FK1706, a novel non-immunosuppressive immunophilin: neurotrophic activity and mechanism of action

Eur J Pharmacol. 2005 Feb 10;509(1):11-9. doi: 10.1016/j.ejphar.2004.12.023. Epub 2005 Jan 20.

Abstract

Immunophilin ligands are neuroregenerative agents, characterized by binding to FK506 binding proteins (FKBPs), which stimulate recovery of neurons in a variety of injury paradigms. Here we report the discovery of a novel, non-immunosuppressive immunophilin ligand, FK1706. FK1706, a derivative of FK506, showed similarly high affinity for two FKBP subtypes, FKBP-12 and FKBP-52, but inhibited T-cell proliferation and interleukin-2 cytokine production with much lower potency and efficacy than FK506. FK1706 (0.1 to 10 nM) significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in SH-SY5Y cells, as did FK506. This neurite potentiation could be blocked by an anti-FKBP-52 antibody, as well as by specific pharmacological inhibitors of phospholipase C (PLC), phosphatidylinositol 3-kinase (PI3K), and the Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) signaling pathway. FK1706 also potentiated NGF-induced MAPK activation, with a similar dose-dependency to that necessary for potentiating neurite outgrowth. Taken together, these data suggest that FK1706 is a non-immunosuppressive immunophilin ligand with significant neurotrophic effects, putatively mediated via FKBP-52 and the Ras/Raf/MAPK signaling pathway, and therefore that FK1706 may have therapeutic potential in a variety of neurological disorders.

Publication types

  • Comparative Study

MeSH terms

  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Humans
  • Immunophilins / chemistry
  • Immunophilins / metabolism
  • Immunophilins / pharmacology*
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Nerve Growth Factors / antagonists & inhibitors
  • Nerve Growth Factors / pharmacology*
  • Nerve Growth Factors / physiology*
  • Receptor, trkB / metabolism
  • Signal Transduction / physiology
  • Tacrolimus / analogs & derivatives
  • Tacrolimus / chemistry
  • Tacrolimus / immunology
  • Tacrolimus / metabolism
  • Tacrolimus / pharmacology
  • Tacrolimus Binding Protein 1A / chemistry
  • Tacrolimus Binding Protein 1A / metabolism
  • Tacrolimus Binding Protein 1A / pharmacology
  • Tritium

Substances

  • FK1706
  • Nerve Growth Factors
  • Tritium
  • Receptor, trkB
  • Mitogen-Activated Protein Kinases
  • Tacrolimus Binding Protein 1A
  • Immunophilins
  • Tacrolimus