A nonimmunosuppressant FKBP-12 ligand increases nerve regeneration.

Abstract

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.

• Authors: B G Gold, M Zeleny-Pooley, M S Wang, P Chaturvedi, D M Armistead
• Journal: Experimental neurology (Exp Neurol) Vol. 147 Issue 2 Pg. 269-78 (Oct 1997) ISSN: 0014-4886 [Print] United States
• PMID: 9344552 (Publication Type: Journal Article)

Chemical References

• Calcineurin Inhibitors
• Carrier Proteins
• DNA-Binding Proteins
• Heat-Shock Proteins
• Neuroprotective Agents
• Pyridines
• V 10367
• Tacrolimus Binding Proteins
• Tacrolimus

Topics

• Animals
• Calcineurin Inhibitors
• Carrier Proteins (antagonists & inhibitors, physiology)
• DNA-Binding Proteins (antagonists & inhibitors, physiology)
• Drug Evaluation, Preclinical
• Heat-Shock Proteins (antagonists & inhibitors, physiology)
• Humans
• Injections, Subcutaneous
• Locomotion
• Male
• Molecular Structure
• Nerve Crush
• Nerve Regeneration (drug effects)
• Neurites (drug effects, ultrastructure)
• Neuroblastoma (pathology)
• Neuroprotective Agents (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Pyridines (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sciatic Nerve (drug effects, injuries, physiology)
• Stimulation, Chemical
• Structure-Activity Relationship
• Tacrolimus (chemistry, pharmacology)
• Tacrolimus Binding Proteins
• Tumor Cells, Cultured