Shunmugavel Anandakumar, Khan Mushfiquddin, Hughes Francis M, Purves J Todd, Singh Avtar, Singh Inderjit
Department of Pediatrics, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina.
Department of Urology, Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina.
Neurourol Urodyn. 2015 Aug;34(6):519-26. doi: 10.1002/nau.22619. Epub 2014 May 22.
AIMS: Bladder and renal dysfunction are secondary events of the inflammatory processes induced by spinal cord injury (SCI). S-Nitrosoglutathione (GSNO), an endogenous nitrosylating agent is pleiotropic and has anti-inflammatory property. Hence, GSNO ameliorates inflammatory sequelae observed in bladder and renal tissues after SCI. Thus, we postulate that GSNO will improve the recovery of micturition dysfunction by quenching the bladder tissue inflammation associated with SCI. METHODS: Contusion-based mild SCI was induced in female Sprague-Dawley rats. Sham operated rats served as the controls. SCI rats were gavaged daily with GSNO (50 µg/kg) or vehicle. Bladder function was assessed by urodynamics at 2 and 14 days following SCI. Urine protein concentration and osmolality were measured. Bladder and kidney tissues were analyzed by histology and immunofluorescence for a variety of endpoints related to inflammation. RESULTS: Two days after SCI, urodynamics demonstrated a hyperreflexive bladder with overflow and no clear micturition events. By Day 14, vehicle animals regained a semblance of a voiding cycle but with no definite intercontraction intervals. GSNO-treated SCI-rats showed nearly normal cystometrograms. Vehicle-treated SCI rats had increased bladder wet weight, proteinuria, and urine osmolality at Day 14, which was reversed by GSNO treatment. In addition, the SCI-induced increase in immune cell infiltration, collagen deposition, iNOS, and ICAM-1 expression and apoptosis were attenuated by GSNO. CONCLUSIONS: These results indicate that oral administration of GSNO hastens the recovery of bladder function after mild contusion-induced SCI through dampening the inflammation sequelae. These findings also suggest that GSNO-mediated redox modulation may be a novel therapeutic target for the treatment of mild SCI-induced renal and bladder dysfunction.
目的:膀胱和肾功能障碍是脊髓损伤(SCI)诱导的炎症过程的继发事件。S-亚硝基谷胱甘肽(GSNO),一种内源性亚硝化剂,具有多效性且具有抗炎特性。因此,GSNO可改善SCI后膀胱和肾组织中观察到的炎症后遗症。因此,我们推测GSNO将通过消除与SCI相关的膀胱组织炎症来改善排尿功能障碍的恢复。 方法:在雌性Sprague-Dawley大鼠中诱导基于挫伤的轻度SCI。假手术大鼠作为对照。SCI大鼠每天灌胃GSNO(50μg/kg)或赋形剂。在SCI后2天和14天通过尿动力学评估膀胱功能。测量尿蛋白浓度和渗透压。通过组织学和免疫荧光分析膀胱和肾组织中与炎症相关的各种终点。 结果:SCI后2天,尿动力学显示膀胱反射亢进伴尿失禁且无明确排尿事件。到第14天,赋形剂处理的动物恢复了排尿周期的表象,但收缩间期不明确。GSNO处理的SCI大鼠显示膀胱压力容积图接近正常。赋形剂处理的SCI大鼠在第14天膀胱湿重增加、蛋白尿和尿渗透压升高,而GSNO处理可使其逆转。此外,GSNO减轻了SCI诱导的免疫细胞浸润、胶原蛋白沉积、诱导型一氧化氮合酶(iNOS)和细胞间黏附分子-1(ICAM-1)表达增加以及细胞凋亡。 结论:这些结果表明,口服GSNO通过减轻炎症后遗症加速轻度挫伤诱导的SCI后膀胱功能的恢复。这些发现还表明,GSNO介导的氧化还原调节可能是治疗轻度SCI诱导的肾和膀胱功能障碍的新治疗靶点。
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