Comparative Protective Effects of ATP and TPP Against Olaparib-Induced Ovarian Injury in Rats: Insights from Biochemical Parameters, Histopathology, and IRE1α, Cleaved Caspase-3, LC3B, and NF-κB p65 Double Immunofluorescence.

IF 6.1 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2026-09-26 eCollection Date: 2026-01-01 DOI:10.2147/DDDT.S634516

Seyma Ilayda Paltaci, Nesrin Yilmaz, Sukran Kozali Uzun, Bulent Yavuzer, Taha Abdulkadir Coban, Mustafa Ozkaraca, Ali Gungor, Kamandar Yaqubov, Halis Suleyman

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引用次数: 0

Abstract

Background: 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.

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ATP和TPP对奥拉帕尼诱导大鼠卵巢损伤的比较保护作用：来自生化参数、组织病理学和IRE1α、Cleaved Caspase-3、LC3B和NF-κB p65双免疫荧光的启示

背景：奥拉帕尼是一种聚（adp -核糖）聚合酶（PARP）抑制剂，用于治疗多种恶性肿瘤。先前的研究报道奥拉帕尼可能通过提高活性氧和损害细胞能量稳态来诱导卵巢损伤。ATP是细胞内能量平衡和抗氧化防御的中心调节器，而维生素B1的活性形式焦磷酸硫胺素（TPP）支持ATP的生物合成并具有抗氧化和抗炎特性。本研究比较了ATP和TPP对奥拉帕尼诱导的大鼠卵巢损伤的保护作用。方法：24只雌性Wistar白化大鼠随机分为健康对照组（HG）、单抗奥拉帕尼组（OLP）、ATP +奥拉帕尼组（ATOL）和TPP +奥拉帕尼组（TPOL），每组6只。奥拉帕尼（100 mg/kg，口服，每日2次）、ATP （5 mg/kg，腹腔注射，每日1次）和TPP （25 mg/kg，腹腔注射，每日1次）连续14天。测定卵巢组织中氧化剂（MDA）、抗氧化剂（tGSH、SOD、CAT）和促炎细胞因子（IL-6）的水平。组织标本进行组织病理学（滤泡和实质变性）和双免疫荧光分析（IRE1α、cleaved Caspase-3、LC3B和NF-κB p65免疫阳性）。结果：奥拉帕尼显著提高氧化和促炎细胞因子水平，降低抗氧化水平。组织病理学显示严重的滤泡和实质变性，免疫荧光分析显示IRE1α、cleaved Caspase-3、LC3B和NF-κB p65免疫阳性显著升高。ATP和TPP预处理均能显著减弱奥拉帕尼诱导的氧化应激、炎症反应、组织病理学损伤和细胞应激标志物免疫阳性。ATP表现出比TPP更明显的保护作用，特别是在抑制滤泡变性和LC3B和NF-κB p65免疫阳性方面。结论：奥拉帕尼诱导卵巢损伤并伴有氧化应激、细胞因子介导的炎症、ire1 α相关内质网应激、裂解型caspase -3相关凋亡、lc3b相关自噬和NF-κ b相关炎症信号。ATP和TPP均能减轻奥拉帕尼相关损伤，其中ATP的作用更大。这些发现表明，维持细胞能量稳态可能是减轻PARP抑制剂诱导的卵巢损伤的一种有希望的策略。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.