Pyridostigmine Mitigates Methotrexate-Induced Liver Fibrosis in Rats: Association with Changes in BMP-9, SIRT1, and Endoglin Expression

Ulusan M., Erdogan M. A., Simsek O., ÜSTÜNDAĞ H., Dogan Z., Ciftci B. B., ...Daha Fazla

Biomedicines, cilt.13, sa.6, 2025 (SCI-Expanded, Scopus) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 13 Sayı: 6
  • Basım Tarihi: 2025
  • Doi Numarası: 10.3390/biomedicines13061502
  • Dergi Adı: Biomedicines
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Directory of Open Access Journals
  • Anahtar Kelimeler: fibrosis, liver injury, methotrexate, oxidative stress, pyridostigmine, sirtuin 1
  • Erzincan Binali Yıldırım Üniversitesi Adresli: Evet

Özet

Background and Objectives: 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. Methods: Thirty-six female Wistar albino rats randomly assigned to three groups: control (n = 12), MTX + saline (n = 12), and MTX + pyridostigmine (n = 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. Results: Pyridostigmine significantly attenuated MTX-induced elevations in plasma alanine aminotransferase (p < 0.05) and cytokeratin-18 levels (p < 0.001), and reduced liver and plasma malondialdehyde (MDA) levels (p < 0.05). Additionally, pyridostigmine treatment resulted in reduced levels of transforming growth factor-beta (p < 0.05), bone morphogenetic protein-9 (p < 0.001), and endoglin levels (p < 0.05), as well as increased sirtuin 1 level (p < 0.05). Histopathological examination revealed that pyridostigmine treatment significantly reduced MTX-induced hepatocyte necrosis, fibrosis, and cellular infiltration. Conclusions: 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.