Non-FK506-binding protein-12 neuroimmunophilin ligands increase neurite elongation and accelerate nerve regeneration

J Neurosci Res. 2005 Apr 1;80(1):56-65. doi: 10.1002/jnr.20447.


Neurotrophic activity of neuroimmunophilin ligands (FK506 and its nonimmunosuppressant derivatives) has been assumed to be mediated by the FK506-binding protein-12 (FKBP-12). We recently showed that activity is retained in hippocampal neurons from FKBP-12 knockout mice, indicating that binding to FKBP-12 is not necessary. Here we show that three nonimmunosuppressant FK506 derivatives (V-13,450, V-13,629, and V-13,670) that do not bind FKBP-12 (>12.5 mM affinity) are equipotent to FKBP-12 ligands (FK506, V-10,367, and V-13,449) for increasing neurite elongation in SH-SY5Y cells. One non-FKBP-12 ligand (V-13,670) is also shown to accelerate functional recovery and nerve regeneration in the rat sciatic nerve crush model. Surprisingly, it exhibited an unusual dose-response effect upon oral administration, showing a novel bimodal dose-response for behavioral functional recovery and myelination, but not for axonal size, suggesting both Schwann cell and neuronal targets. Orally active non-FKBP-12 neuroimmunophilin ligands may be useful for the treatment of human neurological disorders without any potential side effects resulting from FKBP-12 binding.

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Male
  • Microscopy, Electron, Transmission
  • Nerve Crush
  • Nerve Regeneration / drug effects*
  • Neurites / drug effects*
  • Neurites / pathology
  • Neurites / ultrastructure
  • Neuroprotective Agents / administration & dosage*
  • Organic Chemicals
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function / drug effects
  • Sciatic Nerve / drug effects*
  • Sciatic Nerve / pathology
  • Sciatic Nerve / ultrastructure
  • Tacrolimus Binding Proteins / metabolism*


  • Ligands
  • Neuroprotective Agents
  • Organic Chemicals
  • V-13,670
  • Tacrolimus Binding Proteins