目的:骶神经调节(SNM)已被证明可以减轻膀胱过度活动症和非梗阻性尿潴留患者的膀胱功能障碍。然而,SNM在神经源性膀胱功能障碍中的治疗作用和机制尚不完全清楚。使用大鼠脊髓损伤(SCI)模型,本研究旨在探讨膀胱反射期早期SNM对神经源性膀胱功能障碍的治疗作用及其可能机制。
方法:基本生理参数,如身体/膀胱重量,血压,并测量心电图结果以评价SNM的安全性。酶联免疫吸附试验和实时定量聚合酶链反应检测促炎因子的表达。苏木素、伊红和马森三色染色观察形态学变化,和膀胱测压用于评估SNM治疗后的尿动力学变化。采用蛋白质印迹和免疫荧光染色检测L6-S1背根神经节(DRGs)和膀胱瞬时受体电位香草酸1(TRPV1)和降钙素基因相关肽(CGRP)水平。辣椒素脱敏用于研究抑制TRPV1是否可以预防SCI大鼠逼尿肌过度活动。
结果:早期SNM不影响身体/膀胱重量,心率,血压,或促炎细胞因子的表达(PGE2,IL-1,IL-2,IL-6,TGF-β,或TNF-α)在SCI大鼠的膀胱中。形态学上,早期SNM可以预防尿路上皮水肿(p=0.0248),但不影响膀胱中的胶原蛋白/平滑肌。与未经治疗的SCI大鼠相比,SNM治疗的大鼠表现出增加的膀胱容量(p=0.0132)和排尿效率(p=0.0179),无排尿收缩(NVC)频率降低(p=0.0240)。最大压力,基础压力,后空隙残留,NVC振幅无明显变化。SNM治疗后,SCI大鼠膀胱中TRPV1和L6-S1DRGs中CGRP的表达降低(L6,p=0.0160;S1,p=0.0024)。在辣椒素脱敏的SCI大鼠中,尿动力学结果显示膀胱容量(p=0.0116)和排尿效率(p=0.0048)增加,和减少的NVC频率(p=0.0116),而其他参数没有明显变化。
结论:早期SNM可在形态学上预防SCI大鼠尿路上皮水肿和逼尿肌过度活动。抑制膀胱和DRGs中的TRPV1可能是SNM预防逼尿肌过度活动的潜在机制之一。
OBJECTIVE: Sacral neuromodulation (SNM) has been shown to alleviate bladder dysfunction in patients with overactive bladder and nonobstructive urinary retention. However, the therapeutic effect and mechanism of SNM in neurogenic bladder dysfunction are still not fully understood. Using a rat model of spinal cord injury (SCI), this study aims to investigate the therapeutic effect of early SNM in the bladder-areflexia phase on neurogenic bladder dysfunction and evaluate its possible mechanism.
METHODS: Basic physiological parameters such as body/bladder weight, blood pressure, and electrocardiogram results were measured to evaluate the safety of SNM. Enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reaction were used to examine the expression of proinflammatory factors. Hematoxylin and eosin and Masson\'s trichrome staining were used to observe morphological changes, and cystometry was used to evaluate urodynamic changes after SNM treatment. Western blotting and immunofluorescence staining were used to measure the levels of transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in the L6-S1 dorsal root ganglia (DRGs) and bladder. Capsaicin desensitization was used to investigate whether inhibiting TRPV1 could prevent detrusor overactivity in SCI rats.
RESULTS: Early SNM did not affect the body/bladder weight, heart rate, blood pressure, or the expression of proinflammatory cytokines (PGE2, IL-1, IL-2, IL-6, TGF-β, or TNF-α) in the bladders of SCI rats. Morphologically, early SNM prevented urothelial edema (p = 0.0248) but did not influence collagen/smooth muscle in the bladder. Compared with untreated rats with SCI, the rats treated with SNM exhibited increased bladder capacity (p = 0.0132) and voiding efficiency (p = 0.0179), and decreased nonvoiding contraction (NVC) frequency (p = 0.0240). The maximum pressure, basal pressure, postvoid residual, and NVC amplitude did not change significantly. After the SNM treatment, the expression of TRPV1 in the bladder and CGRP in L6-S1 DRGs weredecreased (L6, p = 0.0160; S1, p = 0.0024) in SCI rats. In capsaicin-desensitized SCI rats, urodynamic results showed an increase in bladder capacity (p = 0.0116) and voiding efficiency (p = 0.0048), and diminished NVC frequency (p = 0.0116), while other parameters did not change significantly.
CONCLUSIONS: Early SNM prevented urothelial edema morphologically and detrusor overactivity in SCI rats. Inhibition of TRPV1 in the bladder and DRGs may be one of the potential mechanisms for preventing detrusor overactivity by SNM.