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

Nature Medicine volume 3, pages 421–428 (1997)Cite this article

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.

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Authors and Affiliations

  1. Departments of Neurobiological Research Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, Maryland, 21224, USA

    Joseph P. Steiner, Maureen A. Connolly & Heather L. Valentine

  2. Departments of Medicinal Chemistry Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, Maryland, 21224, USA

    Gregory S. Hamilton

  3. Departments of Neuroscience, Pharmacology and Molecular Sciences, Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland, 21205, USA

    Ted M. Dawson, Lynda Hester & Solomon H. Snyder

  4. Neurology, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland, 21205, USA

    Ted M. Dawson

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  1. Joseph P. Steiner
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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

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