Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
Int Immunopharmacol. 2022 Nov;112:109282. doi: 10.1016/j.intimp.2022.109282. Epub 2022 Oct 3.
The use of cyclophosphamide (CP) as a chemotherapeutic agent is limited by its major complication haemorrhagic cystitis (HC). Finding preventive, safe, and efficient treatments for such problems is extensively ongoing.
This research aims to assess the uroprotective effect of pramipexole (PPX) and/or lactoferrin (LF) against CP-induced HC, in addition to shedding light on their possible molecular targets.
Adult male Sprague-Dawley rats were orally administered PPX (3 mg/kg) and/or LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg).
Pretreatment of CP-intoxicated rats with either PPX or LF mitigated oxidative urinary bladder damage via upregulation of the Nrf2/HO-1 signalling pathway, resulting in a significant reduction in bladder MDA and 8-OHdG levels with concomitant elevations in SOD activity and GSH content. Simultaneously, both drugs markedly halted inflammation in bladder tissue through inhibition of the TLR4/NF-κB signalling pathway, followed by a significant decrease in inflammatory cytokine levels (TNF-α and IL-6). Interestingly, the PPX/LF protocol downregulated p-p38, p-ERK1/2, Sphk1, and S1P protein expression and inhibited the NLRP3/caspase1/IL-1β axis. PPX/LF also significantly reduced BAX and caspase-3, in addition to increasing Bcl-2 levels in bladder tissue of CP-treated animals. These biochemical findings were supported by the improvement in the histological alterations induced by CP in the urinary bladder.
The current study verified the protective effect of PPX and LF against CP-induced HC by halting oxidative stress, inflammation, and apoptosis. The molecular mechanism underlying this protective effect may involve targeting the crosstalk among Sphk1/S1P/MAPK/NF-κB, TLR-4/NF-κB, and NLRP3/caspase-1/IL-1β signalling pathways and modulating the Nrf2/HO-1 signalling pathway.
环磷酰胺（CP）作为化疗药物的使用受到其主要并发症出血性膀胱炎（HC）的限制。寻找预防、安全和有效的治疗方法是广泛进行的。
本研究旨在评估普拉克索（PPX）和/或乳铁蛋白（LF）对 CP 诱导的 HC 的尿保护作用，并阐明其可能的分子靶点。
成年雄性 Sprague-Dawley 大鼠连续 7 天口服给予 PPX（3mg/kg）和/或 LF（300mg/kg），然后单次腹腔注射 CP（150mg/kg）。
CP 中毒大鼠预先给予 PPX 或 LF 可通过上调 Nrf2/HO-1 信号通路减轻氧化尿膀胱损伤，导致膀胱 MDA 和 8-OHdG 水平显著降低，同时 SOD 活性和 GSH 含量升高。同时，两种药物通过抑制 TLR4/NF-κB 信号通路显著抑制膀胱组织炎症，随后炎症细胞因子（TNF-α和 IL-6）水平显著降低。有趣的是，PPX/LF 方案下调了 p-p38、p-ERK1/2、Sphk1 和 S1P 蛋白表达，并抑制了 NLRP3/caspase1/IL-1β 轴。PPX/LF 还显著降低了 CP 处理动物膀胱组织中的 BAX 和 caspase-3，同时增加了 Bcl-2 水平。CP 在尿路上皮引起的组织学改变的改善支持了这些生化发现。
本研究通过阻止氧化应激、炎症和细胞凋亡，验证了 PPX 和 LF 对 CP 诱导的 HC 的保护作用。这种保护作用的分子机制可能涉及针对 Sphk1/S1P/MAPK/NF-κB、TLR-4/NF-κB 和 NLRP3/caspase-1/IL-1β 信号通路的串扰，并调节 Nrf2/HO-1 信号通路。
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