Sildenafil promotes neuroprotection of the pelvic ganglia neurones after bilateral cavernosal nerve resection in the rat

Abstract

Objectives To determine the gene expression profile of pelvic ganglia neurones after bilateral cavernosal nerve resection (BCNR) and subsequent treatment with sildenafil in relation to neurotrophic-related pathways. Materials and methods Fisher rats aged 5 months were subjected to BCNR or sham operation and treated with or without sildenafil (20 mg/kg body-weight in drinking water) for 7 days. Total RNA isolated from pelvic ganglia was subjected to reverse transcription and then to quantitative reverse transcriptase-polymerase chain reaction (PCR) with the RAT-neurotrophic array. Results were corroborated by real-time PCR and western blotting. Another set of animals were injected with a fluorescent tracer at the base of the penis, 7 days before BCNR or sham operation, and were sacrificed 7 days after surgery. Sections of pelvic ganglia were used for immunohistochemistry with antibodies against neurturin, neuronal nitric oxide synthase, tyrosine hydroxylase and glial cell line-derived neurotrophic factor receptor α2. Results A down-regulation of the expression of neuronal nitric oxide synthase accompanied by changes in the level of cholinergic neurotrophic factors, such as neurturin and its receptor glial cell line-derived neurotrophic factor receptor α2, artemin, neurotrophin-4 and cilliary neurotrophic factor, was observed 7 days after BCNR in pelvic ganglia neurones. Treatment with sildenafil, starting immediately after surgery, reversed all these changes at a level similar to that in sham-operated animals. Conclusions Sildenafil treatment promotes changes in the neurotrophic phenotype, leading to a regenerative state of pelvic ganglia neurones. The present study provides a justification for the use of phosphodiesterase 5 inhibitors as a neuroprotective agent after BCNR.

Sildenafil Attenuates Inflammation and Oxidative Stress in Pelvic Ganglia Neurons after Bilateral Cavernosal Nerve Damage

“…BCNR was performed as we previously described [25,26,42,43]. In the sham-operated group both cavernosal nerves were identified but not resected.…”

“…We have also observed that at the level of the pelvic ganglia, Sildenafil (SIL) exerts a neuroprotective effect by activating neurotrophic factors involved in neuronal survival and regeneration [26]. However, little is known of the role of NO/cyclic guanosine monophosphate (cGMP) pathways on cytokines and oxidative stress modulation after nerve resection in autonomic neurons.…”

Erectile function recovery in men treated with phosphodiesterase type 5 inhibitor administration after bilateral nerve‐sparing radical prostatectomy: a systematic review of placebo‐controlled randomized trials with trial sequential analysis

“…These data parallel the growing body of evidence found in animal models, which indicate that smooth muscle (SM) apoptosis and NOS nerve fibre reduction with veno‐occlusive dysfunction may occur within 1–3 weeks after cavernous nerve neurotomy (Carrier et al ., ). The immediate chronic administration of PDE5Is in these animal models reduces anatomical alterations after cavernous nerve neurotomy (Schwartz et al ., ; Vignozzi et al ., , ; Kovanecz et al ., ,b; Sirad et al ., ; Hlaing et al ., ; Garcia et al ., ). In the only RCT assessing the effect of PDE5Is on the preservation of erectile tissue (Montorsi et al ., ), reduced shrinkage of penile length compared with placebo was observed upon low‐dose daily tadalafil administration.…”

Peptide amphiphile nanofiber hydrogel delivery of sonic hedgehog protein to the cavernous nerve to promote regeneration and prevent erectile dysfunction

“…The distal nerve shows overall distortion of normal nerve anatomy, axonal swelling and axonal vacuolization which are microanatomical signs of Wallerian degeneration [19]. Local conditions influence how initial regenerative axon sprouts emerge from parent axons [20], while CN injury triggers a cascade of events in PG neurons, including changes in expression of neurotransmitters, neurotrophic factors, cytokine production [21], and SHH pathway signaling [11–12]. Following injury, the regenerative abilities of these important injured parasympathetic ganglion neurons and the factors in the environment that influence regeneration are poorly understood.…”