Cellular and Molecular Neurobiology

, Volume 26, Issue 7–8, pp 1421–1439 | Cite as

Progressive Reparative Gliosis in Aged Hosts and Interferences with Neural Grafts in an Animal Model of Huntington's Disease

  • Yvona Mazurová
  • Ivan Látr
  • Jan Österreicher
  • Ivana Gunčová

1. Neural transplantation in Huntington's diseased patients is currently the only approach in the treatment of this neurodegenerative disorder. The clinical trial, unfortunately, includes only a small number of patients until now, since many important questions have not been answered yet. One of them is only mild to moderate improvement of the state in most of grafted patients.

2. We examined the morphological correlates in the response to intrastriatal grafting of fragments of foetal rat ventral mesencephalic tissue 1 month after transplantation in male Wistar rats within varying durations (from 2 to 38 weeks) of experimentally induced neurodegenerative process of the striatum (used as a model of Huntington's disease). Our goal was to determine the impact of advanced striatal damage and gliosis on the graft viability and host–graft integration.

3. The findings can be summarized as follows: The progressive reactive gliosis, which is not able to compensate continual reduction of the grey matter leading to an extensive atrophy of the striatum in a long-term lesions, results in formation of the compact glial network. This tissue cannot be considered the suitable terrain for successful graft development and formation of host–graft interconnections.

4. The progression of irreversible morphological changes in long-lasting neurodegenerative process within the striatum can be supposed one of the important factors, which may decrease our prospect of distinct improvement after neural grafting in patients in advanced stage of Huntington's disease, who still remain the leading group in clinical trials.


Huntington's disease animal model aging long-term lesion reactive gliosis foetal neural graft histopathology immunohistochemistry 


  1. Bachoud-Lévi, A. C., Bourdet, C., Brugieres, P., Nguyen, J. P., Grandmougin, T., Haddad, B., Jeny, R., Bartolomeo, P., Boisse, M. F., Barba, G. D., Degos, J. D., Ergis, A. M., Lefaucheur, J. P., Lisovoski, F., Pailhous, E., Remy, P., Palfi, S., Defer, G. L., Césaro, P., Hantraye, P., and Peschanski, M. (2000). Safety and tolerability assessment of intrastriatal neural allografts in five patients with Huntington’s disease. Exp. Neurol. 161:194–202.CrossRefPubMedGoogle Scholar
  2. Beal, M. F., Kowall, N. W., Ellison, D. W., Mazurek, M. F., Schwartz, K. J., and Martin, J. B. (1986). Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature 321:168–171.CrossRefPubMedGoogle Scholar
  3. Björklund, H., Olson, L., Dahl, D., and Schwarcz, R. (1986). Short- and long-term consequences of intracranial injections of the excitotoxin, quinolinic acid, as evidenced by GFA immunohistochemistry of astrocytes. Brain Res. 371:267–277.CrossRefPubMedGoogle Scholar
  4. Brasted, P. J., Robbins, T. W., and Dunnett, S. B. (2000). Behavioral recovery following transplantation into a rat model of Huntington's disease requires both anatomical connectivity and extensive postoperative training. Proc. Natl. Acad. Sci. USA 114:431–436.Google Scholar
  5. Cheng, H. W., Jiang, T., Brown, S. A., Pasinetti, G. M., Finch, C. E., and McNeil, T. H. (1994). Response of striatal astrocytes to neuronal deafferentation: an immunocytochemical and ultrastructural study. Neuroscience 62:425–439.CrossRefPubMedGoogle Scholar
  6. Collier, T. J., Sortwell, C. E., and Daley, B. F. (1999). Diminished viability, growth, and behavioral efficacy of fetal dopamine neuron grafts in aging rats with long-term dopamine depletion: an argument for neurotrophic supplementation. J. Neurosci. 19(13):5563–5573.PubMedGoogle Scholar
  7. Coyle, J. T., and Schwarcz, R. (1976). Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature 263:244–246.CrossRefPubMedGoogle Scholar
  8. DiFiglia, M., Schiff, L., and Deckel, A. W. (1988). Neuronal organization of fetal striatal grafts in kainate- and sham-lesioned rat caudate nucleus: light- and electron-microscopic observations. J. Neurosci. 8:1112–1130.PubMedGoogle Scholar
  9. Dunnett, S. B., and Björklund, A. (1992). Staging and dissection of rat embryos. In Dunnett, S. B., and Björklund, A. (eds.) Neural Transplantation: A Practical Approach, Oxford University Press, Oxford, pp. 1–19.Google Scholar
  10. Dusart, I., Marty, S., and Peschanski, M. (1991). Glial changes following an excitotoxic lesion in the CNS-II. Astrocyt. Neurosci. 45:541–549.CrossRefGoogle Scholar
  11. Ferrante, R. J., Kowall, N. W., Cipolloni, P. B., Storey, E., and Beal, M. F. (1993). Excitotoxin lesions in primates as a model for Huntington's disease: histopathologic and neurochemical characterization. Exp. Neurol. 119:46–71.CrossRefPubMedGoogle Scholar
  12. Freed, C. R., Greene, P. E., Breeze, R. E., Tsai, W. Y., DuMouchel, W., Kao, R., Dillon, S., Winfield, H., Culver, S., Trojanowski, J. Q., Eidelberg, D., and Fahn, S. (2001). Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med. 344(10):710–719.CrossRefPubMedGoogle Scholar
  13. Gates, M. A., Laywell, E. D., Fillmore, H., and Steindler, D. A. (1996). Astrocytes and extracellular matrix following intracerebral transplantation of embryonic ventral mesencephalon or lateral ganglionic eminence. Neuroscience 74(2):579–597.CrossRefPubMedGoogle Scholar
  14. Groves, M., Vonsattel, J. P., Mazzoni, P., and Marder, K. (2003). Huntington's disease. Sci. Aging Knowl. Environ. 43:1–14.Google Scholar
  15. Isacson, O., Brundin, P., Gage, F. H., and Björklund, A. (1985). Neural grafting in a rat model of Huntington's disease: Progressive neurochemical changes after neostriatal ibotenate lesions and striatal tissue grafting. Neuroscience 16:799–817.CrossRefPubMedGoogle Scholar
  16. Isacson, O., Fischer, W., Wictorin, K., Dawbarn, D., and Björklund, A. (1987). Astroglial response in the excitotoxically lesioned neostriatum and its projection areas in the rat. Neuroscience 20:1043–1056.CrossRefPubMedGoogle Scholar
  17. Isacson, O., Hantraye, P., Riche, D., Schumacher, J. M., and Mazière, M. (1991). The relationship between symptoms and functional anatomy in the chronic neurodegenerative diseases: From pharmacological to biological replacement therapy in Huntington's disease. In Lindvall, O., Björklund, A., and Widner, H. (eds.) Intracerebral Transplantation in Movement Disorders, Elsevier, Amsterdam, pp. 245–258.Google Scholar
  18. Jabs, R., Bekar, L. K., and Walz, W. (1998). Reactive astrogliosis in the injured and postischemic brain. In Walz, W. (ed.) Cerebral Ischemia: Molecular and Cellular Pathophysiology, Humana Press Inc., Totowa, pp. 233–249.Google Scholar
  19. Kimelberg, H. K. (2004). The problem of astrocyte identity. Neurochem. Int. 45:191–202.CrossRefPubMedGoogle Scholar
  20. Kopyov, O. V., Jacques, S., Lieberman, A., Duma, C. M., and Eagle, K. S. (1998). Safety of intrastriatal neurotransplantation for Huntington's disease patients. Exp. Neurol. 149:97–108.CrossRefPubMedGoogle Scholar
  21. Leegwater-Kim, J., and Cha, J. H. (2004). The paradigm of Huntington's disease: Therapeutic opportunities in neurodegeneration. NeuroRx 1(1):128–138.CrossRefPubMedGoogle Scholar
  22. Liu, F. Ch., Graybiel, A. M., Dunnett, S. B., and Banghman, R. W. (1990). Intrastriatal grafts derived from fetal striatal primordia: II. Reconstruction of cholinergic and dopaminergic systems. J. Comp. Neurol. 295:1–14.CrossRefPubMedGoogle Scholar
  23. Ludwin, S. K. (1985). Reaction of oligodendrocytes and astrocytes to trauma and implantation. A combined autoradiographic and immunohistochemical study. Lab. Invest. 52:20–30.PubMedGoogle Scholar
  24. Madrazo, I., Franco-Bourland, R. E., Castrejon, H., Cuevas, C., and Ostrosky-Solis, F. (1995). Fetal striatal homotransplantation for Huntington's disease: first two case reports. Neurol. Res. 17:312–315.PubMedGoogle Scholar
  25. Mathewson, A. J., and Berry, M. (1985). Observations on the astrocyte response to a cerebral stab wound in adult rats. Brain Res. 18:61–69.CrossRefGoogle Scholar
  26. Mazurová, Y., Valoušková, V., Österreicher, J. (2002). The reaction of subependymal layer of the lateral brain ventricles to the striatal ibotenic acid lesion in long-term study. Acta Histochem. 104(4):375–379.CrossRefPubMedGoogle Scholar
  27. Murabe, Y., Ibata, Y., and Sano, Y. (1981). Morphological studies on neuroglia. II. Response of glial cells to kainic acid-induced lesions. Cell Tissue Res. 216:569–580.PubMedCrossRefGoogle Scholar
  28. Ogawa, M., Araki, M., Nagatsu, I., and Yoshida, M. (1989). Astroglial cell alteration caused by neurotoxins: immunohistochemical observations with antibodies to glial fibrillary acidic protein, laminin, and tyrosine hydroxylase. Exp. Neurol. 106:187–196.CrossRefPubMedGoogle Scholar
  29. Peschanski, M., Bachoud-Lévi, A. C., and Hantraye, P. (2004). Integrating fetal neural transplants into a therapeutic strategy: the example of Huntington's disease. Brain 127:1219–1228.CrossRefPubMedGoogle Scholar
  30. Pritzel, M., Isacson, O., Brundin, P., Wiklund, L., and Björklund, A. (1986). Afferent and efferent connections of striatal grafts implanted into the ibotenic acid-lesioned neostriatum in adult rats. Exp. Brain Res. 65:112–126.CrossRefPubMedGoogle Scholar
  31. Roberts, R. C., and DiFiglia, M. (1989). Short- and long-term survival of large neurons in the excitotoxic lesioned rat caudate nucleus: a light and electron microscopic study. Synapse 3:363–371.CrossRefPubMedGoogle Scholar
  32. Rosser, A. E., and Dunnett, S. B. (2003). Neural Transplantation in patients with Huntington's disease. CNS Drugs 17:853–867.CrossRefPubMedGoogle Scholar
  33. Schiffer, D., Giordana, M. T., Cavalla, P., Vigliani, M. C., and Attanasio, A. (1993). Immunohistochemistry of glial reaction after injury in the rat: double stainings and markers of cell proliferation. Int.. J. Dev. Neurosci. 11:269–280.CrossRefPubMedGoogle Scholar
  34. Schwarcz, R., Hökfeld, T., Fuxe, K., Jonsson, G., Goldstein, M., and Terenius, L. (1979). Ibotenic acid-induced neuronal degeneration: a morphological and neurochemical study. Exp. Brain Res. 37:199–216.CrossRefPubMedGoogle Scholar
  35. Sortwell, C. E., Camargo, M. D., Pitzer, M. R., Gvawali, S., and Collier, T. J. (2001). Diminished survival of mesencephalic dopamine neurons grafted into aged hosts occurs during the immediate postgrafting interval. Exp. Neurol. 169(1):23–29.CrossRefPubMedGoogle Scholar
  36. Šramka, M., Rattaj, M., Molina, H., Vojtassak, J., Belan, V., and Ružický, E. (1992). Stereotactic technique and pathophysiological mechanisms of neurotransplantation in Huntington's chorea. Stereotact. Funct. Neurosurg. 58:79–83.PubMedGoogle Scholar
  37. Takamiya, Y., Kohsaka, S., Toya, S., Otani, M., and Tsukada, Y. (1988). Immunohistochemical studies on the proliferation of reactive astrocytes and the expression of cytoskeletal proteins following brain injury in rats. Brain Res. 466:201–210.PubMedGoogle Scholar
  38. Teismann, P., Tieu, K., Cohen, O., Choi, D. K., Wu du, C., Marks, D., Vila, M., Jackson-Lewis, V., and Przedborski, S. (2003). Pathogenic role of glial cells in Parkinson's disease. Mov. Disord. 18:121–129.CrossRefPubMedGoogle Scholar
  39. Watts, C., and Dunnett, S. B. (1998). Effects of severity of host striatal damage on the morphological development of intrastriatal transplants in a rodent model of Huntington's disease: implications for timing of surgical intervention. J. Neurosurg. 89(2):267–274.PubMedCrossRefGoogle Scholar
  40. Wictorin, K. (1992). Anatomy and connectivity of intrastriatal striatal transplants. Prog. Neurobiol. 38:611–639.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Yvona Mazurová
    • 1
    • 4
  • Ivan Látr
    • 2
  • Jan Österreicher
    • 3
  • Ivana Gunčová
    • 1
  1. 1.Department of Histology and EmbryologyCharles University in Prague, Faculty of Medicine in Hradec KrálovéHradec KrálovéCzech Republic
  2. 2.Neurosurgery ClinicFaculty HospitalHradec KrálovéCzech Republic
  3. 3.Department of RadiobiologyFaculty of Military Health Sciences, University of DefenceHradec KrálovéCzech Republic
  4. 4.Department of Histology and EmbryologyCharles University in Prague, Faculty of Medicine in Hradec KrálovéHradec KrálovéCzech Republic

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