背景:由骨盆手术或外伤引起的海绵状神经(CN)损伤引起的勃起功能障碍(ED)是常规药物治疗的难治性疾病,需要替代治疗。低强度脉冲超声(LIPUS)是一种促进神经再生的无创机械疗法。
目的:探讨LIPUS治疗神经源性勃起功能障碍的疗效及可能机制。
方法:30只大鼠随机分为假手术组,双侧CN损伤(BCNI)组和BCNI+LIPUS组。在每日LIPUS治疗后3周评估勃起功能。收集阴茎组织和CN组织并进行组织学分析。从成年大鼠中提取原代雪旺氏细胞(SC)和外植体。LIPUS对增殖的影响,在体外检查了SC的迁移和NGF表达以及轴突伸长。应用RNA测序和westernblot技术预测和验证LIPUS诱导SCs活化的分子机制。
结果:我们的研究表明LIPUS促进SCs增殖,迁移和神经营养因子NGF表达。同时,LIPUS表现出更强的体外增强主要骨盆神经节(MPG)神经元和MPG/CN外植体的SCs介导的神经突生长的能力。体内实验表明,BCNILIPUS组大鼠的勃起功能明显高于BCNI组。此外,BCNI+LIPUS组平滑肌和海绵体内皮的表达水平也显著升高。此外,我们观察到BCNI+LIPUS组海绵状神经再生轴突的密度和数量较高,表明LIPUS在体内海绵状神经损伤后促进轴突再生。RNA测序分析和生物信息学分析提示LIPUS可能触发PI3K/Akt通路的激活。Western印迹测定证实LIPUS通过TrkB/Akt/CREB信号传导激活SC。
结论:LIPUS通过促进SCs增殖促进神经再生,改善勃起功能,迁移和神经营养因子NGF表达。TrkB/Akt/CREB轴是LIPUS介导的SC活化的可能机制。基于LIPUS的治疗可能是海绵状神经损伤引起的神经源性ED的一种新的潜在治疗策略。本文受版权保护。保留所有权利。
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 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.
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.