Neuroimmunophilin ligands protect cavernous nerves after crush injury in the rat: new experimental paradigms.
OBJECTIVE
We investigated the effects of the orally bioavailable non-immunosuppressive immunophilin ligand GPI 1046 (GPI) on erectile function and cavernous nerve (CN) histology following unilateral or bilateral crush injury (UCI, BCI, respectively) of the CNs.


METHODS
Adult male Sprague-Dawley rats were administered GPI 15 mg/kg intraperitoneally (ip) or 30 mg/kg orally (po), FK506 1 mg/kg, ip, or vehicle controls for each route of administration just prior to UCI or BCI and daily up to 7 d following injury. At day 1 or 7 of treatment, erectile function induced by CN electrical stimulation was measured, and electron microscopic analysis of the injured CN was performed.


RESULTS
Intraperitoneal administration of GPI to rats with injured CN protected erectile function, in a fashion similar to the prototypic immunophilin ligand FK506, compared with vehicle-treated animals (93%+/-9% vs. 70%+/-5% vs. 45%+/-1%, p<0.01, respectively). Oral administration of GPI elicited the same level of significant protection from CN injury. GPI administered po at 30 mg/kg/d, dosing either once daily or four times daily with 7.5 mg/kg, provided nearly complete protection of erectile function. In a more severe BCI model, po administration of GPI maintained erectile function at 24 h after CN injury. Ultrastructural analysis of injured CNs indicated that GPI administered at the time of CN injury prevents degeneration of about 83% of the unmyelinated axons at 7 d after CN injury.


CONCLUSIONS
The orally administered immunophilin ligand GPI neuroprotects CNs and maintains erectile function in rats under various conditions of CN crush injury.
Valentine
Heather
H
Department of Research, Guilford Pharmaceuticals Inc (now MGI Pharma), Baltimore, Maryland 21287, United States.
Chen
Yi
Y
Guo
Hongzhi
H
McCormick
Jocelyn
J
Wu
Yong
Y
Sezen
Sena F
SF
Hoke
Ahmet
A
Burnett
Arthur L
AL
Steiner
Joseph P
JP
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects*; D010413:Penis / Q000293:injuries* / Q000294:innervation*; D059348:Peripheral Nerve Injuries; D011468:Prostatectomy / Q000009:adverse effects; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*
C104949:GPI 1046; D008024:Ligands; D011759:Pyrrolidines; D016559:Tacrolimus