Immunophilin ligand FK506 is neuroprotective for penile innervation
Author(s): Sena F. Sezen ; Ahmet Hoke ; Arthur L. Burnett ; Solomon H. Snyder 
To the editor
Erectile dysfunction following radical prostatectomy is common even with presumably intact cavernous nerves, the principal autonomic innervation of the penis . The immunosuppressant drugs FK506 and cyclosporin A act through their respective binding proteins FKBP12 and cyclophilin, collectively termed immunophilins . Immunophilin ligands also exert neurotrophic and neuroprotective effects . We show here that FK506 treatment of rats protects penile innervation from degeneration following nerve-crush injury, and preserves erectile function.
To mimic the partial nerve injury associated with radical prostatectomy that does not sever the cavernous nerves, we subjected rats to a partial nerve-crush injury involving three 15-second applications of forceps crush. We administered FK506 (1 mg/kg i.p.) at the same time as the crush and on successive days, with penile erection and cavernous nerve (CN) morphology evaluated 1, 3 or 7 days later (Fig. 1a ). In saline-treated rats, crush injury reduced intracavernous pressure response to CN stimulation to 50% of the sham-operated side in the same rat. FK506 prevents this loss of erectile function. In the group receiving a single injection of FK506, erectile response was restored to 90% of sham-operated values. Pronounced preservation of erectile function was also evident in the groups treated on days 3 and 7. In saline-treated rats there was no difference in the erectile response 1, 3 or 7 days following nerve crush (Fig. 1a ) or, in preliminary experiments, at 2 weeks (data not shown). Also, the erectile response in the FK506-treated group does not differ significantly between 1, 3 or 7 days or at two weeks (preliminary data not shown ).
In limited experiments, we evaluated a more extensive crush injury, with two 60-second crushes. In this study using 3-5 rats per group, saline-treated rats showed 24 [plus or minus] 3.4% of erection on the uncrushed side while FK506-treated rats had 54 [plus or minus] 7% response (P < 0.05). In a group treated for 7 days, we observe no drug effect (FK506, 53 [plus or minus] 5.3%; saline, 46 [plus or minus] 10%).
The ability of FK506 to preserve penile erection as early as one day following treatment implies a...