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

Joseph P. Steiner, Maureen A. Connolly, Heather L. Valentine, Gregory S. Hamilton, Ted M Dawson, Lynda D Hester, Solomon H Snyder

Research output: Contribution to journalArticle

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 neuronal 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.

Original languageEnglish (US)
Pages (from-to)421-428
Number of pages8
JournalNature Medicine
Volume3
Issue number4
DOIs
StatePublished - 1997

Fingerprint

Immunophilins
Tacrolimus
Sirolimus
Immunosuppressive Agents
Cyclosporine
Calcineurin
L 685818
Ligands
Tacrolimus Binding Protein 1A
Pharmaceutical Preparations
Neurodegenerative diseases
Cyclophilins
PC12 Cells
Spinal Ganglia
Sciatic Nerve
Neurodegenerative Diseases
Biological Availability
Rats
Animals
Derivatives

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. / Steiner, Joseph P.; Connolly, Maureen A.; Valentine, Heather L.; Hamilton, Gregory S.; Dawson, Ted M; Hester, Lynda D; Snyder, Solomon H.

In: Nature Medicine, Vol. 3, No. 4, 1997, p. 421-428.

Research output: Contribution to journalArticle

Steiner, Joseph P. ; Connolly, Maureen A. ; Valentine, Heather L. ; Hamilton, Gregory S. ; Dawson, Ted M ; Hester, Lynda D ; Snyder, Solomon H. / Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. In: Nature Medicine. 1997 ; Vol. 3, No. 4. pp. 421-428.
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