Abstract / Summary
Seyma Ilayda Paltaci,1 Nesrin Yilmaz,1 Sukran Kozali Uzun,1 Bulent Yavuzer,2 Taha Abdulkadir Coban,3 Mustafa Ozkaraca,4 Ali Gungor,5 Kamandar Yaqubov,6 Halis Suleyman2,71Department of Obstetrics and Gynecology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey; 2Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey; 3Department of Medical Biochemistry, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey; 4Department of Pathology, Faculty of Veterinary Medicine, Sivas Cumhuriyet University, Sivas, Turkey; 5Laboratory and Veterinary Health Program, Vocational School of Health Services, Osmaniye Korkut Ata University, Osmaniye, Turkey; 6Department of Pharmacology, Azerbaijan Medical University, Baku, Azerbaijan; 7Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, TurkeyCorrespondence: Halis Suleyman, Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey, Tel +90 530 9211909, Fax +90 446 2261819, Email hsuleyman@erzincan.edu.trBackground: Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor used to treat several malignancies. Previous studies have reported that olaparib may induce ovarian injury by elevating reactive oxygen species and impairing cellular energy homeostasis. ATP is a central regulator of intracellular energy balance and antioxidant defense, whereas thiamine pyrophosphate (TPP), the active form of vitamin B1, supports ATP biosynthesis and possesses antioxidant and anti-inflammatory properties. This study compared the protective effects of ATP and TPP against olaparib-induced ovarian injury in rats.Methods: Twenty-four female Wistar albino rats were randomly assigned to four groups (n=6 each): healthy control (HG), olaparib-only (OLP), ATP plus olaparib (ATOL), and TPP plus olaparib (TPOL). Olaparib (100 mg/kg, orally, twice daily), ATP (5 mg/kg, intraperitoneally, once daily), and TPP (25 mg/kg, intraperitoneally, once daily) were administered for 14 consecutive days. Ovarian tissue levels of oxidant (MDA), antioxidants (tGSH, SOD, CAT), and pro-inflammatory cytokine (IL-6) were determined. Tissue specimens underwent histopathological (follicular and parenchymal degeneration) and double immunofluorescence analyses (IRE1α, cleaved Caspase-3, LC3B, and NF-κB p65 immunopositivity).Results: Olaparib significantly increased oxidant and pro-inflammatory cytokine levels and decreased antioxidant levels. Histopathology revealed severe follicular and parenchymal degeneration, and immunofluorescence analysis showed significantly increased IRE1α, cleaved Caspase-3, LC3B, and NF-κB p65 immunopositivity. Both ATP and TPP pre-treatment significantly attenuated olaparib-induced oxidative stress, inflammatory responses, histopathological injury, and cellular stress marker immunopositivity. ATP demonstrated a more pronounced protective effect than TPP, particularly regarding follicular degeneration suppression and LC3B and NF-κB p65 immunopositivity.Conclusion: Olaparib induced ovarian injury accompanied by oxidative stress, cytokine-mediated inflammation, IRE1α-related endoplasmic reticulum stress, cleaved Caspase-3-related apoptosis, LC3B-related autophagy, and NF-κB-related inflammatory signaling. Both ATP and TPP attenuated olaparib-associated injury, with greater effects for ATP. These findings suggest that maintenance of cellular energy homeostasis may represent a promising strategy for attenuating PARP inhibitor-induced ovarian injury.Keywords: adenosine triphosphate, apoptosis, autophagy, endoplasmic reticulum stress, inflammation, olaparib, ovarian diseases/chemically induced, oxidative stress, rats, thiamine pyrophosphate