A nonimmunosuppressant FKBP-12 ligand increases nerve regeneration.
The immunosuppressant drugs FK506 and cyclosporin A inhibit T-cell proliferation via a common mechanism: calcineurin inhibition following binding to their respective binding proteins, the peptidyl prolyl isomerases FKBP-12 and cyclophilin A. In contrast, FK506, but not cyclosporin A, accelerates nerve regeneration. In the present study, we show that the potent FKBP-12 inhibitor V-10,367, which lacks the structural components of FK506 required for calcineurin inhibition, increases neurite outgrowth in SH-SY5Y neuroblastoma cells and speeds nerve regeneration in the rat sciatic nerve crush model. In SH-SY5Y cells, V-10,367 increased the lengths of neurite processes in a concentration-dependent (between 1 and 10 nM) fashion over time (up to 168 h). Daily subcutaneous injections of V-10,367 accelerated the onset of clinical signs of functional recovery in the hind feet compared to vehicle-treated control animals. Interdigit distances (between the first and fifth digits) measured on foot prints obtained during walking showed an increase in toe spread in V-10,367-treated rats compared to vehicle-treated controls. Electron microscopy demonstrated larger regenerating axons distal to the crush site in the sciatic nerve from V-10,367-treated rats. Quantitation of axonal areas in the soleus nerve revealed a shift to larger axonal calibers in V-10,367-treated rats (400 or 200 mg/kg/day); mean axonal areas were increased by 52 and 59%, respectively, compared to vehicle-treated controls. FKBP-12 ligands lacking calcineurin inhibitory activity represent a new class of potential drugs for the treatment of human peripheral nerve disorders.
Gold
B G
BG
Center for Research on Occupational and Environmental Toxicology and Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland 97201-3098, USA.
Zeleny-Pooley
M
M
Wang
M S
MS
Chaturvedi
P
P
Armistead
D M
DM
D000818:Animals; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D007279:Injections, Subcutaneous; D008124:Locomotion; D008297:Male; D015394:Molecular Structure; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects* / Q000648:ultrastructure; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000737:chemistry / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins; D014407:Tumor Cells, Cultured
D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D011725:Pyridines; C108850:V 10367; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus