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

Publisher Website
Google Scholar
Abstract
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.