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Induction of activin A is essential for the neuroprotective action of basic fibroblast growth factor in vivo

Nature Medicine volume 6, pages 812–815 (2000)Cite this article

Abstract

Exogenous application of neurotrophic growth factors has emerged as a new and particularly promising approach not only to promote functional recovery after acute brain injury but also to protect neurons against the immediate effect of the injury. Among the various growth factors and cytokines studied so far, the neuroprotective and neurotrophic profile of basic fibroblast growth factor (bFGF) is the best documented1,2,3,4,5. Using an animal model of acute excitotoxic brain injury6, we report here that the neuroprotective action of bFGF, which is now being tested in stroke patients, depends on the induction of activin A, a member of the transforming growth factor-β superfamily. Our evidence for this previously unknown mechanism of action of bFGF is that bFGF strongly enhanced lesion-associated induction of activin A; in the presence of the activin-neutralizing protein follistatin, bFGF was no longer capable of rescuing neurons from excitotoxic death; and recombinant activin A exerted a neuroprotective effect by itself. Our data indicate that the development of substances influencing activin expression or receptor binding should offer new ways to fight neuronal loss in ischemic and traumatic brain injury.

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Figure 1: Neuroprotection by bFGF is associated with increased expression of activin βA mRNA.
Figure 2: Activin is of neuronal origin.
Figure 3: Neuroprotective function of exogenous and endogenous activin.

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References

  1. Ay, H., Ay, I., Koroshetz, W.J. & Finklestein, S.P. Potential usefulness of basic fibroblast growth factor as a treatment for stroke. Cerebrovasc. Dis. 9, 131–135 (1999).

    Article  CAS  Google Scholar 

  2. Bethel, A., Kirsch, J.R., Koehler, R.C., Finklestein, S.P. & Traystman, R.J. Intravenous basic fibroblast growth factor decreases brain injury resulting from focal ischemia in cats . Stroke 28, 609–615 (1997).

    Article  CAS  Google Scholar 

  3. Kirschner, P.B. et al. Basic fibroblast growth factor protects against excitotoxicity and chemical hypoxia in both neonatal and adult rats. J. Cereb. Blood Flow Metab. 15, 619–623 (1995).

    Article  CAS  Google Scholar 

  4. Anderson, K.J., Dam, D. Lee, S. & Cotman, C.W. Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo. Nature 332, 360–361 ( 1988).

    Article  CAS  Google Scholar 

  5. Peterson, D.A., Lucidi-Phillipi, C.A., Murphy, D.P. Ray, J. & Gage, F.H. Fibroblast growth factor-2 protects entorhinal layer II glutamatergic neurons from axotomy-induced death. J. Neurosci. 16, 886–898 (1996).

    Article  CAS  Google Scholar 

  6. Nadler, J.V., Perry, B.W., Gentry, C. & Cotman, C.W. Degeneration of hippocampal CA3 pyramidal cells induced by intraventricular kainic acid . J. Comp. Neurol. 192, 333– 359 (1980).

    Article  CAS  Google Scholar 

  7. Tretter, Y.P. et al. Strong induction of activin expression after hippocampal lesion . Neuroreport 7, 1819–1823 (1996).

    Article  CAS  Google Scholar 

  8. Munz, B., Hübner, G., Tretter, Y., Alzheimer, C. & Werner, S. A novel role of activin in inflammation and repair. J. Endocrinol. 161, 187– 193 (1999).

    Article  CAS  Google Scholar 

  9. McDowell, N., Zorn, A.M., Crease, D.J. & Gurdon, J.B. Activin has direct long-range signaling activity and can form a concentration gradient by diffusion . Curr. Biol. 7, 671–681 (1997).

    Article  CAS  Google Scholar 

  10. Munz, B. et al. Overexpression of activin A in the skin of transgenic mice reveals new activities of activin in epidermal morphogenesis, dermal fibrosis and wound repair. EMBO J. 18, 5205– 5215 (1999).

    Article  CAS  Google Scholar 

  11. Krieglstein, K., Suter-Crazzolara, C., Fischer, W.H. & Unsicker, K. TGF-β superfamily members promote survival of midbrain dopaminergic neurons and protect them against MPP+ toxicity. EMBO J. 14, 736–742 (1995).

    Article  CAS  Google Scholar 

  12. Wu, D.D. et al. Expression of the activin axis and neuronal rescue effects of recombinant activin A following hypoxic-ischemic brain injury in the infant rat. Brain Res. 835, 369– 378 (1999).

    Article  CAS  Google Scholar 

  13. Hughes, P.E., Alexi, T., Williams, C.E., Clark, R.G. & Gluckman, P.D. Administration of recombinant human activin-A has powerful neurotrophic effect on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease. Neuroscience 92, 197–209 ( 1999).

    Article  CAS  Google Scholar 

  14. Nakamura, T. et al. Activin-binding protein from rat ovary is follistatin. Science 247, 836–838 ( 1990).

    Article  CAS  Google Scholar 

  15. de Winter, J.P. et al. Follistatins neutralize activin bioactivity by inhibition of activin binding to its type II receptors. Mol. Cell. Endocrinol. 116, 105–114 ( 1996).

    Article  CAS  Google Scholar 

  16. Lai, M., Gluckman, P., Dragunow, M. & Hughes, P.E. Focal brain injury increases activinβ A mRNA expression in hippocampal neurons. Neuroreport 8, 2691– 2694 (1997).

    Article  CAS  Google Scholar 

  17. Riva, M.A., Donati, E., Tascedda, F., Zolli, M. & Racagni, G. Short- and long-term induction of basic fibroblast growth factor gene expression in rat central nervous system following kainate injection . Neuroscience 59, 55–65 (1994).

    Article  CAS  Google Scholar 

  18. Fainsod, A. et al. The dorsalizing and neural inducing gene follistatin is an antagonist of BMP-4. Mech. Dev. 63, 39– 50 (1997).

    Article  CAS  Google Scholar 

  19. Iemura, S.-I. et al. Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc. Natl. Acad. Sci. USA 95, 9337–9342 (1998).

    Article  CAS  Google Scholar 

  20. Sugino, H., Sugino, K., Hashimoto, O., Shoji, H. & Nakamura, T. Follistatin and its role as an activin-binding protein. J. Med. Invest. 44, 1–14 (1997).

    CAS  PubMed  Google Scholar 

  21. Krieglstein, K., Reuss, B., Maysinger, D. & Unsicker K. Transforming growth factor-β mediates the neurotrophic effect of fibroblast growth factor-2 on midbrain dopaminergic neurons. Eur. J. Neurosci. 10, 2746–2750 (1998).

    Article  CAS  Google Scholar 

  22. Yasuda, H. et al. Activin A: An autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes. J. Clin. Invest. 92, 1491–1496 (1993).

    Article  CAS  Google Scholar 

  23. Werner, S. et al. Targeted expression of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals a role of FGF in keratinocyte organization and differentiation. EMBO J. 12, 2635–2643 (1993).

    Article  CAS  Google Scholar 

  24. Wisden, W., Morris, B.J. & Hunt, S.P. in Molecular Neurobiology—A Practical Approach (eds. Chad, J. & Wheal, H.) 205–225 (Oxford University Press, New York, 1991).

    Google Scholar 

  25. Hübner, G. & Werner, S. Serum growth factors and proinflammatory cytokines are potent inducers of activin expression in cultured keratinocytes. Exp. Cell Res. 228, 106–113 (1996).

    Article  Google Scholar 

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Acknowledgements

We thank B. Sutor (Department of Physiology, University of Munich, Germany) for letting us use his image analysis system and G. Klausa for help with nerve cell counting. The immunofluorescence micrographs were acquired using the equipment of J. Büttner-Ennever (Department of Anatomy, University of Munich, Germany) with the help of A. Messoudi. We thank R. Grose for reading the manuscript. This work was supported by the German Ministry for Education and Research (BMBF). C.A. is a Heisenberg fellow of the Deutsche Forschungsgemeinschaft.

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  1. Barbara Munz

    Present address: Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California, 94305, USA

Authors and Affiliations

  1. Department of Physiology, University of Munich, Pettenkoferstr.12, D-80336, München, Germany

    Yvonne P. Tretter, Gerrit ten Bruggencate & Christian Alzheimer

  2. Max-Planck-Institute for Biochemistry,, Martinsried, D-82152, Germany

    Moritz Hertel, Barbara Munz & Sabine Werner

  3. Department of Cell Biology, Swiss Federal Institute of Technology, Zurich, CH-8093, Switzerland

    Moritz Hertel & Sabine Werner

Authors
  1. Yvonne P. Tretter
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Correspondence to Christian Alzheimer.

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Tretter, Y., Hertel, M., Munz, B. et al. Induction of activin A is essential for the neuroprotective action of basic fibroblast growth factor in vivo. Nat Med 6, 812–815 (2000). https://doi.org/10.1038/77548

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