Ulusan Mehmet, Erdogan Mumin Alper, Simsek Ozkan, Ustundag Hilal, Dogan Zafer, Ciftci Bertug Bekir, Kocamuftuoglu Mesih, Orhan Imdat, Erbas Oytun
Department of Internal Medicine, Faculty of Veterinary Medicine, Burdur Mehmet Akif Ersoy University, Burdur 15030, Turkey.
Department of Physiology, Faculty of Medicine, Izmir Katip Celebi University, Izmir 35620, Turkey.
Biomedicines. 2025 Jun 19;13(6):1502. doi: 10.3390/biomedicines13061502.
Methotrexate (MTX) is a widely utilised pharmaceutical agent in the treatment of various malignancies and inflammatory diseases. However, its clinical utility is often constrained by its potential for hepatotoxicity. Although pyridostigmine is a well-established reversible acetylcholinesterase inhibitor, its potential therapeutic role in preventing hepatic injury remains incompletely defined. The present study aimed to investigate whether pyridostigmine provides protective effects against MTX-triggered liver damage in a rat model. Thirty-six female Wistar albino rats randomly assigned to three groups: control ( = 12), MTX + saline ( = 12), and MTX + pyridostigmine ( = 12). Hepatotoxicity was induced by a single-dose MTX injection (20 mg/kg), followed by daily oral administration of either pyridostigmine (5 mg/kg) or saline for ten consecutive days. Hepatic function markers, oxidative stress parameters, fibrosis-associated mediators, and histopathological changes were assessed. Pyridostigmine significantly attenuated MTX-induced elevations in plasma alanine aminotransferase ( < 0.05) and cytokeratin-18 levels ( < 0.001), and reduced liver and plasma malondialdehyde (MDA) levels ( < 0.05). Additionally, pyridostigmine treatment resulted in reduced levels of transforming growth factor-beta ( < 0.05), bone morphogenetic protein-9 ( < 0.001), and endoglin levels ( < 0.05), as well as increased sirtuin 1 level ( < 0.05). Histopathological examination revealed that pyridostigmine treatment significantly reduced MTX-induced hepatocyte necrosis, fibrosis, and cellular infiltration. Pyridostigmine exerted hepatoprotective effects against MTX-induced liver injury by attenuating oxidative stress, restoring SIRT1 expression, and suppressing pro-fibrotic signaling. These findings indicate that pyridostigmine may hold therapeutic potential for the prevention of MTX-associated hepatotoxicity.
甲氨蝶呤（MTX）是一种广泛应用于治疗各种恶性肿瘤和炎症性疾病的药物。然而，其临床应用常常受到肝毒性的限制。虽然吡啶斯的明是一种成熟的可逆性乙酰胆碱酯酶抑制剂，但其在预防肝损伤方面的潜在治疗作用仍未完全明确。本研究旨在探讨吡啶斯的明在大鼠模型中是否能对MTX引发的肝损伤提供保护作用。36只雌性Wistar白化大鼠随机分为三组：对照组（n = 12）、MTX + 生理盐水组（n = 12）和MTX + 吡啶斯的明组（n = 12）。通过单次注射MTX（20 mg/kg）诱导肝毒性，随后连续10天每日口服吡啶斯的明（5 mg/kg）或生理盐水。评估肝功能指标、氧化应激参数、纤维化相关介质和组织病理学变化。吡啶斯的明显著减轻了MTX诱导的血浆丙氨酸氨基转移酶升高（P < 0.05）和细胞角蛋白-18水平升高（P < 0.001），并降低了肝脏和血浆丙二醛（MDA）水平（P < 0.05）。此外，吡啶斯的明治疗导致转化生长因子-β水平降低（P < 0.05）、骨形态发生蛋白-9水平降低（P < 0.001）和内皮糖蛋白水平降低（P < 0.05），同时沉默调节蛋白1水平升高（P < 0.05）。组织病理学检查显示，吡啶斯的明治疗显著减少了MTX诱导的肝细胞坏死、纤维化和细胞浸润。吡啶斯的明通过减轻氧化应激、恢复SIRT1表达和抑制促纤维化信号传导，对MTX诱导的肝损伤发挥了肝保护作用。这些发现表明，吡啶斯的明可能具有预防MTX相关肝毒性的治疗潜力。
