stage of PD.

키워드

참고문헌

  1. Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, Howells DW. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell linederived neurotrophic factor. J Neurosci 19: 1708-1716, 1999
  2. Brundin P, Isacson O, Bjorklund A. Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res 331: 251-259, 1985 https://doi.org/10.1016/0006-8993(85)91550-1
  3. Choi-Lundberg DL, Lin Q, Yung-Nien C, Chiang YL, Hay CM, Mohajeri H, Davidson BL, Bohn MC. Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275: 838-841, 1997 https://doi.org/10.1126/science.275.5301.838
  4. Espejo M, Cutillas B, Arenas TE, Ambrosio S. Increased survival of dopaminergic neurons in striatal grafts of fetal ventral mesencephalic cells exposed to neurotrophin-3 or glial cell linederived neurotrophic factor. Cell Transplant 9: 45-53, 2000
  5. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 344: 710-719, 2001 https://doi.org/10.1056/NEJM200103083441002
  6. Ho A, Blum M. Regulation of astroglial-derived dopaminergic neurotrophic factors by interleukin-1 beta in the striatum of young and middle-aged mice. Exp Neurol 148: 348-359, 1997 https://doi.org/10.1006/exnr.1997.6659
  7. Joo WS, Jin BK, Park CW, Maeng SH, Kim YS. Melatonin increases striatal dopaminergic function in 6-OHDA-lesioned rats. Neuroreport 9: 4123-4126, 1998 https://doi.org/10.1097/00001756-199812210-00022
  8. Kim YS, Joo WS, Jin BK, Cho YH, Baik HH, Park CW. Melatonin protects 6-OHDA-induced neuronal death of nigrostriatal dopaminergic system. Neuroreport 9: 2387-2390, 1998 https://doi.org/10.1097/00001756-199807130-00043
  9. Kirik D, Rosenblad C, Bjorklund A. Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 152: 259-277, 1998 https://doi.org/10.1006/exnr.1998.6848
  10. Kirik D, Rosenblad C, Bjorklund A. Preservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor. Eur J Neurosci 12: 3871-3882, 2000. https://doi.org/10.1046/j.1460-9568.2000.00274.x
  11. Kirik D, Winkler C, Bjorklund A. Growth and functional efficacy of intrastriatal nigral transplants depend on the extent of nigrostriatal degeneration. J Neurosci 21: 2889-2896, 2001
  12. Lee CS, Sauer H, Bjorklund A. Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by instrastriatal 6-hydroxydopamine in the rat. Neuroscience 72: 641-653, 1996 https://doi.org/10.1016/0306-4522(95)00571-4
  13. Lindvall O. Neural transplantation. Cell Transplant 4: 393-400, 1995 https://doi.org/10.1016/0963-6897(95)00022-P
  14. Moukhles H, Amalric M, Nieoullon A, Daszuta A. Behavioural recovery of rats grafted with dopamine cells after partial striatal dopaminergic depletion in a conditioned reaction-time task. Neuroscience 63: 73-84, 1994 https://doi.org/10.1016/0306-4522(94)90008-6
  15. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. In: 2nd ed. Academic press, San Diego, 1986
  16. Plunkett RJ, Ip NY, Asada H, Friedman B, Pan L, Kaseloo PA, Parfitt MM. Trauma-induced striatal CNTF and BDNF mRNA in hemiparkinsonian rats. Neuroreport 8: 507-511, 1997 https://doi.org/10.1097/00001756-199701200-00026
  17. Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, Togasaki DM. Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience 67:631-647, 1995 https://doi.org/10.1016/0306-4522(95)00066-R
  18. Rodter A, Winkler C, Samii M, Nikkhah G. Complex sensorimotor behavioral changes after terminal striatal 6-OHDA lesion and transplantation of dopaminergic embryonic micrografts. Cell Transplant 9: 197-214, 2000 https://doi.org/10.1177/096368970000900206
  19. Satake K, Matsuyama Y, Kamiya M, Kawakami H, Iwata H, Adachi K, Kiuchi K. Up-regulation of glial cell line-derived neurotrophic factor (GDNF) following traumatic spinal cord injury. Neuroreport 11: 3877-3881, 2000 https://doi.org/10.1097/00001756-200011270-00054
  20. Sauer H, Oertel WH. 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, 1994 https://doi.org/10.1016/0306-4522(94)90605-X
  21. Shults CW, Kimber T, Martin D. Intrastriatal injection of GDNF attenuates the effects of 6-hydroxydopamine. Neuroreport 7: 627 -631, 1996 https://doi.org/10.1097/00001756-199601310-00060
  22. Tonder N. Neural transplantation to the normal and lesioned brain. An experimental study of the rat hippocampus. Acta Neurol Scand Suppl 160: 1-30, 1995
  23. Tseng JL, Baetge EE, Zurn AD, Aebischer P. GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine. J Neurosci 17: 325-333, 1997
  24. Ungerstedt U, Arbuthnott GW. Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 24: 485-493, 1970 https://doi.org/10.1016/0006-8993(70)90187-3