A clear clinical need for the development of therapeutic neuromodulatory interventions has been defined as both sympathetic and parasympathetic pelvic innervation is at high risk of injury during surgery or radiation therapy for prostate, bladder, and colorectal malignancies. Penile erection, controlled by adrenergic, cholinergic, and nonadrenergic noncholinergic (NANC) neuroeffectors carried in the cavernous nerves, is often compromised by these treatments, and subsequent patient quality-of-life diminished . Despite advances in operative technique, the probability of a man undergoing open radical retropubic prostatectomy for clinically localized disease and achieving cancer-control, continence and potency is approximately 60% at 24 months . Neurturin, which is expressed in peripheral neuronal targets including the penis, has demonstrated key neuromodulatory properties including retrograde transport from the periphery to cell body, enhancement of neuronal survival and promotion of neurite outgrowth [13-15]. In this study, we demonstrate neurturin's ability to confer an in vivo advantage for the functional recovery of erectile function following cavernous nerve injury.
Various methods of inducing injury to the cavernous nerves are described in literature and include nerve transection, cryoablation, crush and partial excision . We prefer to use a controlled bilateral nerve crush technique, as significant but reversible damage to penile innervation occurs and allows for the evaluation of functional recovery. Advantages of this technique include simplicity, reliability, and reproducibility, albeit the relationship to surgical trauma incurred by prostatectomy is inexact as the prostate itself is not removed . Because NOS-containing nerves and neurons are the principal sites where the erection-inducing neurotransmitter nitric oxide (NO) is synthesized, their loss after nerve injury is therefore chiefly responsible for the development of ED. Using this animal model of neurogenic ED, we have previously demonstrated a significant loss of nitric oxide syntheses (NOS)-containing nerve fibers and neurons in the corpora cavernosa and in the major pelvic ganglia (MPG) respectively, within one month of bilateral cavernous nerve crush injury .
Neurturin applied directly to the area of injury facilitated the preservation of erectile function as compared to untreated control animals and extended release neurotrophin-4. The primary outcome measure, mean intracavernous pressure increase, has been used extensively as the measure of penile rigidity (function) in a wide variety of ED animal models, and is a unifying factor for defining response in the treatment of erectile dysfunction in humans . In a recently reported study investigating the relationship between mean arterial pressure and ICP, MacKenzie et al demonstrated that changes in ICP values were adversely effected only when mean arterial pressure (MAP) fell below 70 mmHg (regardless of the cause) . Aortic pressures following determination of ICP did not differ between groups and each animal demonstrated values of 100 mmHg or greater. Therefore, a carotid artery catheter was not placed to monitor arterial pressure concurrently with cavernous nerve stimulation as performed in the past, minimizing undue operative morbidity and physiologic stress on the rat as recommended by our Institutional Review Board. In addition, our preference is to observe the wave form and the ICP change rather than the ratio of ICP/BP; hypertensive patients can have abnormal ICP/MAP ratios but sufficient penile rigidity (with intracavernous pressures exceeding 100 mmHg) and would not be labelled as impotent.
Following injury, compensatory and regenerative sprouting of penile-projecting nerve fibres is likely driven by, and dependent upon, various neurotrophic factors including NTN, which is synthesized in urogenital tissues including the penis and may also be secreted by glial cells within the ganglion or glia associated with the injured axon(s) . Known receptors for neurturin include the GDNF family receptors α1, α2 (predominant), and α4, and have been identified in the major pelvic ganglion . Pelvic parasympathetic ganglion neurons respond to axotomy by altering expression of NTN receptors; altered glial secretions or glial coupling represent a complimentary second mechanism of adapative signalling in early phases of regeneration . As penis-projecting pelvic neurons express neuronal nitric oxide (nNOS) and GFRα2, accumulating tissue culture, cell-line, in vivo signalling, and with this report functional evidence, suggests that neurturin plays a role in regeneration, as well as maintainence of adult parasympathetic neurons [11,22]. Given the limitations of this pilot study, including unknown optimal dosing or site of NTN delivery (crush site versus major pelvic ganglion or penis), and an incomplete understanding of the neurobiology of cavernous nerve and neurturin interaction, results are encouraging and warrant further study of NTN in this role. Following a similar course to our investigations of brain-derived nerve growth factor and its role in cavernous nerve response to injury, we plan to focus upon identifying the primary molecular signalling pathway(s), concentration-dependent effects, and pattern(s) of endogenous neurturin release in an effect to better delineate its neuroregenerative or neuroprotective properties [23,24].
A growing body of literature suggests neurturin may represent a promising therapeutic agent for both central and peripheral neurologic diseases states, enhancing survival, differentiation, and regeneration of neurons alone or synergistically with other molecules. In addition to traumatic injury, neurogenic impotence is often associated with diseases related to sensory and/or peripheral neuropathy such as diabetes mellitus . As penile tissues are known to express mRNA transcripts for at least 10 neurotrophic factors, treatment strategies utilizing neurturin and these neuromodulators alone or in combination may represent future approaches to alleviate ED caused by injury, neurological or vascular changes [25,26]. From a broader perspective, elucidating the mechanisms by which neurturin enhances peripheral nerve repair and functional recovery may translate into clinical applications for such diverse conditions as recurrent laryngeal nerve and brachial plexus injuries, iatrogenic neuropraxias, or urinary incontinence secondary to hysterectomy.