Mersal Ezat A, Morsi Ahmed A, Alkahtani Jana, Alhalal Raneem, Alessa Sarah, Shehab Abeer, Sakr Eman M, Sabir Deema Kamal, Dawood Amal F, Abdelmoneim Ahmed M
Vision Colleges, Riyadh, Saudi Arabia.
Department of Medical Surgical Nursing, College of Nursing, Princess Nourah bint Abdulrahman University, P.O. Box 84428, 11671, Riyadh, Saudi Arabia.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb;398(2):2003-2014. doi: 10.1007/s00210-024-03407-x. Epub 2024 Sep 2.
Testicular injury and affected spermatogenesis are major complications of methotrexate (MTX) use. Oxidative stress is one contributing process leading to inflammation and apoptosis induction. Pirfenidone (PFD) is a well-known anti-fibrotic drug prescribed for interstitial lung fibrosis, in addition to anti-inflammatory, antioxidative, and antiapoptotic capabilities. The study aimed to explore the potential protection afforded by PFD in a rat model of MTX-induced testiculopathy. The experimental design included four groups, each containing seven adult Wistar rats: control, PFD (500 mg/kg/day, orally)-, MTX (0.5 mg/kg, intraperitoneal, twice weekly)-, and PFD/MTX-treated groups. Treatment continued for 4 weeks. Blood and testicular samples were harvested for biochemical, histological, immunohistochemical, and polymerase chain reaction (PCR) analyses. Also, the testicular damage and spermatogenic activity were graded by the testicular injury and Johnsen scoring system, respectively. PFD positively affected the serum testosterone (TST) level, reduced the testicular inflammatory mediators [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β)], reduced the testicular oxidative burden, increased superoxide dismutase (SOD), and protected the testicular histological structure. In addition, antifibrotic effects, anti-caspase-3, and PCNA enhancement activity were recorded. PFD exhibited a protective potential and mitigated the MTX-induced testiculopathy via suppression of testicular oxidative stress, inflammation, fibrosis, and apoptosis and retaining the testicular proliferative efficacy as confirmed by histological, immunohistochemical, and biochemical methods.
睾丸损伤和精子发生受影响是使用甲氨蝶呤（MTX）的主要并发症。氧化应激是导致炎症和诱导细胞凋亡的一个促成过程。吡非尼酮（PFD）是一种著名的抗纤维化药物，除了具有抗炎、抗氧化和抗凋亡能力外，还用于治疗间质性肺纤维化。本研究旨在探讨PFD对MTX诱导的睾丸病变大鼠模型的潜在保护作用。实验设计包括四组，每组有七只成年Wistar大鼠：对照组、PFD组（500毫克/千克/天，口服）、MTX组（0.5毫克/千克，腹腔注射，每周两次）和PFD/MTX治疗组。治疗持续4周。采集血液和睾丸样本进行生化、组织学、免疫组织化学和聚合酶链反应（PCR）分析。此外，分别通过睾丸损伤评分系统和约翰森评分系统对睾丸损伤和生精活性进行分级。PFD对血清睾酮（TST）水平有积极影响，降低了睾丸炎症介质[肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）]，减轻了睾丸氧化负担，增加了超氧化物歧化酶（SOD），并保护了睾丸组织结构。此外，还记录了抗纤维化作用、抗半胱天冬酶-3和增殖细胞核抗原（PCNA）增强活性。组织学、免疫组织化学和生化方法证实，PFD具有保护潜力，通过抑制睾丸氧化应激、炎症、纤维化和细胞凋亡以及保留睾丸增殖功效，减轻了MTX诱导的睾丸病变。
