El-Dessouki Ahmed M, Eissa Mohamed E, Al Khatib Arwa Omar, Yousef Tarek A, Alwakeel Asmaa I, Ramadan Asmaa, Ashour Nada A, Al-Karmalawy Ahmed A
Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6Th of October City, Giza, 12566, Egypt.
College of Science, Chemistry Department, Imam Mohammad Ibn Saud Islamic University, 11623, Riyadh, Saudi Arabia.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 1. doi: 10.1007/s00210-025-04393-4.
This study explores the molecular pathways through which Ivabradine (IVN) exerts protective effects against Cyclophosphamide (CP)-induced hepatotoxicity, aiming to identify the underlying mechanisms involved.
Animals were assigned at random into four groups (10 rats in each group): Group 1 was administered 1 mL of distilled water orally for 10 consecutive days, along with a single intraperitoneal injection of 0.9% saline on the seventh day. Group 2 received distilled water for 10 days and a single CP injection (200 mg/kg, IP) on day 7. Groups 3 and 4 were administered IVN at either 5 or 10 mg/kg orally each day for 10 consecutive days, plus CP on day 7. Rats were euthanized for biochemical, histological, immunostaining, qRT-PCR, and western blot assessments.
Rats treated with CP exhibited notable elevations in liver enzymes (ALT, AST) along with decreased levels of antioxidant indicators (HO-1, Nrf2, GSH). Concentrations of MPO, MDA, and iNOS, along with IL-1β, TNF-α, and IL-6, were markedly elevated (p < 0.01). Immunostaining showed elevated NF-kB p65 and caspase-9, aligning with observed liver histopathology. Conversely, IVN administration reduced hepatic enzymes and alleviated tissue alterations. It provided antioxidant defense by correcting redox imbalance and lowering inflammation through targeting the p38MAPK/NF-κB p65 axis and the JAK1-STAT3 pathway (p < 0.01). IVN also prevented CP-induced PI3K-Akt suppression and reduced caspase-related apoptotic activity.
The current findings indicate that IVN could represent a valuable treatment option to mitigate CP-induced liver injury via its antioxidant, anti-inflammatory, and apoptosis- suppressing properties, thereby supporting the need for further exploration in future studies.
本研究探索伊伐布雷定（IVN）对环磷酰胺（CP）诱导的肝毒性发挥保护作用的分子途径，旨在确定其中涉及的潜在机制。
将动物随机分为四组（每组10只大鼠）：第1组连续10天口服1 mL蒸馏水，并在第7天腹腔注射一次0.9%生理盐水。第2组接受10天蒸馏水，并在第7天单次注射CP（200 mg/kg，腹腔注射）。第3组和第4组连续10天每天口服5或10 mg/kg的IVN，第7天加用CP。对大鼠实施安乐死以进行生化、组织学、免疫染色、qRT-PCR和蛋白质印迹评估。
用CP处理的大鼠肝酶（ALT、AST）显著升高，抗氧化指标（HO-1、Nrf2、GSH）水平降低。MPO、MDA和iNOS的浓度以及IL-1β、TNF-α和IL-6显著升高（p < 0.01）。免疫染色显示NF-κB p65和caspase-9升高，与观察到的肝脏组织病理学一致。相反，给予IVN可降低肝酶并减轻组织改变。它通过纠正氧化还原失衡提供抗氧化防御，并通过靶向p38MAPK/NF-κB p65轴和JAK1-STAT3途径减轻炎症（p < 0.01）。IVN还可防止CP诱导的PI3K-Akt抑制并降低caspase相关的凋亡活性。
目前的研究结果表明，IVN可能是一种有价值的治疗选择，可通过其抗氧化、抗炎和抑制凋亡的特性减轻CP诱导的肝损伤，从而支持在未来研究中进一步探索的必要性。
