Therapeutic potential of alpha-pinene in methotrexate-induced testicular toxicity: focus on apoptosis, oxidative stress, and inflammatory pathways

Kabartan E., Cirrik S., Hacioglu G., Tezcan Yavuz B., TELKOPARAN AKILLILAR P., Sirin Tomruk C.

Naunyn-Schmiedeberg's Archives of Pharmacology, 2025 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1007/s00210-025-04441-z
  • Dergi Adı: Naunyn-Schmiedeberg's Archives of Pharmacology
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, Veterinary Science Database
  • Anahtar Kelimeler: Alpha-pinene, Cytokine modulation, Monoterpenes, Nrf2 signaling pathway, Oxidative stress, Reproductive toxicity
  • Gazi Üniversitesi Adresli: Evet

Özet

Purpose: Methotrexate (MTX), a widely used chemotherapeutic agent, induces testicular toxicity via oxidative stress, inflammation, and apoptosis. This study aimed to investigate the protective effects of alpha-pinene (APN) against MTX-induced testicular damage in male rats. Methods: Animals were divided into four groups: vehicle control (VHC), toxicity group (MTX), APN treatment group (APN), and combined group (APN + MTX). Key assessments included body weight changes (BWCs), relative testis weight (RTW), epididymal sperm count (ESC), sperm motility and viability, histopathology, oxidative stress index (OSI), mRNA expression levels of Nrf2, Keap1, and Hmox1, inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-10), and apoptotic markers (Caspase 3 and the BAX/BCL-2 ratio). Results: MTX significantly reduced BWC (d = –1.84), RTW (d = –3.00), ESC (d = –3.08), sperm motility (d = –7.53), and viability (d = –3.37) while increasing OSI (d = 2.21), TNF-α (d = 2.31), IL-1 (d = 1.97), Caspase 3 (d = 2.43), and BAX/BCL-2 (d = 2.68) (p < 0.05). APN preserved testicular structure and reduced OSI (d = 2.14), TNF-α (d = 2.12), and IL-1 (d = 2.72). Nrf2 expression increased with APN (vs. MTX, d = 1.35), while IL-6, IL-10, and Hmox1 remained statistically unchanged (p > 0.05), despite a large effect size for Hmox1 (d = 1.49). Conclusion: APN attenuated MTX-induced testicular damage by reducing oxidative stress, inflammation, and apoptosis. The unchanged IL-6 and IL-10 levels suggest that APN preserves MTX’s immunomodulatory effects while offering protection against fertility impairment.