Skip to main content
Log in

Transforming Growth Factor-β and Ischemic Brain Injury

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

1. Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by using the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man.

2. Over the last years, the cytokine termed Transforming Growth Factor-β1 (TGF-β1) has been found to be strongly up-regulated in the central nervous system following ischemia-induced brain damage.

3. Recent studies have shown a neuroprotective activity of TGF-β1 against ischemia-induced neuronal death. In vitro, TGF-β1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes.

4. In addition, TGF-β1 has been recently characterized as an antiapoptotic factor in a model of staurosporine-induced neuronal death through a mechanism involving activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) and a concomitant increase phosphorylation of the antiapoptotic protein Bad.

5. Altogether, these observations suggest that either TGF-β signaling or TGF-β1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Ali, C., Nicole, O., Docagne, F., Lesné, S., MacKenzie, E. T., Buisson, A., and Vivien D. (2000). Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain. J. Cereb. Blood Flow Metab. 20:956–966.

    PubMed  Google Scholar 

  • Artavanis-Tsakonas, S., Rand, M. D., and Lake, R. (1999). Notch signaling: Cell fate control and signal integration in development. Science 284:770–776.

    PubMed  Google Scholar 

  • Boldin, M. P., Goncharov, T. M., Goltsev, Y. V., and Wallach, D. (1996). Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1-and TNF receptor-induced cell death. Cell 85:803–815.

    PubMed  Google Scholar 

  • Buisson, A., Nicole, O., Docagne, F., Sartelet, H., MacKenzie, E. T., and Vivien, D. (1998). Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor β1. FASEB J. 12:1683–1691.

    PubMed  Google Scholar 

  • Cataldo, A. M., Barnett, J. L., Pieroni, C., and Nixon, R. A. (1997). Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: Neuropathologic evidence for a mechanism of increased β-amyloidogenesis. J. Neurosci. 17:6142–6151.

    PubMed  Google Scholar 

  • Choi, D. W. (1992). Excitotoxic cell death. J. Neurobiol. 23:1261–1276.

    PubMed  Google Scholar 

  • Docagne, F., Nicole, O., Marti, H. H., MacKenzie, E. T., Buisson, A., and Vivien D. (1999). Transforming growth factor-β1 as a regulator of the serpins/t-PA axis in cerebral ischemia. FASEB J. 13:1315–1324.

    PubMed  Google Scholar 

  • Feuerstein, G. Z., Wang, X., and Baronne, F. C. (1998). The role of cytokines in the neuropathology of stroke and neurotrauma. Neuroimmunomodulation 5:143–159.

    PubMed  Google Scholar 

  • Fiumelli, H., Jabaudon, D., Magistretti, P. J., and Martin, J. L. (1999). BDNF stimulates expression, activity and release of tissue-type plasminogen activator in mouse cortical neurons Eur. J. Neurosci. 11:1639–1646.

    PubMed  Google Scholar 

  • Flanders, K. C., Lippa, C. F., Smith, T. W., Pollen, D. A., and Sporn, M. B. (1995). Altered expression of transforming growth factor-β in Alzheimer's disease. Neurology 45:1561–1569.

    PubMed  Google Scholar 

  • Flanders, K. C., Ren, R. F., and Lippa, C. F. (1998). Transforming growth factor-βs in neurodegenerative disease. Prog. Neurobiol. 54:71–85.

    PubMed  Google Scholar 

  • Frautschy, S. A., Horn, D. L., Sigel, J. J., Harris-White, M. E., Mendoza, J. J., Yang, F., Saido, T. C., and Cole, G. M. (1998). Protease inhibitor coinfusion with amyloid β-protein results in enhanced deposition and toxicity in rat brain. J. Neurosci. 18:8311–8321.

    PubMed  Google Scholar 

  • Henrich-Noack, P., Prehn, J. H., and Krieglstein, J. (1996). TGF-β1 protects hippocampal neurons against degeneration caused by transient global ischemia. Dose–response relationship and potential neuroprotective mechanisms. Stroke 27:1609–1614.

    PubMed  Google Scholar 

  • Hill, I. E., Preston, E., Monette, R., and MacManus, J. P. (1997). A comparison of cathepsin-B processing and distribution during neuronal death in rats following global ischemia or decapitation necrosis. Brain Res. 751:206–216.

    PubMed  Google Scholar 

  • Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E. A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., and Tournier-Lasserve, E. (1996). Notch3-mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710.

    PubMed  Google Scholar 

  • Kaufmann, S. H., and Hengartner, M. O. (2001). Programmed cell death: Alive and well in the new millennium. Biology, 11:526–534.

    Google Scholar 

  • Krupinski, J., Kumar, P., Kumar, S., and Kaluza, J. (1996). Increased expression of TGF-β1 in brain tissue after ischemic stroke in humans. Stroke 27:852–857.

    PubMed  Google Scholar 

  • Lee, J. M., Zipfel, G. J., and Choi, D. W. (1999). The changing landscape of ischaemic brain injury mechanisms. Nature 399 (6738, Suppl):A7–1.

    PubMed  Google Scholar 

  • Lehrmann, E., Kiefer, R., Christensen, T., Toyka, K. V., Zimmer, J., Diemer, N. H., Hartung, H. P., and Finsen, B. (1998). Microglia and macrophages are major sources of locally produced transforming growth factor-β1 after transient middle cerebral artery occlusion in rats. Glia 24:437–448.

    PubMed  Google Scholar 

  • Lesné, S., Blanchet, S., Docagne, F., Liot, G., Plawinski, L., MacKenzie E. T., Auffray, C., Buisson, A., Piétu, G., and Vivien, D. (2002). Transforming growth factor-β1-modulated cerebral gene expression. J. Cereb. Blood Flow Metab. 22:1114–1123.

    PubMed  Google Scholar 

  • Lippa, C. F., Smith, T. W., and Flanders, K. C. (1995). Transforming growth factor-β: Neuronal and glial expression in CNS degenerative diseases. Neurodegeneration 4:425–432.

    PubMed  Google Scholar 

  • Massagué, J. (2000). How cells read TGF-beta signals. Nat. Rev. Mol. Cell Biol. 1:169–178.

    PubMed  Google Scholar 

  • Massague, J., and Wotton, D. (2000). Transcriptional control by the TGF-β/Smad signaling system. EMBO J, 19:1745–1754.

    PubMed  Google Scholar 

  • Muzio, M., Chinnaiyan, A. M., Kischkel, F. C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J. D., Zhang, M., Gentz, R., Mann, M., Krammer, P. H., Peter, M. E., and Dixit, V. M. (1996). FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817–827.

    PubMed  Google Scholar 

  • Muzio, M., Stockwell, B. R., Stennicke, H. R., Salvesen, G. S., and Dixit, D. M. (1998). An induced proximity model for caspase-8 activation. J. Biol. Chem. 273:2926–2930.

    PubMed  Google Scholar 

  • Nagai, N., De Mol, M., Lijnen, H. R., Carmeliet, P., and Collen, D. (1999). Role of plasminogen system components in focal cerebral ischemic infarction: A gene targeting and gene transfer study in mice. Circulation 99:2440–2444.

    PubMed  Google Scholar 

  • National Institute of Neurological Diisorders and Stroke rt-PA Stroke Study Group (1995). Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333(24):1581–1587.

    Google Scholar 

  • Nicole, O., Docagne, F., Ali, C., Margaill, I., Carmeliet, P., MacKenzie E. T., Vivien D., and Buisson, A. (2001). The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nat Med. 7:59–64.

    PubMed  Google Scholar 

  • Nunez, G., and del Peso, L. (1998). Linking extracellular survival signals and the apoptotic machinery. Curr. Opin. Neurobiol. 8:613–618.

    PubMed  Google Scholar 

  • Peter, M. E., and Krammer, P. H. (1998). Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. Curr. Opin. Immunol. 10:545–551.

    PubMed  Google Scholar 

  • Pinkoski, M. J., and Green, D. R. (1999). Fas ligand, death gene. Cell Death Differ. 6:1174–1181.

    PubMed  Google Scholar 

  • Prehn, J. H., Backhauss, C., and Krieglstein, J. (1993). Transforming growth factor-β1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J. Cereb. Blood Flow Metab. 3:521–525.

    Google Scholar 

  • Prehn, J. H., Bindokas, V. P., Marcuccilli, C. J., Krajewski, S., Reed, J. C., Miller, R. J. (1994). Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type-β confers wide-ranging protection on rat hippocampal neurons. Proc. Natl. Acad. Sci. U.S.A. 91:12599–12603.

    PubMed  Google Scholar 

  • Prehn, J. H., and Miller, R. J. (1996). Opposite effects of TGF-β 1 on rapidly-and slowly-triggered excitotoxic injury. Neuropharmacology 35:249–256.

    PubMed  Google Scholar 

  • Raff, M. C., Barres, B. A., Burne, J. F., Coles, H. S., Ishizaki, Y., Jacobson, M. D. (1993). Programmed cell death and the control of cell survival: Lessons from the nervous system. Science 262:695–700.

    PubMed  Google Scholar 

  • Rogister, B., Leprince, P., Delree, P., Van Damme, J., Billiau, A., and Moonen, G. (1990). Enhanced release of plasminogen activator inhibitor(s) but not of plasminogen activators by cultured rat glial cells treated with interleukin-1 Glia 3:252–257.

    PubMed  Google Scholar 

  • Rogister, B., Leprince, P., Pettmann, B., Labourdette, G., Sensenbrenner, M., and Moonen, G. (1988). Brain basic fibroblast growth factor stimulates the release of plasminogen activators by newborn rat cultured astroglial cells. Neurosci. Lett. 91:321–326.

    PubMed  Google Scholar 

  • Rosenbaum, D. M., Gupta, G., D'Amore, J., Singh, M., Weidenheim, K., Zhang, H., and Kessler, J. A. (2000). Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia. J. Neurosci. Res. 61:686–692.

    PubMed  Google Scholar 

  • Ruocco, A., Nicole, O., Docagne, F., Ali, C., Chazalviel L., Komesli, S., Yablonsky, F., Roussel, S., MacKenzie, E. T., Vivien, D., and Buisson, A. (1999). A transforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury. J. Cereb. Blood Flow Metab. 19:1345–1353.

    PubMed  Google Scholar 

  • Schneider, P., and Tschopp, J. (2000). Apoptosis induced by death receptors. Pharm. Acta. Helv. 74:281–286.

    PubMed  Google Scholar 

  • Segal, R. A., and Greenberg, M. E. (1996). Intracellular signaling pathways activated by neurotrophic NeuroSci. 19:463–489.

    Google Scholar 

  • Selkoe, D. J. (2000). Notch and presenilins in vertebrates and invertebrates: Implications for neuronal development and degeneration. Curr. Opin. Neurobiol. 10:50–57.

    PubMed  Google Scholar 

  • Stennicke, H. R., Jurgensmeier, J. M., Shin, H., Deveraux, Q., Wolf, B. B., Yang, X., Zhou, Q., Ellerby, H. M., Ellerby, L. M., Bredesen, D., Green, D. R., Reed, J. C., Froelich, C. J., and Salvesen, G. S. (1998). Pro-caspase-3 is a major physiologic target of caspase-8. J. Biol. Chem. 273:27084–27090.

    PubMed  Google Scholar 

  • Tamura, A., Graham, D. I., McCulloch, J., and Teasdale, G. M. (1981). Focal cerebral ischaemia in the rat: 2. Regional cerebral blood flow determined by [14C]iodoantipyrine autoradiography following middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 1:61–69.

    PubMed  Google Scholar 

  • Tsirka, S. E., Gualandris, A., Amaral, D. G., and Strickland, S. (1995). Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377:340–344.

    PubMed  Google Scholar 

  • Tsirka, S. E., Rogove, A. D., Bugge, T. H., Degen, J. L., and Strickland, S. (1997). An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J. Neurosci. 17:543–552.

    PubMed  Google Scholar 

  • Wang, Y. F., Tsirka, S. E., Strickland, S., Stieg, P. E., Soriano, S. G., and Lipton, S. A. (1998). Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat. Med. 4:228–231.

    PubMed  Google Scholar 

  • Weinmaster, G. (1997). The ins and outs of notch signaling. Mol. Cell. Neurosci. 9:91–102.

    PubMed  Google Scholar 

  • Westerhausen, D. R., Hopkins, W. E., and Billadello, J. J. (1991). Multiple transforming growth factor-beta-inducible elements regulate expression of the plasminogen activator inhibitor type-1 gene in Hep G2 cells. J. Biol. Chem. 266:1092–1100.

    PubMed  Google Scholar 

  • Wiessner, C., Gehrmann, J., Lindholm, D., Topper, R., Kreutzberg, G. W., and Hossmann, K. A. (1993). Expression of transforming growth factor-β 1 and interleukin-1β mRNA in rat brain following transient forebrain ischemia. Acta Neuropathol. (Berl.) 86:439–446.

    Google Scholar 

  • Yuan, J., and Yankner, B. A. (2000). Apoptosis in the nervous system. Nature 12(407):802–809.

    Google Scholar 

  • Zhu, Y., Culmsee, C., Roth-Eichhorn, S., and Krieglstein, J. (2001). Beta(2)-adrenoceptor stimulation enhances latent transforming growth factor-β-binding protein-1 and transforming growth factor-beta1 expression in rat hippocampus after transient forebrain ischemia. Neuroscience 107(4):593–602.

    PubMed  Google Scholar 

  • Zhu, Y., Yang, G. Y., Ahlemeyer, B., Pang, L., Che, X. M., Culmsee, C., Klumpp, S., and Krieglstein, J. (2002). Transforming growth factor-β1 increases bad phosphorylation and protects neurons against damage. J. Neurosci. 22:3898–3909.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Denis Vivien.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buisson, A., Lesne, S., Docagne, F. et al. Transforming Growth Factor-β and Ischemic Brain Injury. Cell Mol Neurobiol 23, 539–550 (2003). https://doi.org/10.1023/A:1025072013107

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025072013107

Navigation