Abstract
Erectile dysfunction is a common complication for patients undergoing surgeries for prostate, bladder, and colorectal cancers, due to damage of the nerves associated with the major pelvic ganglia (MPG). Functional re-innervation of target organs depends on the capacity of the neurons to survive and switch towards a regenerative phenotype. PDE5 inhibitors (PDE5i) have been successfully used in promoting the recovery of erectile function after cavernosal nerve damage (BCNR) by up-regulating the expression of neurotrophic factors in MPG. However, little is known about the effects of PDE5i on markers of neuronal damage and oxidative stress after BCNR. This study aimed to investigate the changes in gene and protein expression profiles of inflammatory, anti-inflammatory cytokines and oxidative stress related-pathways in MPG neurons after BCNR and subsequent treatment with sildenafil. Our results showed that BCNR in Fisher-344 rats promoted up-regulation of cytokines (interleukin- 1 (IL-1) β, IL-6, IL-10, transforming growth factor β 1 (TGFβ1), and oxidative stress factors (Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), TNF receptor superfamily member 5 (CD40) that were normalized by sildenafil treatment given in the drinking water. In summary, PDE5i can attenuate the production of damaging factors and can up-regulate the expression of beneficial factors in the MPG that may ameliorate neuropathic pain, promote neuroprotection, and favor nerve regeneration.
Highlights
Radical prostatectomy (RP) is currently the method of choice for the treatment of early stage prostate cancer
We have demonstrated that the use of PDE5 inhibitors, after bilateral cavernosal nerve resection (BCNR), preserves penile corporal smooth muscle and ameliorates fibrotic degeneration by down-regulating genes related to fibrosis and up-regulating genes related to smooth muscle preservation [25]
In order to confirm the findings obtained by both PCR and proteome array and to determine whether the expression of interleukins was localized in neurons or glial cells after BCNR, we studied the expression of IL-1β by Western blot and immunofluorescence respectively
Summary
Radical prostatectomy (RP) is currently the method of choice for the treatment of early stage prostate cancer. Damage of the cavernosal nerves causes changes in oxidative stress in the corpora cavernosa and a decrease of the neuronal nitric oxide synthase (nNOS) fibers in the dorsal and intracavernosal nerves [3], which in term causes apoptosis of the cavernosal smooth muscle cells and a change in the smooth muscle collagen ratio due to an increase in fibrosis, negatively affecting erectile function [4]. The return of potency after surgical injury of the cavernosal nerves partially depends on axon regeneration in the remaining neural tissue by increasing the number of nNOS positive fibers in the corpora cavernosa [5,6] or by prophylactics pharmacological therapies aimed to reduce oxidative stress [7,8]. Preserve the smooth muscle and reduce fibrosis in the penile corpora cavernosa These palliative therapies cannot be sustained if nerve regeneration does not occur. Surgical trauma causes an inflammatory response and oxidative stress around the degenerating axons, which may cause neuronal damage due to retrograde reaction and chromatolysis [9]
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