Non-FK506-binding protein-12 neuroimmunophilin ligands increase neurite elongation and accelerate nerve regeneration.
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.
Gold
Bruce G
BG
Department of Neurology, Oregon Health and Science University, Portland, Oregon 97239-3098, USA. gold@ohsu.edu
Armistead
David M
DM
Wang
Min-Sheng
MS
D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008297:Male; D046529:Microscopy, Electron, Transmission; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009930:Organic Chemicals; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
D008024:Ligands; D018696:Neuroprotective Agents; D009930:Organic Chemicals; C444011:V-13,670; D022021:Tacrolimus Binding Proteins