FK1706 Enhances the Recovery of Erectile Function Following Bilateral Cavernous Nerve Crush Injury in the Rat

Abstract

Introduction Advances in neurobiology have led to a surge of clinical interest in the development of protective and regenerative neuromodulatory strategies, as surgical therapies for prostate cancer often result in neuronal damage and debilitating loss of sexual function. Aim To investigate the dose-dependent efficacy of FK1706, a nonimmunosuppressant immunophilin ligand, for the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. Main Outcome Measures Recovery of erectile function was assessed by cavernous nerve electrostimulation and reported as maximal increase of intracavernous pressure (ICP) and area under the curve (AUC). Changes in animal weights, percentage completion of treatment course, and survival were compared between groups. Methods Thirty-five Sprague–Dawley male rats were randomly divided into five equal groups: seven animals received a sham operation, whereas 28 animals underwent bilateral cavernous nerve crush injury, followed by subcutaneous injection of vehicle alone (1.0 mL/kg), or low (0.1 mg/kg), medium (0.32 mg/kg), or high dose (1.0 mg/kg) FK1706 5 days per week for 8 weeks. Results Erectile dysfunction did not occur in the sham group (mean maximal ICP increase of 100.8 ± 6.3 cmH2O), whereas nerve injury and vehicle treatment produced a significant reduction in ICP response to 34.4 ± 12.8 cmH2O. The mean ICP increase for high-dose FK106 treatment was 73.9 ± 6.3 cmH2O (P < 0.01 vs. vehicle) compared with 58.3 ± 7.4 cmH2O and 56.9 ± 8.3 for low and medium doses (P > 0.05). Similar stepwise findings were observed using AUC data. No significant maximal aortic blood pressure or weight differences occurred between groups and all animals completed treatment. Conclusion High-dose subcutaneous FK1706 therapy promoted recovery of erectile function following bilateral cavernous nerve crush injury in the rat. No significant differences between groups were observed for changes in weight, and the 8-week treatment course was completed for all animals.

FKBPs and their role in neuronal signaling

“…1) became available as tool compounds and were extensively tested in a variety of animal models such as sciatic [6,7,9,10], cavernous [11,12] or optic nerve crush [13], spinal cord injury [14][15][16], streptozotocin-induced diabetic neuropathy [17,18], or MPTP-or 6-OHDA-induced degeneration of dopaminergic neurons (Table 1) [19][20][21]. These studies provided enticing indications that non-immunosuppressive FK506 analogs might be useful for the treatment of various forms of physical nerve injury, painful diabetic neuropathy or Parkinson's disease.…”

Immunophilin Dysfunction and Neuropathology

“…In a bilateral CNs crush model, FK1706 has been shown to enhance the recovery of erectile function in a concentration dependent manner, with higher dose-treated group showing a statistically significant elevation of intracavernous pressure (ICP) compared to vehicle-only treated control animals (73.9 vs. 34.4 mean cmH 2 O) and low/medium FK1706 dose-treated groups showing improvement of more than 60% [98]. Oral and intraperitoneal administration of GPI 1046 results in similar erectile function recovery to that of FK506 in both unilateral and bilateral CNs-injured animals following short-term 1-and 7-day administration.…”

Preclinical Evidence for the Benefits of Penile Rehabilitation Therapy following Nerve-Sparing Radical Prostatectomy

“…FK1706 treatment restored axon shape and staining patterns. Injury significantly decreased nicotinamide adenine dinucleotide phosphate staining and FK1706 treatment showed a trend toward increased staining [81, 82]. …”