Oral administration of a nonimmunosuppressant FKBP-12 ligand speeds nerve regeneration

Abstract

We recently showed that s.c. injections of a nonimmunosuppressant FK506 binding protein-12 (FKBP-12) ligand (V-10,367) accelerates nerve regeneration in the rat sciatic nerve crush model. Here we examined the oral efficacy of this compound for speeding nerve regeneration. Rats receiving V-10,367 (5, 15 or 50 mg/kg/day) by oral gavage all demonstrated an increase in nerve regeneration compared to vehicle-treated controls. Functional recovery was observed earliest and axonal calibers of regenerating axons in the soleus nerve were largest in the 15 mg/kg group, mean axonal areas being increased by 66% compared to controls. Orally active nonimmunosuppressant FKBP-12 ligands may be useful for the treatment of human peripheral nerve disorders.

The effects of cold preservation and subimmunosuppressive doses of FK506 on axonal regeneration in murine peripheral nerve isografts

“…The neuroregenerative effects of FK506 are now thought to be independent of calcineurin, but to still involve binding to FKBP-12, or perhaps another binding ligand such as FKBP-52 (19)(20)(21)59). The administration of other nonimmunosuppressive FKBP-12-binding ligands has demonstrated a neuroregenerative effect in some in vivo (25,26,60,61) and in vitro studies (21,22,62), but not in others (23,24,63,64). By demonstrating a neuroregenerative effect in the absence of immunosuppression, the present study provides further in vivo evidence that the neuroregenerative and immunosuppressive effects of FK506 are distinct from one another.…”

“…Such agents include insulin-like growth factor (2-4), prosaposin (5,6), ciliary neurotrophic factor (7,8), acidic fibroblast growth factor (9), hyaluronic acid (10), leupeptin (11) and ganglioside GM1 (12). The immunosuppressive agent FK506, a neuro-immunophilin-binding ligand, has consistently demonstrated significant neuroregenerative properties both in vivo (13)(14)(15)(16)(17)18) and in vitro (19)(20)(21)(22), while the neuroregenerative properties of other neuroimmunophilin-binding ligands such as GPI-1046, L-685,818, V-10,367 and rapamycin are less conclusive (21)(22)(23)(24)(25)(26)(27).…”

The Specific FKBP38 Inhibitor N-(N′,N′-Dimethylcarboxamidomethyl)cycloheximide Has Potent Neuroprotective and Neurotrophic Properties in Brain Ischemia

“…: 49-345-55-22800; Fax: 49-345-55-11972; E-mail: fischer@enzyme-halle.mpg.de. 2 dopamine neurons in culture, enhance neurite outgrowth of fetal dopamine transplants, increase nerve regeneration, and accelerate functional recovery following peripheral nerve injury (24,25). Although the dramatic neuroprotective and neurotrophic effects of FKBP inhibitors imply an involvement of FKBP activity in neuronal cell death, the nature of the FKBP representing the primary target of these drugs remained enigmatic.…”

Immunophilin ligands in peripheral nerve regeneration

“…Both GAP-43 and neuronal phosphates are concentrated in growth cones of the proximal stump of the lesioned nerve, where they are believed to play an important role in nerve regeneration [64]. In an elegant study, Gold et al [32] demonstrated that non-FKBP-12 ligand (V-13.670) accelerates functional recovery and nerve regeneration in the rat sciatic nerve crush model.…”