Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt.
Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
J Biochem Mol Toxicol. 2021 Nov;35(11):e22889. doi: 10.1002/jbt.22889. Epub 2021 Aug 13.
Hemorrhagic cystitis is a potentially deadly complication associated with radiation therapy and chemotherapy. This study explored the protective effect of edaravone (ED) on cyclophosphamide (CP)-induced hemorrhagic cystitis, oxidative stress, and inflammation in rats. The animals received 20 mg/kg ED for 10 days and a single injection of 200 mg/kg CP on day 7. CP induced tissue injury manifested by the diffuse necrotic changes, disorganization of lining mucosa, focal hemorrhagic patches, mucosal/submucosal inflammatory cells infiltrates, and edema. CP increased malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha, and interleukin 6 (IL-6), decreased IL-10, and upregulated toll-like receptor 4 (TLR-4), nuclear factor-kappa B (NF-κB) p65, Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) in the urinary bladder of rats. ED effectively prevented the histopathological alterations, decreased MDA, NO, and inflammatory mediators, and downregulated TLR-4, NF-κB, JAK1, and STAT3 in CP-induced rats. Treatment with ED upregulated ikβ kinase β, IL-10, nuclear factor-erythroid 2 related factor 2 (Nrf2), and cytoglobin, and boosted glutathione, superoxide dismutase, and glutathione S-transferase. Molecular docking simulations revealed the ability of ED to bind TLR-4, NF-κB, JAK1, and STAT3. In vitro, ED increased the cytotoxic activity of CP against HeLa, Caco-2, and K562 cell lines. In conclusion, ED prevented CP-induced hemorrhagic cystitis in rats by attenuating oxidative stress, suppressing TLR-4/NF-κB, and JAK1/STAT3 signaling and boosted Nrf2, cytoglobin, and antioxidants.
出血性膀胱炎是一种与放射治疗和化学疗法相关的潜在致命并发症。本研究探讨了依达拉奉（ED）对环磷酰胺（CP）诱导的大鼠出血性膀胱炎、氧化应激和炎症的保护作用。动物接受 20mg/kg ED 治疗 10 天，并在第 7 天接受单次 200mg/kg CP 注射。CP 诱导的组织损伤表现为弥漫性坏死改变、衬里黏膜紊乱、局灶性出血斑、黏膜/黏膜下炎症细胞浸润和水肿。CP 增加了丙二醛（MDA）、一氧化氮（NO）、肿瘤坏死因子-α和白细胞介素 6（IL-6），降低了白细胞介素 10（IL-10），并上调了 Toll 样受体 4（TLR-4）、核因子-κB（NF-κB）p65、Janus 激酶 1（JAK1）和信号转导和转录激活因子 3（STAT3）在大鼠膀胱中的表达。ED 有效预防了组织病理学改变，降低了 MDA、NO 和炎症介质的水平，并下调了 CP 诱导大鼠的 TLR-4、NF-κB、JAK1 和 STAT3。ED 治疗还上调了 ikβ 激酶β、IL-10、核因子-红细胞 2 相关因子 2（Nrf2）和细胞色素蛋白 b，并增强了谷胱甘肽、超氧化物歧化酶和谷胱甘肽 S-转移酶。分子对接模拟表明 ED 能够与 TLR-4、NF-κB、JAK1 和 STAT3 结合。在体外，ED 增加了 CP 对 HeLa、Caco-2 和 K562 细胞系的细胞毒性活性。总之，ED 通过减轻氧化应激、抑制 TLR-4/NF-κB 和 JAK1/STAT3 信号通路以及增强 Nrf2、细胞色素蛋白 b 和抗氧化剂来预防 CP 诱导的大鼠出血性膀胱炎。
