Second Department of Gynaecology, Medical University of Lublin, Lublin, Poland.
Chair and Department of Applied Pharmacy, Medical University of Lublin, Lublin, Poland.
Neurourol Urodyn. 2019 Apr;38(4):1044-1052. doi: 10.1002/nau.23973. Epub 2019 Mar 14.
The main goal of our study was to investigate whether blebbistatin would prevent the cyclophosphamide (CYP)-induced changes in cystometric and inflammatory parameters indicating the development of bladder inflammation and bladder overactivity. As the nature of CYP-induced urotoxicity is inflammatory, we assume that agents presenting an anti-inflammatory potential, such as blebbistatin, are worth special attention.
The experiments were carried out in female Wistar rats. Surgical procedures, cystometric investigations, measurements of bladder edema and urothelium thickness as well as biochemical analyses were performed according to the published literature.
As expected, an acute administration of CYP (200 mg/kg, intraperitoneally) induced changes in the cystometric parameters and the levels of the tested biomarkers (ie, interleukin 1-β, interleukin 6, interleukin 10, tumor necrosis factor-α, nerve growth factor, brain-derived neurotrophic factor, heparin-binding epidermal growth factor-like growth factor, insulin-like growth factor-binding protein 3, C-X-C motif chemokine 10, orosomucoid-1, Tamm-Horsfall protein, hemopexin, and occludin), indicating the development of bladder overactivity and bladder inflammation, respectively. These changes were accompanied by bladder edema and increased urothelium thickness. Intravesical infusion of blebbistatin for 7 days (125 nmol/day) prevented all symptoms of the CYP-induced urotoxicity.
Blebbistatin might be a promising novel agent for the treatment of bladder dysfunctions, like CYP-induced hemorrhage cystitis or bladder overactivity, since it diminished the increased urinary bladder levels of proinflammatory markers and normalized the concentrations of the anti-inflammatory ones. This effect was accompanied by amelioration of bladder edema and permeability, and normalization of both urothelium thickness and values of the cystometric parameters.
本研究的主要目的是探讨 blebbistatin 是否可以预防环磷酰胺 (CYP) 引起的膀胱过度活动和炎症参数变化，这些变化表明膀胱炎症的发生和发展。由于 CYP 诱导的尿毒性具有炎症性质，我们假设具有抗炎潜力的药物，如 blebbistatin，值得特别关注。
实验在雌性 Wistar 大鼠中进行。根据已发表的文献，进行了外科手术、膀胱测压研究、膀胱水肿和尿路上皮厚度的测量以及生化分析。
正如预期的那样，急性给予 CYP（200mg/kg，腹腔内）会引起膀胱测压参数和测试生物标志物（即白细胞介素 1-β、白细胞介素 6、白细胞介素 10、肿瘤坏死因子-α、神经生长因子、脑源性神经营养因子、肝素结合表皮生长因子样生长因子、胰岛素样生长因子结合蛋白 3、C-X-C 基序趋化因子 10、粘蛋白 1、Tamm-Horsfall 蛋白、血红素结合蛋白和紧密连接蛋白）的水平发生变化，分别表明膀胱过度活动和膀胱炎症的发生。这些变化伴随着膀胱水肿和尿路上皮厚度增加。膀胱内输注 blebbistatin 7 天（125nmol/天）可预防 CYP 诱导的尿毒性的所有症状。
Blebbistatin 可能是一种有前途的新型药物，可用于治疗膀胱功能障碍，如 CYP 诱导的出血性膀胱炎或膀胱过度活动，因为它降低了尿液中促炎标志物的水平，并使抗炎标志物的浓度正常化。这种作用伴随着膀胱水肿和通透性的改善，以及尿路上皮厚度和膀胱测压参数值的正常化。
