GGF2 Is Neuroprotective in a Rat Model of Cavernous Nerve Injury-Induced Erectile Dysfunction

Abstract

Introduction Erectile dysfunction is a major complication of radical prostatectomy, commonly associated with penile neuropathy. In animal models of peripheral nerve injury, glial growth factor-2 (GGF2), a member of the neuregulin family of growth factors, has neuroprotective and neurorestorative properties, but this potential has not been established after cavernous nerve (CN) injury. Aims The effectiveness of GGF2 in preserving axonal integrity and recovering erectile function in a rat model of radical prostatectomy-associated CN injury. Methods Adult male Sprague-Dawley rats underwent bilateral CN crush injury (BCNI) or sham surgery. Rats were administered GGF2 (0.5, 5, or 15 mg/kg) or vehicle subcutaneously 24h pre- and 24h post-BCNI, and once weekly for 5 weeks. Erectile function was assessed in response to electrical stimulation of the CN. CN survival was assessed by fluorogold retrograde axonal tracing in major pelvic ganglia (MPG). Unmyelinated axons in the CNs were quantitated by electron microscopy. Main Outcome Measures Erectile function recovery, CN survival, and unmyelinated CN axon preservation in response to GGF2 treatment following BCNI. Results Erectile function was decreased (P<0.05) after BCNI, and it was improved (P<0.05) by all doses of GGF2. The number of fluorogold-labeled cells in the MPG was reduced (P<0.05) by BCNI, and was increased (P<0.05) by GGF2 (0.5 and 5 mg/kg). The percentage of denervated Schwann cells in the BCNI group was higher (P<0.05) than that in the sham-treated group, and was decreased (P<0.05) in the GGF2 treated (5 mg/kg) BCNI group. In the BCNI+GGF2 (5mg/kg) group, the unmyelinated fiber histogram demonstrated a rightward shift, indicating an increased number of unmyelinated axons per Schwann cell compared to the BCNI group. Conclusions GGF2 promotes erectile function recovery following CN injury in conjunction with preserving unmyelinated CN fibers. Our findings suggest the clinical opportunity to develop GGF2 as a neuroprotective therapy for radical prostatectomy.

S-nitrosylation of NOS pathway mediators in the penis contributes to cavernous nerve injury-induced erectile dysfunction

“…To limit variability, all surgeries were completed by the same trained investigator. BCNI was induced by crushing nerves with a fine-grade hemostat for 2 minutes ( 25 ). Sham surgeries were completed by exposing the cavernous nerves but not manipulating them.…”

Neuroprotective and Nerve Regenerative Approaches for Treatment of Erectile Dysfunction after Cavernous Nerve Injury

“…Neuregulins have been studied in many disease processes and due to their regenerative mechanism in nerve injury, they have recently been investigated for their potential role in neurogenic ED. GGF-2 was first explored in a CNI rat model by Burnett et al in 2015 [ 50 ]. After inducing a bilateral CNI, GGF-2 protein was administered intracavernosally once weekly for 5 weeks.…”

“…Erectile function was evaluated in the study groups by CN stimulation. Treatment with GGF-2 preserved unmyelinated CN fibers, sustained axonal integrity, and promoted erectile function recovery after CNI [ 50 ]. This early study provides some insight into the role of neuregulins in the treatment of ED, although further pre-clinical studies are necessary before expanding to human trials.…”

Research in pharmacotherapy for erectile dysfunction

“…Intracavernous administration of GGF-2 protein (neuregulin-1β3 type II), a soluble full-length splice variant of the neuregulin-1 gene, promoted axonal integrity and preserved erectile function in a rat model of CNI (48). …”