A NONIMMUNOSUPPRESSANT FKBP-12 LIGAND INCREASES NERVE REGENERATION

The immunosuppressant drugs FK506 and cyclosporin A inhibit T-cell pro liferation via a common mechanism: calcineurin inhibition following bi nding to their respective binding proteins, the peptidyl prolyl isomer ases 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 com ponents of FK506 required for calcineurin inhibition, increases neurit e outgrowth in SH-SY5Y neuroblastoma cells and speeds nerve regenerati on in the rat sciatic nerve crush model. In SH-SY5Y cells, V-10,367 in creased the lengths of neurite processes in a concentration-dependent (between 1 and 10 nM) fashion over time (up to 168 h). Daily subcutane ous injections of V-10,367 accelerated the onset of clinical signs of functional recovery in the hind feet compared to vehicle-treated contr ol 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 contro ls. Electron microscopy demonstrated larger regenerating axons distal to the crush site in the sciatic nerve from V-10,367-treated rats. Qua ntitation of axonal areas in the soleus nerve revealed a shift to larg er axonal calibers in V-10,367-treated rats (400 or 200 mg/kg/day); me an axonal areas were increased by 52 and 59%, respectively, compared t o vehicle-treated controls. FKBP-12 ligands lacking calcineurin inhibi tory activity represent a new class of potential drugs for the treatme nt of human peripheral nerve disorders. (C) 1997 Academic Press.