Intracavernous Pressure Recording in a Cavernous Nerve Injury Rat Model

et al. 2023

CNS Neurosci Ther

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ObjectiveClinical treatment of erectile dysfunction (ED) caused by cavernous nerve (CN) injury during pelvic surgery is difficult. Low‐intensity pulsed ultrasound (LIPUS) can be a potential strategy for neurogenic ED (NED). However, whether Schwann cells (SCs) can respond to LIPUS stimulation signals is unclear. This study aims to elucidate the signal transmission between SCs paracrine exosome (Exo) and neurons stimulated by LIPUS, as well as to analyze the role and potential mechanisms of exosomes in CN repair after injury.MethodsThe major pelvic ganglion (MPG) neurons and MPG/CN explants were stimulated with LIPUS of different energy intensities to explore the appropriate LIPUS energy intensity. The exosomes were isolated and purified from LIPUS‐stimulated SCs (LIPUS‐SCs‐Exo) and non‐stimulated SCs (SCs‐Exo). The effects of LIPUS‐SCs‐Exo on neurite outgrowth, erectile function, and cavernous penis histology were identified in bilateral cavernous nerve crush injury (BCNI)‐induced ED rats.ResultsLIPUS‐SCs‐Exo group can enhance the axon elongation of MPG/CN and MPG neurons compared to SCs‐Exo group in vitro. Then, the LIPUS‐SCs‐Exo group showed a stronger ability to promote the injured CN regeneration and SCs proliferation compared to the SCs‐Exo group in vivo. Furthermore, the LIPUS‐SCs‐Exo group increased the Max intracavernous pressure (ICP)/mean arterial pressure (MAP), lumen to parenchyma and smooth muscle to collagen ratios compared to the SCs‐Exo group in vivo. Additionally, high‐throughput sequencing combined with bioinformatics analysis revealed the differential expression of 1689 miRNAs between the SCs‐Exo group and the LIPUS‐SCs‐Exo group. After LIPUS‐SCs‐Exo treatment, the phosphorylated levels of Phosphatidylinositol 3‐kinase (PI3K), protein kinase B (Akt) and forkhead box O (FoxO) in MPG neurons increased significantly compared to negative control (NC) and SCs‐Exo groups.ConclusionOur study revealed that LIPUS stimulation could regulate the gene of MPG neurons by changing miRNAs derived from SCs‐Exo, then activating the PI3K‐Akt‐FoxO signal pathway to enhance nerve regeneration and restore erectile function. This study had important theoretical and practical significance for improving the NED treatment.

Section: Methodsmentioning

confidence: 99%

“…Cavernosal hemodynamic changes were evaluated as previously described 28 . The rats were exposed to MPG and CN through a median abdominal incision after anesthesia.…”

Section: Methodsmentioning

confidence: 99%

LIPUS‐SCs‐Exo promotes peripheral nerve regeneration in cavernous nerve crush injury‐induced ED rats via PI3K/Akt/FoxO signaling pathway

et al. 2023

CNS Neurosci Ther

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“…Thirty adult male Sprague‐Dawley rats (12 weeks old) weighing between 300–350 g were randomly divided into three groups ( n = 10 per group): sham‐operation group (NC) group, bilateral CN injury (BCNI) group and BCNI with LIPUS treatment (LIPUS) group. The rats of the BCNI group and LIPUS group were subjected to BCNI as previously described 23 . Briefly, rats were anesthetized by sodium pentobarbital (60 mg/kg; Sigma, USA) intraperitoneal injection.…”

Section: Methodsmentioning

confidence: 99%

“…The rats of the BCNI group and LIPUS group were subjected to BCNI as previously described. 23 Briefly, rats were anesthetized by sodium pentobarbital (60 mg/kg; Sigma, USA) intraperitoneal injection. After confirming a proper anesthetization, a 4 cm incision was made at the lower, midline abdominal to fully expose the bilateral CN.…”

Section: Animal Model Of Bilateral Cn Crush Injurymentioning

confidence: 99%

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

et al. 2023

Andrology

Background 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. Objectives To investigate the therapeutic effect and potential mechanism of low‐intensity pulsed ultrasound in the treatment of neurogenic erectile dysfunction. Materials and methods 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 3 weeks 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. Results 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. Conclusions 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 caverno...

“…Intracavernous pressure (ICP) was measured by electrical stimulation, as previously reported ( 17 , 18 ). All rats were anesthetized by injection with pentobarbital (40 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

Cisplatin causes erectile dysfunction by decreasing endothelial and smooth muscle content and inducing cavernosal nerve senescence in rats

Zhou

et al. 2023

Front. Endocrinol.

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IntroductionCisplatin (cis‐diamminedichloroplatinum II, CDDP), a drug widely used for cancer worldwide, may affect erectile function, but its side effects have not received enough attention. To investigate the effect of CDDP on erectile function and its possible mechanism.MethodsSprague−Dawley rats were intraperitoneally administered CDDP (CDDP group) or the same volume of normal saline (control group). Erectile function was evaluated after a one-week washout. Then, histologic changes in the corpus cavernosum and cavernous nerve (CN) were measured. Other Sprague-Dawley rats were used to isolate the major pelvic ganglion and cavernous nerve (MPG/CN). RSC96 cells were then treated with CDDP. SA-β-gal staining was used to identify senescent cells, and qPCR was used to detect the senescence-associated secretory phenotype (SASP). Finally, the supernatant of RSC96 cells was used to culture MPG/CN. Erectile function was measured after administration of CDDP. The cavernosum levels of α-SMA, CD31, eNOS, and γ-H2AX, the apoptosis rate and the expression of p16, p21 and p53 in CN were also assayed. The senescent phenotype of RSC96 cells treated with CDDP was identified, and neurite growth from the MPG/CN was photographed and measured.ResultsThe CDDP group had a significantly lower ICP/MAP ratio than the control group. Compared to the control group, the CDDP group exhibited significantly lower α-SMA, CD31 and eNOS levels and significantly higher γ-H2AX and apoptosis rates in corpus cavernosum. In addition, CDDP increased some senescence markers p16, p21 and p53 in CN. In vitro, CDDP induced RSC96 senescence and SASP, and the supernatant of senescent cells slowed neurite outgrowth of MPG/CN.DiscussionsCDDP treatment could induce erectile dysfunction, by affecting the content of endothelial and smooth muscle and causing SASP in CN. The results indicate that CDDP treatment should be considered as a risk factor for ED. Clinicians should pay more attention to the erectile function of cancer patients who receive CDDP treatment.