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.