Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A

Abstract

We show that the nonimmunosuppressive analogues of the immunosuppressive drugs FK506, rapamycin and cyclosporin A promote neurite outgrowth both in PC12 cells and sensory neu-ronal cultures of dorsal root ganglia with potencies resembling their immunosuppressive homologues. Neurotrophic potencies of the immunophilin ligands resemble their potencies in binding to and inhibiting the rotamase activity of FKBP-12 or cyclophilin. Since nonimmunosuppressive immunophilin ligands, which are devoid of calcineurin inhibitory activity, are equally neurotrophic, inhibition of calcineurin activity is not the mediator of the neurotrophic effects. The immunophilin ligands are neurotrophic in intact animals. FK506 and L-685,818 (the C18-hydroxy, C21-ethyl derivative of FK506) treatment of rats with crushed sciatic nerves enhances both functional and morphologic recovery. The striking potency of these agents, their bioavailability and the dissociation of neurotrophic from immunosuppressant actions argue for their therapeutic relevance in the treatment of neurodegenerative diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Lyons, W.E., George, E.B., Dawson, T.M., Steiner, J.P. & Snyder, S.H. Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 Cells and sensory ganglia. Proc. Natl. Acad. Sci. USA 91, 3191–3195 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schreiber, S.L. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science 253, 283–287 (1991).

    Article  Google Scholar 

  3. Handschumacher, R.E., Harding, M.W., Rice, J., Drugge, R.J. & Speicher, D.W. Cyclophilin: A specific cytosolic binding protein for cyclosporin A. Science 226, 544–547 (1984).

    Article  CAS  PubMed  Google Scholar 

  4. Siekierka, J.J., Hung, S.H.Y., Poe, M., Lin, C.S. & Sigal, N.H. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341, 755–757 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Harding, M.W., Galat, A., Uehling, D.E. & Schreiber, S.L. A receptor for the immunosuppressant FK5O6 is a cis-trans peptidyl-prolyl isomerase. Nature 341, 758–760 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. Snyder, S.H. & Sabatini, D.M. Immunophilins and the nervous system. Nature Med. 1, 32–37 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Fischer, G., Bang, H. & Mech, C. Determination of enzymatic catalysis for the cistrans isomerization of peptide binding in proline containing peptides. Biomed. Biochim. Acta. 43, 1101–1111 (1984).

    CAS  PubMed  Google Scholar 

  8. Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. & Schmid, F.X. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 340, 351–352 (1989).

    Google Scholar 

  9. Dumont, F.J. et al. The immunosuppressive and toxic effects of FK506 are mechanistically related: Pharmacology of a novel antagonist of FK506 and rapamycin. J. Exp. Med. 176, 751–760 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Bierer, B.E., Somers, P.K., Wandless, T.J., Burakoff, S.J. & Schreiber, S.L. Probing immunosuppressant action with a non-natural immunophiiin ligand. Science 250, 556–559 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Bierer, B.E. et al. Two distinct signal transduction pathways in T lymphocytes are inhibited by complexes formed between an immunophiiin and either FK506 or rapamycin. Proc. Natl. Acad. Sci. USA 87, 9231–9235 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu, J. et al. Calcineurin is a common target of cyclophilin-cydosporin A and FKBP-FK506 complexes. Cell 66, 807–815 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Steiner, J.P. et al. High brain densities of the immunophiiin FKBP colocalized with calcineurin. Nature 358, 584–587 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Lyons, W.E., Steiner, J.P., Snyder, S.H. & Dawson, T.M. Neuronal regeneration enhances the expression of the immunophiiin FKBP. J. Neurosci. 15, 2985–2994 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gold, B.G., Storm-Dickerson, T. & Austin, D.R. The immunosuppressant FK506 increases functional recovery and nerve regeneration following peripheral nerve injury. Restorative Neurol. Neurosci. 6, 287–296 (1994).

    CAS  Google Scholar 

  16. Cold, B.G., Katoh, K. & Storm-Dickerson, T. The immunosuppressant FK506 increases the rate of axonal regeneration in rat sciatic nerve. J. Neurosci. 15, 7509–7516 (1995).

    Article  Google Scholar 

  17. The US Multicenter FK506 Liver Study Group. A comparison of tacroiimus (FK506) and cyclosporin for immunosuppression in liver transplantation. N. Engl. J. Med. 331, 1154–1155 (1994).

  18. Mueller, A.R., Platz, K.P., Bechstein, W.O. & Schattenfroh, N. Neurotoxicity after orthotopic liver transplantation. A comparison between cyclosporin and FK506. Transplantation 58, 155–170 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Sigal, N.H. et al. Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A?. J. Exp. Med. 173, 619–628 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Sabatini, D.M. et al. RAFT1 (Rapamycin and FKBP12 Target): A mammalian protein that binds to FKBP 12 in a raparnycin-dependent fashion and is homologous to yeast TORS. Cell 78, 35–43 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Brown, E.J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994)

    Article  CAS  PubMed  Google Scholar 

  22. Chen, Y. et al. A putative sirolimus (rapamycin) effector protein. Biochem. Biophys. Res. Commun. 203, 1–7 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Ocain, T.D., Longhi, D., Steffan, R.J., Caccese, R.G. & Sehgal, S.N. A non-immunosuppressive triene-modified rapamycin analog is a potent inhibitor of peptidyl prolyl cis-trans isomerase. Biochem. Biophys. Res. Commun. 192, 1340–1346 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Holt, D.A. et al. Design, synthesis and kinetic evaluation of high-affinity FKBP ligands and the x-ray crystal structures of their complexes with FKBP12. J. Am. Chem. Soc. 115, 9925–9938 (1993).

    Article  CAS  Google Scholar 

  25. Price, E.R. et al. Human cyclophilin B: A second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proc. Natl. Acad. Sci. USA 88, 1903–1906 (1991)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Spik, G. et. al. A novel secreted cyclophilin-like protein (SCYLP). J. Biol. Chem. 266, 10735–10739 (1991).

    CAS  PubMed  Google Scholar 

  27. Sewell, T.J. et al. Inhibition of calineurin by a novel FK-506-binding protein. J. Biol. Chem. 269, 21094–21102 (1994).

    CAS  PubMed  Google Scholar 

  28. Steiner, J.P. et al. Neurotrophic immunophiiin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc. Natl. Acad. Sci. USA 94, 2019–2024 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Apfel, S.C., Arezzo, J.C., Brownlee, M., Federoff, H. & Kessler, J.A. Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res. 634, 7–12 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Apfel, S.C., Arezzo, J.C., Lipson, L. & Kessler, J.A. Nerve growth factor prevents experimental cisplatin neuropathy. Ann. Neurol. 31, 76–80 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. McMahon, S.B. & Priestly, J.V. Peripheral neuropathies and neurotrophic factors: Animal models and clinical perspectives. Current Biol. 5, 616–624 (1995).

    CAS  Google Scholar 

  32. Hefti, F. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J. Neurosci. 6, 2155–2162 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Martinez-Serrano, A. et al. CNS-derived neural progenitor Cells for gene transfer of nerve growth factor to the adult rat brain: Complete rescue of axotomized cholinergic neurons after transplantation into the septum. Neurosci. 15, 5668–5680 (1995).

    Article  CAS  Google Scholar 

  34. Starzl, T.E. et al. Kidney transplantation under FK506. J. Am. Med. Assoc. 264, 63–67 (1990).

    Article  CAS  Google Scholar 

  35. Kahan, B.D. Role of cyclosporin: Present and future. Transplant. Proc. 26, 3082–3087 (1994).

    CAS  PubMed  Google Scholar 

  36. Begley, D.J. et al. Permeability of the blood-brain barrier to the immunosuppressive cyclic peptide cyclosporin A. J. Neurochem. 55, 1222–1230 (1990).

    Article  CAS  PubMed  Google Scholar 

  37. Kofron, J.L. Kuzmic, P. Kishore, V. Colon-Bonilla, E. & Rich, D.H. Determination of kinetic constants for peptidyl prolyl cis-trans isomerases by an improved spectrophotometric assay. Biochemistry 30, 6127–6134 (1991).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Steiner, J., Connolly, M., Valentine, H. et al. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. Nat Med 3, 421–428 (1997). https://doi.org/10.1038/nm0497-421

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0497-421

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing