Cavernous Nerve Injury-induced Erectile Dysfunction Research Articles

Lacosamide alleviates bilateral cavernous nerve injury-induced erectile dysfunction in the rat model by ameliorating pathological changes in the corpus cavernosum.

Bilateral cavernous nerve injury-related erectile dysfunction (BCNI-ED) shows a limited response to type 5 phosphodiesterase inhibitors. Furthermore, lacosamide (LCM) can alleviate peripheral neuropathy. To explore whether LCM can improve the erectile response after BCNI, we randomly divided 30 young Sprague-Dawley rats into three groups (n = 10 per group), namely, the sham operation, 0.9% normal saline-treated (BCNI + 0.9% NS), and LCM-treated BCNI (BCNI + LCM) groups. LCM was injected intraperitoneally at a dose of 90 mg/kg/day for 7 consecutive days. Erectile function was assessed by measuring the ratio of peak intracavernous pressure (ICP) to mean arterial pressure (MAP), and tissues were harvested for transmission electron microscopy, immunofluorescence, Masson's trichrome staining, TUNEL staining, and Western blot analysis. The BCNI + 0.9% NS group showed reduced ICP/MAP ratio (0.93 ± 0.04 vs. 0.44 ± 0.05, P < 0.0001). An increased proportion of TUNEL-positive cells (0.04 ± 0.01 vs 0.87 ± 0.03, P < 0.0001) and a decreased smooth muscle/collagen ratio (0.44 ± 0.01 vs. 0.33 ± 0.01, P < 0.001) were observed in the BCNI + 0.9% NS compared with the sham group. Administration of LCM significantly restored the ICP/MAP ratio (0.44 ± 0.05 vs. 0.74 ± 0.05, P < 0.001) and decreased the proportion of TUNEL positive cells (0.87 ± 0.03 vs. 0.60 ± 0.04, P < 0.0001) in the corpus cavernosum following BCNI. The ratio of smooth muscle to collagen (0.43 ± 0.01vs. 0.33 ± 0.01, P < 0.01) and expression of α-SMA (P < 0.0001) in the BCNI + LCM group significantly increased compared with BCNI + 0.9% NS group, indicating alleviation of fibrosis. Apoptotic markers, including Bax/Bcl-2 (P < 0.01) and Caspase-3 (P < 0.0001) in the BCNI + LCM group was significantly lower than that in the BCNI + 0.9% NS group. LCM treatment partially upregulated the expression of vWF and eNOS in cavernous tissue in rats subjected to BCNI (P < 0.05). Increases in S100-β and nNOS expression in the major pelvic ganglion (MPG) were observed after LCM administration. In summary, LCM can recover erectile function in BCNI-ED rat model by suppressing corporal apoptosis and fibrosis, and protecting the cavernous nerve.

Low-intensity pulsed ultrasound ameliorates erectile dysfunction induced by bilateral cavernous nerve injury through enhancing Schwann cell-mediated cavernous nerve regeneration.

Cavernous nerve injury-induced erectile dysfunction caused by pelvic surgery or trauma is refractory to conventional medications and required an alternative treatment. Low-intensity pulsed ultrasound is a noninvasive mechanical therapy that promotes nerve regeneration. To investigate the therapeutic effect and potential mechanism of low-intensity pulsed ultrasound in the treatment of neurogenic erectile dysfunction. Thirty rats were randomly divided into the sham-operated group, bilateral cavernous nerve injury group, and bilateral cavernous nerve injury + low-intensity pulsed ultrasound group. The erectile function was assessed 3weeks after daily low-intensity pulsed ultrasound treatment. The penile tissues and cavernous nerve tissues were harvested and subjected to histologic analysis. Primary Schwann cells and explants were extracted from adult rats. The effects of low-intensity pulsed ultrasound on proliferation, migration, and nerve growth factor expression of Schwann cells and axonal elongation were examined in vitro. RNA sequencing and western blot assay were applied to predict and verify the molecular mechanism of low-intensity pulsed ultrasound-induced Schwann cell activation. Our study showed that low-intensity pulsed ultrasound promoted Schwann cells proliferation, migration, and neurotrophic factor nerve growth factor expression. Meanwhile, low-intensity pulsed ultrasound exhibits a stronger ability to enhance Schwann cells-mediated neurite outgrowth of major pelvic ganglion neurons and major pelvic ganglion/cavernous nerve explants in vitro. In vivo experiments demonstrated that the erectile function of the rats in the bilateral cavernous nerve injury + low-intensity pulsed ultrasound group was significantly higher than those in the bilateral cavernous nerve injury groups. Moreover, the expression levels of smooth muscle and cavernous endothelium also increased significantly in the bilateral cavernous nerve injury + low-intensity pulsed ultrasound group. In addition, we observed the higher density and number of cavernous nerve regenerating axons in the bilateral cavernous nerve injury + low-intensity pulsed ultrasound group, indicating that low-intensity pulsed ultrasound promotes axonal regeneration following cavernous nerve injury in vivo. RNA sequencing analysis and bioinformatic analysis suggested that low-intensity pulsed ultrasound might trigger the activation of the PI3K/Akt pathway. Western blot assay confirmed that low-intensity pulsed ultrasound activated Schwann cells through TrkB/Akt/CREB signaling. Low-intensity pulsed ultrasound promoted nerve regeneration and ameliorated erectile function by enhancing Schwann cells proliferation, migration, and neurotrophic factor nerve growth factor expression. The TrkB/Akt/CREB axis is the possible mechanism of low-intensity pulsed ultrasound-mediated Schwann cell activation. Low-intensity pulsed ultrasound-based therapy could be a novel potential treatment strategy for cavernous nerve injury-induced neurogenic erectile dysfunction.

Molecular pathogenesis and treatment of cavernous nerve injury-induced erectile dysfunction: A narrative review.

Introduction: Erectile dysfunction (ED) is a common complication after radical prostatectomy (RP), and it seriously affects the quality of life in patients and their partners. The primary trigger of postoperative ED is surgical injury to the cavernous nerves that control penile erection and run along the anterolateral aspect of the prostate. Despite the introduction and ongoing innovation of nerve-sparing techniques, a significant number of patients still suffer from moderate cavernous nerve injury (CNI), which is thought to be transient and reversible. Therefore, early postoperative penile rehabilitation therapy may salvage patients’ erectile function by promoting cavernous nerve regeneration and preventing penile structural alterations. Aims: To present a comprehensive overview of the current molecular pathogenesis of CNI-induced ED, as well as novel therapeutic strategies and their potential mechanisms. Methods: A literature search was performed using PubMed. Search terms included erectile dysfunction, cavernous nerve injury, pathogenesis, pathway, and treatment. Results: The NOS/NO pathway, oxidative stress-related pathway, RhoA/ROCK pathway, transforming growth factor-β (TGF-β), sonic hedgehog (Shh), and hydrogen sulfide (H2S) are involved in the molecular pathogenesis of CNI-induced ED. Multiple neurotrophins, including brain-derived nerve growth factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and neurturin (NTN), were found to promote cavernous nerve regeneration. Emerging therapeutic approaches can be roughly summarized into four categories, namely small molecule and drug, stem cell-based therapy (SCT), micro-energy therapy and platelet-rich plasma (PRP) therapy. Conclusion: These pathways collectively lead to the irreversible damage to the penile structure after CNI. The combined early rehabilitation strategies of promoting upstream nerve regeneration and recovering abnormal molecular signals of downstream penis are presumed to save patients’ erectile function after RP. In future studies, the cross-talk between these molecular pathways needs to be further clarified, and the questions of how denervation injury induces the molecular alterations in the penis also need to be addressed.

Comparative study of different transplantation methods of adipose tissue-derived stem cells in the treatment of erectile dysfunction caused by cavernous nerve injury.

We aimed to compare intracavernosal injection (ICI), tail vein injection (IV), and periprostatic injection (PPI) of adipose-derived stem cells (ADSCs) for their ability to improve erectile function in cavernous nerve injury-induced erectile dysfunction (CNIED) rats and to explore the possible mechanism. Eighty-four male SD rats were divided into the sham group (n=6), BCNI group (bilateral CN crush injury, n=6), PBS-ICI group (n=6), PBS-IV group (n=6), PBS-PPI group (n=6), ADSC-ICI group (n=18), ADSC-IV group (n=18) and ADSC-PPI group (n=18). ADSCs were labelled with 5-ethynyl-2'-deoxyuridine (EdU), and six rats each in the ADSC-ICI group, ADSC-IV group, and ADSC-PPI group were sacrificed 2, 7, and 28days after injection. EdU-labelled ADSCs were tracked by immunofluorescence staining. The intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio, neuronal nitric oxide synthase (nNOS)-positive nerve fibres in the dorsal penile nerve and the smooth muscle/collagen ratio in the cavernosum between groups were also evaluated. ADSCs can significantly improve erectile function through ICI or IV. The two are similar in efficacy and superior to PPI. The mechanism may be that after CN injury, ADSCs are recruited to around the MPG and secrete a variety of neurotrophic factors that promote the repair of the CN, thereby improving erectile function.

Adipose Tissue-Derived Stem Cell Therapy for Cavernous Nerve Injury-Induced Erectile Dysfunction in the Rat Model: A Systematic Review and Meta-Analysis Using Methodological Quality Assessment.

Background and ObjectivesFew studies were evaluated the effect of blindness on outcome in animal models, though a potential effect of blinding has been reported in clinical trials. We evaluated the effects of adipose tissue-derived stem cells (ADSCs) on cavernous nerve injury (CNI)-induced erectile dysfunction (ED) in the rat and examined how proper blinding of the outcome assessor affected treatment effect.Methods and ResultsWe searched in Pubmed, EMBASE, Cochrane and Web of Science databases from inception to January 2019. We included CNI animal model, randomized controlled experiments, and ADSC intervention. Erectile function and structural changes were assessed by intracavernous pressure and mean arterial pressure (ICP/MAP) ratios, neuronal nitric oxide synthase (nNOS) levels, cavernous smooth muscle and collagen (CSM/collagen) ratios, and cyclic guanosine monophosphate (cGMP).ResultsNineteen studies were included in the final meta-analysis. The ICP/MAP ratio of the ADSC treatment group increased compared to the control group (SMD=1.33, 95%CI: 1.11~1.56, I2=72%). The nNOS level (SMD=2.29, 95%CI: 1.74~2.84, I2=75%), CSM/collagen (SMD=2.57, 95%CI: 1.62~3.52; I2=85%), and cGMP (SMD=2.96, 95%CI: 1.82~4.10, I2=62%) were also increased in the ADSC treatment group. Preplanned subgroup analysis was conducted to explore the source of heterogeneity. Five studies with blinded outcome assessment were significantly less effective than the unblinded studies (SMD=1.33, 95%CI: 0.86~1.80; SMD=1.81, 95%CI: 1.17~2.46, respectively).ConclusionsADSCs might be effective in improving erectile function and structural change in CNI-induced ED. However, non-blinded outcome assessors might cause detection bias and overestimate treatment efficacy. Therefore, the ADSC efficacy must be further evaluated with a rigorous study design to avoid bias.

188 Evaluation of the Antioxidant and Antifibrotic Effects of Ziziphus Fruit on Cavernosal Tissues of Rats in Bilateral Cavernous Nerve Injury-induced Erectile Dysfunction Model

188 Evaluation of the Antioxidant and Antifibrotic Effects of Ziziphus Fruit on Cavernosal Tissues of Rats in Bilateral Cavernous Nerve Injury-induced Erectile Dysfunction Model

The effects of single versus combined therapy using LIM-kinase 2 inhibitor and type 5 phosphodiesterase inhibitor on erectile function in a rat model of cavernous nerve injury-induced erectile dysfunction.

We aimed to determine whether combination of LIM-kinase 2 inhibitor (LIMK2i) and phosphodiesterase type-5 inhibitor (PDE5i) could restore erectile function through suppressing cavernous fibrosis and improving cavernous apoptosis in a rat model of cavernous nerve crush injury (CNCI). Seventy 12-week-old Sprague–Dawley rats were equally distributed into five groups as follows: (1) sham surgery (Group S), (2) CNCI (Group I), (3) CNCI treated with daily intraperitoneal administration of 10.0 mg kg−1 LIMK2i (Group I + L), (4) daily oral administration of 20.0 mg kg−1 udenafil, PDE5i (Group I + U), and (5) combined administration of 10.0 mg kg−1 LIMK2i and 20.0 mg kg−1 udenafil (Group I + L + U). Rats in Groups I + L, I + U, and I + L + U were treated with respective regimens for 2 weeks after CNCI. At 2 weeks after surgery, erectile response was assessed using electrostimulation. Penile tissues were processed for histological studies and western blot. Group I showed lower intracavernous pressure (ICP)/mean arterial pressure (MAP), lower area under the curve (AUC)/MAP, decreased immunohistochemical staining for alpha-smooth muscle (SM) actin, higher apoptotic index, lower SM/collagen ratio, increased phospho-LIMK2-positive fibroblasts, decreased protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) phosphorylation, increased LIMK2/cofilin phosphorylation, and increased protein expression of fibronectin, compared to Group S. In all three treatment groups, erectile responses, protein expression of fibronectin, and SM/collagen ratio were improved. Group I + L + U showed greater improvement in erectile response than Group I + L. SM content and apoptotic index in Groups I + U and I + L + U were improved compared to those in Group I. However, Group I + L did not show a significant improvement in SM content or apoptotic index. The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I + L and I + L + U, but not in Group I + U. Akt/eNOS phosphorylation was improved in Groups I + U and I + L + U, but not in Group I + L. LIMK2/cofilin phosphorylation was improved in Groups I + L and I + L + U, but not in Group I + U. Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis. Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.

Effect of platelet-derived growth factor-BB on gap junction and connexin43 in rat penile corpus cavernosum smooth muscle cells.

We explored whether platelet-derived growth factor (PDGF)-BB regulates corpus cavernosum smooth muscle cell gap junctions and can ameliorate erectile dysfunction and how it modulates connexin43 (CX43) after bilateral cavernous neurectomy. Primary cultured rat corpus cavernosum smooth muscle cells were treated with PDGF-BB with or without a PDGFR inhibitor, Akt siRNA or the depletion or promotion of β-catenin. PDGF-BB improved CCSMCs gap junction coupling and increased CX43 and PDGFRβ expression; inhibition of PDGFR activity down-regulated CX43 and decreased Akt and nuclear β-catenin. Knockdown or promotion of β-catenin down-regulated and up-regulated CX43 expression respectively. Moreover, β-catenin activation induced CX43 nuclear accumulation, which impeded CX43 down-regulation induced by PDGFR inhibition, suggesting that CX43 expression is positively correlated with nuclear β-catenin expression. Furthermore, CX43 promoter luciferase and chromatin immunoprecipitation assays indicated that β-catenin regulates CX43 transcription by directly interacting with its promoter. Male rats underwent bilateral cavernous neurectomy. After 12weeks, they were injected with PDGF-BB, CX43 and PDGFRβ expression was significantly lower than in the control group, which was reversed by PDGF-BB injection. These results suggested that PDGF-BB contributed to the improvement of gap junction intracellular communication among corpus cavernosum smooth muscle cells, increased CX43 through PDGFRβ/Akt/nuclear β-catenin signalling, and ameliorated cavernous nerve injury-induced erectile dysfunction.

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

cGMP-independent nitric oxide (NO) signaling occurs via S-nitrosylation. We evaluated whether aberrant S-nitrosylation operates in the penis under conditions of cavernous nerve injury and targets proteins involved in regulating erectile function. Adult male Sprague-Dawley rats underwent bilateral cavernous nerve crush injury (BCNI) or sham surgery. Rats were given a denitrosylation agent N-acetylcysteine (NAC, 300 mg/kg/day) or vehicle in drinking water starting 2 days before BCNI and continuing for 2 weeks following surgery. After assessment of erectile function (intracavernous pressure), penes were collected for measurements of S-nitrosylation by Saville-Griess and TMT-switch assays and PKG-I function by immunoblotting of phospho (P)-VASP-Ser-239. Erectile function was decreased (P<0.05) after BCNI, and it was preserved (P<0.05) by NAC treatment. Total S-nitrosothiols and total S-nitrosylated proteins were increased (P<0.05) after BCNI, and these were partially prevented by NAC treatment. S-nitrosylation of sGC was increased (P<0.05) after BCNI, and it was prevented (P<0.05) by NAC treatment. S-nitrosylation of eNOS was increased (P<0.05) after BCNI, and showed a trend towards decrease by NAC treatment. Protein expression of P-VASP-Ser-239 was decreased (P<0.05) after BCNI, and showed a trend towards increase by NAC treatment. In conclusion, erectile dysfunction following BCNI is mediated in part by S-nitrosylation of eNOS and its downstream signaling mediator GC, while denitrosylation protects erectile function by preserving the NO/cGMP signaling pathway.

Evaluation of the antioxidant and antifibrotic effects of Ziziphus fruit on cavernosal tissues of rats in bilateral cavernous nerve injury-induced erectile dysfunction model

Evaluation of the antioxidant and antifibrotic effects of Ziziphus fruit on cavernosal tissues of rats in bilateral cavernous nerve injury-induced erectile dysfunction model

Application of hNGFβ-Modified Adipose-Derived Stem Cells in Treating Cavernous Nerve Injury-Induced Erectile Dysfunction in Rat Models

Application of hNGF<i>β</i>-Modified Adipose-Derived Stem Cells in Treating Cavernous Nerve Injury-Induced Erectile Dysfunction in Rat Models

MP41-14 HUMAN URINE-DERIVED STEM CELLS GENETICALLY-MODIFIED WITH PEDF IMPROVE CAVERNOUS NERVE INJURY-INDUCED ERECTILE DYSFUNCTION IN A RAT MODEL

You have accessJournal of UrologyStem Cell Research1 Apr 2017MP41-14 HUMAN URINE-DERIVED STEM CELLS GENETICALLY-MODIFIED WITH PEDF IMPROVE CAVERNOUS NERVE INJURY-INDUCED ERECTILE DYSFUNCTION IN A RAT MODEL Qiyun Yang, Xin Chen, Tao Zheng, Kai Xia, Xiangzou Sun, Guihua Liu, Yuanyuan Zhang, and Chunhua Deng Qiyun YangQiyun Yang More articles by this author , Xin ChenXin Chen More articles by this author , Tao ZhengTao Zheng More articles by this author , Kai XiaKai Xia More articles by this author , Xiangzou SunXiangzou Sun More articles by this author , Guihua LiuGuihua Liu More articles by this author , Yuanyuan ZhangYuanyuan Zhang More articles by this author , and Chunhua DengChunhua Deng More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1282AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The aim of this study was to investigate whether intracavernous injection of urine-derived stem cells (USCs) or USCs overexpressing pigment epithelium-derived factor (PEDF) could protect the erectile function and cavernous structure in a bilateral cavernous nerve injury-induced erectile dysfunction (CNIED) rat model. METHODS USCs were cultured from the urine of eight healthy male donors. Seventy-five rats were randomly divided into five groups (n = 15 per group): sham, bilateral cavernous nerve (CN) crush injury (BCNI), USC, GFP-USC , and PEDF-USC groups. The sham group received only laparotomy without CN crush injury and intracavernous injection with phosphate-buffered saline (PBS). All of the other groups were subjected to BCNI and intracav- ernous injection with PBS, USCs, GFP-USCs, or GFP/PEDF-USCs, respectively. The total intracavernous pressure (ICP) and the ratio of ICP to mean arterial pressure (ICP/MAP) were recorded. The penile dorsal nerves, the endothelium, and the smooth muscle were assessed within the penile tissue. RESULTS The penile dorsal nerves, the endothelium, and the smooth muscle were assessed within the penile tissue. The USC and PEDF-USC groups displayed more significantly enhanced ICP and ICP/MAP ratio (p < 0.05) 28 days after cell transplantation. Immunohistochemistry (IHC) and Western blot analysis demonstrated that the protection of erectile function and the cavernous structure by PEDF-USC was associated with an increased number of nNOS-positive fibers within the penile dorsal nerves, improved expression of endothelial markers (CD31 and eNOS) and smoothelin, an enhanced smooth muscle to collagen ratio, decreased expression of TGF-b1, and decreased cell apoptosis in the cavernous tissue. CONCLUSIONS The paracrine effect of USCs and PEDF-USCs prevented the destruction of erectile function and the cavernous structure in the CNIED rat model by nerve protection, thereby improving endothelial cell function, increasing the smooth muscle content, and decreasing fibrosis and cell apoptosis in the cavernous tissue. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e541 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Qiyun Yang More articles by this author Xin Chen More articles by this author Tao Zheng More articles by this author Kai Xia More articles by this author Xiangzou Sun More articles by this author Guihua Liu More articles by this author Yuanyuan Zhang More articles by this author Chunhua Deng More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

072 S-nitrosylation of NOS Pathway Mediators in the Penis Contributes to Cavernous Nerve Injury-induced Erectile Dysfunction

072 S-nitrosylation of NOS Pathway Mediators in the Penis Contributes to Cavernous Nerve Injury-induced Erectile Dysfunction

Transplantation of Human Urine-Derived Stem Cells Transfected with Pigment Epithelium-Derived Factor to Protect Erectile Function in a Rat Model of Cavernous Nerve Injury

The aim of this study was to investigate whether intracavernous injection of urine-derived stem cells (USCs) or USCs genetically modified with pigment epithelium-derived factor (PEDF) could protect the erectile function and cavernous structure in a bilateral cavernous nerve injury-induced erectile dysfunction (CNIED) rat model. USCs were cultured from the urine of six healthy male donors. Seventy-five rats were randomly divided into five groups ( n = 15 per group): sham, bilateral cavernous nerve (CN) crush injury (BCNI), USC, USCGFP+, and USCGFP/PEDF+ groups. The sham group received only laparotomy without CN crush injury and intracavernous injection with phosphate-buffered saline (PBS). All of the other groups were subjected to BCNI and intracavernous injection with PBS, USCs, USCsGFP+, or USCsGFP/PEDF+, respectively. The total intracavernous pressure (ICP) and the ratio of ICP to mean arterial pressure (ICP/MAP) were recorded. The penile dorsal nerves, the endothelium, and the smooth muscle were assessed within the penile tissue. The USC and USCGFP/PEDF+ groups displayed more significantly enhanced ICP and ICP/MAP ratio ( p < 0.05) 28 days after cell transplantation. Immunohistochemistry (IHC) and Western blot analysis demonstrated that the protection of erectile function and the cavernous structure by USCsGFP/PEDF+ was associated with an increased number of nNOS-positive fibers within the penile dorsal nerves, improved expression of endothelial markers (CD31 and eNOS) and a smooth muscle marker (smoothelin), an enhanced smooth muscle to collagen ratio, decreased expression of transforming growth factor-β1 (TGF-β1), and decreased cell apoptosis in the cavernous tissue. The paracrine effect of USCs and USCsGFP/PEDF+ prevented the destruction of erectile function and the cavernous structure in the CNIED rat model by nerve protection, thereby improving endothelial cell function, increasing the smooth muscle content, and decreasing fibrosis and cell apoptosis in the cavernous tissue.

Advances in stem cell research for the treatment of male sexual dysfunctions.

To summarize recent literature on basic stem cell research in erectile dysfunction in cavernous nerve injury, aging, diabetes, and Peyronie's disease and to provide a perspective on clinical translation of these cellular therapies. Stem cell research has been concentrated on mesenchymal stem (stromal) cells from bone marrow and adipose tissue. Application of both cell types has produced positive effects on erectile function in various animal models of erectile dysfunction. In acute animal models, such as cavernous nerve injury-induced erectile dysfunction and chemically induced Peyronie's disease, engraftment and differentiation have not been observed, and stem cells are believed to interact with the host tissue in a paracrine fashion, whereas in chronic disease models some evidence suggests both engraftment and paracrine factors may support improved function. Clinical trials are now investigating therapeutic efficacy of cellular therapy, whereas the first safety studies in humans have recently been published. Evidence from preclinical studies has established stem cells as a potential curative treatment for erectile dysfunction and early phase clinical trials are currently performed.

Neurotrophic Effect of Adipose Tissue-Derived Stem Cells on Erectile Function Recovery by Pigment Epithelium-Derived Factor Secretion in a Rat Model of Cavernous Nerve Injury.

The paracrine effect is the major mechanism of stem cell therapy. However, the details of the effect's mechanism remain unknown. The aim of this study is to investigate whether adipose tissue-derived stem cells (ADSCs) can ameliorate cavernous nerve injury-induced erectile dysfunction (CNIED) rats and to determine its mechanism. Twenty-eight days after intracavernous injection of 5-ethynyl-2-deoxyuridine- (EdU-) labeled ADSCs, the erectile function of all the rats was evaluated by intracavernosal pressure (ICP). The ADSCs steadily secreted detectable pigment epithelium-derived factor (PEDF) in vitro. The expression of PEDF increased in the penis of the bilateral cavernous nerve injury (BCNI) group for 14 days and then gradually decreased. On day 28 after the intracavernous injection, the ADSCs group exhibited a significantly increased ICP compared with the phosphate buffered saline- (PBS-) treated group. Moreover, the neuronal nitric oxide synthase (nNOS) and S100 expression in penile dorsal nerves and the smooth muscle content to collagen ratio in penile tissues significantly increased. Furthermore, elevated PEDF, p-Akt, and p-eNOS were identified in the ADSCs group. This study demonstrated that intracavernous injection of ADSCs improved erectile function, repaired the nerve, and corrected penile fibrosis. One potential mechanism is the PEDF secretion of ADSCs and subsequent PI3K/Akt pathway activation.

GGF2 is neuroprotective in a rat model of cavernous nerve injury-induced erectile dysfunction.

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. The effectiveness of GGF2 in preserving axonal integrity and recovering erectile function in a rat model of radical prostatectomy-associated CN injury. 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 24 hour pre and 24-hour 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. Erectile function recovery, CN survival, and unmyelinated CN axon preservation in response to GGF2 treatment following BCNI. 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 (5 mg/kg) group, the unmyelinated fiber histogram demonstrated a rightward shift, indicating an increased number of unmyelinated axons per Schwann cell compared with the BCNI group. 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.

Nerve Injury-Induced Protein 1 (Ninjurin-1) Is a Novel Therapeutic Target for Cavernous Nerve Injury-Induced Erectile Dysfunction in Mice

IntroductionRadical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI) but also result in structural changes in the cavernous tissues. Nerve injuryinduced protein 1, Ninjurin1 (Ninj1), is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period. AimThe study aims to determine whether and how Ninj1 neutralizing antibody (Ninj1Ab) restores erectile function in mice with CNI. MethodsTwelveweekold C57BL/6J mice were used and distributed into four groups: sham operation group and CNI groups receiving a single intracavernous injection of immunoglobulin G (IgG) control antibody, lowdose Ninj1Ab (1.0 μg/20 μL), or highdose Ninj1Ab (2.5 μg/20 μL). Main Outcome MeasuresOne week after bilateral cavernous nerve crush, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was harvested for histologic examinations and Western blot analysis. ResultsThe cavernous expression of Ninj1 protein was upregulated up to 7 days after CNI and returned to baseline levels thereafter. Local delivery of Ninj1Ab significantly increased penile neuronal nitric oxide synthase and neurofilament contents, induced cavernous endothelial proliferation and phosphorylation of Akt and endothelial nitric oxide synthase, and decreased endothelial cell apoptosis in the CNI mice by upregulating angiopoietin1 and downregulating angiopoietin2. Highdose Ninj1Ab induced profound restoration of erectile function in the CNI mice (91% of sham control values), whereas lowdose Ninj1Ab elicited partial improvement. ConclusionThe dual neurotrophic and angiogenic effects of Ninj1 blockade may provide a good opportunity for treating erectile dysfunction resulting from radical prostatectomy.

480 Nerve injury-induced protein 1 (Ninjurin 1) is a novel therapeutic target for cavernous nerve injury-induced erectile dysfunction

480 Nerve injury-induced protein 1 (Ninjurin 1) is a novel therapeutic target for cavernous nerve injury-induced erectile dysfunction

A Mouse Model of Cavernous Nerve Injury-Induced Erectile Dysfunction: Functional and Morphological Characterization of the Corpus Cavernosum

With the advent of genetically engineered mice, it seems important to develop a mouse model of cavernous nerve injury (CNI). To establish a mouse model of CNI induced either by nerve crushing or by neurectomy and to evaluate time-dependent derangements in penile hemodynamics in vivo and subsequent histologic alterations in the cavernous tissue. Twelve-week-old C57BL/6J mice were divided into 4 groups (N=36 per group): control, sham operation, bilateral cavernous nerve crush, and bilateral cavernous neurectomy group. Three days and 1, 2, 4, 8, and 12 weeks after CNI, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was then harvested and TUNEL was performed. Immunohistochemical analysis was performed assaying for caspase-3, transforming growth factor-β1 (TGF-β1), phospho-Smad2, PECAM-1, factor VIII, and smooth muscle α-actin. The numbers of apoptotic cells and phospho-Smad2-immunopositive cells in endothelial cells or smooth muscle cells were counted. Erectile function was significantly less in the cavernous nerve crushing and neurectomy groups than in the control or sham group. This difference was observed at the earliest time point assayed (day 3) and persisted up to 4 weeks after nerve crushing and to 12 weeks after neurectomy. The apoptotic index peaked at 1 or 2 weeks after CNI and decreased thereafter. Cavernous TGF-β1 and phospho-Smad expression was also increased after CNI. The numbers of apoptotic cells and phospho-Smad2-immunopositive cells in cavernous endothelial cells and smooth muscle cells were significantly greater in the cavernous nerve crush and cavernous neurectomy groups than in the control or sham group. Conclusion. The mouse is a useful model for studying pathophysiologic mechanisms involved in erectile dysfunction after CNI. Early intervention to prevent apoptosis in smooth muscle cells and endothelial cells or to inhibit cavernous tissue fibrosis is required to restore erectile function.