Urinary incontinence and erectile dysfunction remain a common cause of debilitating post-operative morbidity for a significant proportion of patients undergoing radical therapies for prostate, bladder, and colorectal cancers, as pelvic autonomic neurons are inadvertently axotomized, lacerated, or stretched at time of surgery . For example, contemporary series report that the probability of erectile dysfunction following radical prostatectomy for clinically localized cancer of the prostate is 30–80% at 24 months. Despite advances in surgical technique, most men demonstrate compromised erectile function (incomplete, delayed, or lack of post-surgical potency) as varying degrees of cavernous nerve damage occur even with bilateral nerve-sparing procedures .
The emerging concept of neuromodulatory therapy recognizes that although the peripheral nervous system demonstrates an intrinsic ability to regenerate after injury, this innate response is somewhat limited and does not usually allow for a full recovery of function . Accumulating evidence suggests that a return to potency following injury to the cavernous nerves is partially dependent upon axonal regeneration in the remaining neural tissues and several treatment strategies offering the potential to facilitate recovery are currently under investigation in animal models, including neurotrophins, immunophilin ligands, phosphodiesterase-5 inhibitors, and embryonic stem cells [1,4-6]. Collateral sprouting of axons occurs acutely following injury to adult peripheral neurons and growth cones target local environments supportive of regeneration. Molecular mechanisms of this process remain incompletely understood for parasympathetic neurons, as research is often hampered by difficulties selectively injuring these neurons, which are often found in close proximity or within their target organs . Glial cell line-derived neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN), persephin, and artemin represent a class of novel agents with neuroprotective and neuroregenerative properties . The retrograde axonal transport mechanism of motor neurons has previously been exploited to deliver the gene encoding GDNF into the central nervous system, providing trophic support following injury . NTN and GDNF have also been shown to promote survival and maintainence of cranial parasympathetic neurons via a Ret receptor tyrosine-kinase signalling component and a glycosylphosphatidylinositol-anchored GDNF family receptor α (GFRα) protein receptor complex . In vitro studies of neurturin have demonstrated stimulation of parasympathetic neurite extension from sacral ganglia tissue cultures via the PI3-kinase pathway and suggest NTN acts as a target-derived survival and/or neuritogenic factor for penile erection-inducing postganglionic neurons via a neurotrophic signaling mechanism distinct from other parasympathetic neurons [10-12]. To date, functional improvements secondary to neurturin treatment have not been tested. In this study, the in vivo neuromodulatory effects of neurturin upon the recovery of erectile function following bilateral cavernous nerve crush injury are demonstrated using a rat model of neurogenic impotence.