Experimental Brain Research

, Volume 95, Issue 3, pp 450–456 | Cite as

Alterations in striatal glial fibrillary acidic protein expression in response to 6-hydroxydopamine-induced denervation

  • Jin G. Sheng
  • Susumu Shirabe
  • Nobuyoshi Nishiyama
  • Joan P. Schwartz


Following injection of 6-hydroxydopamine (6OHDA) into one side of the substantia nigra, immunohistochemical studies showed that the number of glial fibrillary acidic protein-positive [GFAP(+)] astrocytes in the striatum was significantly increased 1 day later and reached a maximum value, with intense immunoreactivity, 4 days after 6-OHDA injection. The number of GFAP(+) cells then gradually declined but was still 1.7 times the control value by 28 days postlesion. GFAP content, determined by immunoblot, and GFAP messenger RNA (mRNA) both reached maximal increases in the striatum 7 days after lesion: the mRNA returned to control values by 28 days, whereas GFAP content remained significantly elevated. Although the increases were all larger on the lesioned side, there were also significant changes on the contralateral side, as well as following saline injection. These results support the hypothesis that products released from damaged neurons are responsible for the induction of reactive gliosis, but cannot distinguish between effects mediated directly on the astrocytes or indirectly via other cells such as the microglia.

Key words

Neurodegeneration Striatum Substantia nigra Immunoblot Glial fibrillary acidic protein messenger RNA Rat 


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  1. Angulo JA, Davis LG, Burkhart BA, Christoph GR (1986) Reduction of striatal dopaminergic neurotransmission elevates striatal proenkephalin mRNA. Eur J Pharmacol 130:341–343Google Scholar
  2. Aquino DA, Chiu F-C, Brosnan CF, Norton WT (1988) Glial fibrillary acidic protein increases in the spinal cord of Lewis rats with acute experimental autoimmune encephalomyelitis. J Neurochem 51:1085–1096Google Scholar
  3. Aquino DA, Shafit-Zagardo B, Brosnan CF, Norton WT (1990) Expression of glial fibrillary acidic protein and neurofilament mRNA in gliosis induced by experimental autoimmune encephalomyelitis. J Neurochem 54:1398–1404Google Scholar
  4. Assouline JG, Borch P, Lim R, Kim IS, Jensen R, Pantazis NJ (1987) Rat astrocyte and Schwann cells in culture synthesize nerve growth factor-like neurite-promoting factors. Brain Res Dev Brain Res 31:103–118Google Scholar
  5. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  6. Brenner M, Lampel K, Nakatani Y, Mill J, Banner C, Mearow K, Dohadwala M, Lipsky R, Freese E (1990) Characterization of human cDNA and genomic clones for glial fibrillary acidic protein. Brain Res Mol Brain Res 7:277–286Google Scholar
  7. Cadet JL, Angulo JA, McEwen BS (1990) Nerve growth factor (NGF) potentiates the changes in striatal proenkephalin mRNA subsequent to 6-hydroxydopamine-induced lesions of the substantia nigra. Brain Res Bull 25:401–405Google Scholar
  8. Chiu F-C, Goldman JE (1985) Regulation of glial fibrillary acidic protein (GFAP) expression in CNS development and in pathological states. J Neuroimmunol 8:283–292Google Scholar
  9. Eng LF, Vanderhaegen JJ, Bignami A, Gerstl B (1972) An acidic protein isolated from fibrous astrocytes. Brain Res 28:351–354Google Scholar
  10. Giulian D, Vaca K, Johnson B (1988) Secreted peptides as regulators of neuron-glia and glia-glia interactions in the developing nervous system. J Neurosci Res 21:487–500Google Scholar
  11. Hatten ME, Liem RKH, Shelanski ML, Mason CA (1991) Astroglia in CNS injury. GLIA 4:233–243Google Scholar
  12. Hozumi I, Chiu F-C, Norton WT (1990a) Biochemical and immunocytochemical changes in glial fibrillary acidic protein after stab wounds. Brain Res 524:64–71Google Scholar
  13. Hozumi I, Aquino DA, Norton WT (1990b) GFAP mRNA levels following stab wounds in rat brain. Brain Res 534:291–294Google Scholar
  14. Kostrzewa RM, Jacobowitz DM (1974) Pharmacological actions of 6-hydroxydopamine. Pharmacol Rev 26:199–288Google Scholar
  15. Kraig RP, Dong L, Thisted R, Jaeger CB (1991) Spreading depression increases immunohistochemical staining of glial fibrillary acidic protein. J Neurosci 11:2187–2198Google Scholar
  16. Liesi P, Kaakkola S, Dahl D, Vaheri A (1984) Laminin is induced in astrocytes of adult brain by injury. EMBO J 3:683–686PubMedGoogle Scholar
  17. Lipsky RH, Silverman SJ (1987) Effects of mycophenolic acid on detection of glial filaments in human and rat astrocytoma cultures. Cancer Res 47:4900–4904Google Scholar
  18. Lu SY, Shipley MT, Norman AB, Sanberg PL (1991) Striatal, ventral mesencephalic and cortical transplants into intact rat striatum: a neuroanatomical study. Exp Neurol 113:109–130Google Scholar
  19. Mathewson AJ, Berry M (1985) Observations on the astrocyte response to a cerebral stab wound in adult rats. Brain Res 327:61–69Google Scholar
  20. McKeon RJ, Schreiber RC, Rudge JS, Silver J (1991) Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci 11:3398–3411Google Scholar
  21. Milner RJ, Sutcliffe JG (1983) Gene expression in rat brain. Nucleic Acids Res. 11:5497–5520Google Scholar
  22. Morrison RS, De Vellis J, Lee YL, Bradshaw RA, Eng LF (1985) Hormones and growth factors induce the synthesis of glial fibrillary acidic protein in rat brain astrocytes. J Neurosci Res 14:167–176Google Scholar
  23. Ogawa M, Araki M, Nagatsu I, Yoshida M (1989) Astroglial cell alteration caused by neurotoxins: immunohistochemical observations with antibodies to glial fibrillary acidic protein, laminin, and tyrosine hydroxylase. Exp Neurol 106:187–196Google Scholar
  24. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
  25. Rataboul P, Faucon Biguet N, Vernier P, De Vitry F, Boularand S, Privat A, Mallet J (1988) Identification of a human glial fibrillary acidic protein cDNA: a tool for the molecular analysis of reactive gliosis in the mammalian central nervous system. J Neurosci Res 20:165–175Google Scholar
  26. Reinhard JF, Miller DB, O'Callaghan JP (1988) The neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) increases glial fibrillary acidic protein and decreases dopamine levels of the mouse striatum: evidence for glial response to injury. Neurosci Lett 95:246–251Google Scholar
  27. Rudge JS, Silver J (1990) Inhibition of neurite outgrowth on astroglial scars in vitro. J Neurosci 10:3594–3603Google Scholar
  28. Schmidt-Kastner R, Szymas J (1990) Immunohistochemistry of glial fibrillary acidic protein, vimentin, and S-100 protein for study of astrocytes in hippocampus of rat. J Chem Neuroanat 3:179–192Google Scholar
  29. Schneider JS, Denaro FJ (1988) Astrocytic responses to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in cat and mouse brain. J Neuropathol Exp Neurol 47:452–458Google Scholar
  30. Schwartz JP, Mishler K (1990) β-Adrenergic receptor regulation, through cyclic AMP, of nerve growth factor expression in rat cortical and cerebellar astrocytes. Cell Mol Neurobiol 10:447–457Google Scholar
  31. Schwartz JP, Mocchetti I (1986) Pharmacological studies on the regulation of biosynthesis of enkephalins. In: Shagass C (ed) Biological psychiatry, 1985. Elsevier, Amsterdam, pp 284–286Google Scholar
  32. Sheng JG, Plunkett RJ, Cummins AC, Oldfield E, Kopin IJ, Palmatier M (1993) Neuronal sprouting and behavioral recovery in hemiparkinsonian rats after implantation of term amnion cells. Exp Neurol (in press)Google Scholar
  33. Steward O, Torre ER, Phillips LL, Trimmer PA (1990) The process of reinnervation in the dentate gyrus of adult rats: time course of increases in mRNA for glial fibrillary acidic protein. J Neurosci 10:2373–2384Google Scholar
  34. Stromberg I, Bjorklund H, Dahl D, Jonsson G, Sundstrom E, Olson L (1986) Astrocyte responses to dopaminergic denervations by 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as evidenced by glial fibrillary acidic protein immunohistochemistry. Brain Res Bull 17:225–236CrossRefPubMedGoogle Scholar
  35. Takamiya Y, Kohsaka S, Toya S, Otani M, Tsukada Y (1988) Immunohistochemical studies on the proliferation of reactive astrocytes and the expression of cytoskeletal proteins following brain injury in rats. Brain Res Dev Brain Res 38:201–210Google Scholar
  36. Trimmer PA, Reier PJ, Oh TH, Eng LF (1982) An ultrastructural and immunocytochemical study of astrocytic differentiation in vitro. J Neuroimmunol 2:235–260Google Scholar
  37. Voorn P, Roest G, Groenewegen HJ (1987) Increase of enkephalin and decrease of substance P immunoreactivity in the dorsal and ventral striatum of the rat after midbrain 6-hydroxydopamine lesions. Brain Res 412:391–396Google Scholar
  38. Zini I, Zoli M, Grimaldi R, Pich EM, Biagini G, Fuxe K, Agnati LF (1990) Evidence for a role of neosynthesized putrescine in the increase of glial fibrillary acidic protein immunoreactivity induced by a mechanical lesion in the rat brain. Neurosci Lett 27:13–16Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Jin G. Sheng
    • 1
  • Susumu Shirabe
    • 2
  • Nobuyoshi Nishiyama
    • 2
  • Joan P. Schwartz
    • 2
  1. 1.Surgical Neurology BranchNational Institute of Neurological Disorders and Stroke, National Institutes of HealthBethesdaUSA
  2. 2.Clinical Neuroscience BranchNational Institute of Neurological Disorders and Stroke, National Institutes of HealthBethesdaUSA

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