title: Irbesartan, an angiotensin II receptor antagonist, with selective PPAR-gamma-modulating activity improves function and structure of chemotherapy-damaged ovaries in rats.
abstract: Cyclophosphamide (CYP) is a chemotherapeutic agent with a potent ovarian toxic effect. CYP induces granulosa cell apoptosis and oxidative stress. Irbesartan (IRB) is a unique ARB with a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonistic activity. As PPAR-ɣ activation exerts anti-inflammatory effects and reduces ROS production, IRB may further reduce inflammatory chemokine expression and suppress apoptotic cell death. Therefore, this study aimed to evaluate the effects of IRB on the development of CYP-induced ovarian damage. Rats were divided into four groups: control group, IRB group (100 mg/kg, orally), CYP group (100 mg/kg, i.p. single injection), and IRB+CYP group (IRB administered 9 days before and 6 days after CYP administration). Rats sacrificed on day 16 of experiment; estradiol (E2), FSH, and TNF-α levels were estimated in serum. Reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) and caspase-3 activities, myeloperoxidase (MPO), and IL-10 levels were determined in ovarian tissues. Protein expressions of p53, caspase-3, Ki-67, and Rad-51 were estimated by immunohistochemical and Western blot techniques. CYP produced ovarian damage as indicated from the decline in serum E2; elevation in FSH; unbalance in tissue oxidative stress parameters; increase in MPO, TNF-α levels, caspase-3 activity/expression, p53, and Rad-51 expression; and decrease in IL-10 contents, without effect on Ki-67. On the other hand, IRB, significantly reduced the toxic effects of CYP as indicted from normalization of E2, FSH, oxidative stress, apoptotic, and inflammatory mediators. These data were further supported by histopathological studies. Thus, co-administration of IRB may be promising in alleviating the ovarian toxic effects of CYP.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22111, Egypt.
authors.forename: Ihab T
authors.initials: IT
authors.lastname: Abdel-Raheem
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour, 22111, Egypt.
authors.forename: Gamal A
authors.initials: GA
authors.lastname: Omran
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22111, Egypt.
authors.forename: Mohamed Alaa
authors.initials: MA
authors.lastname: Katary
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000633:toxicity*; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D018836:Inflammation Mediators / Q000097:blood; D000077405:Irbesartan; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000893:Anti-Inflammatory Agents; D018906:Antineoplastic Agents, Alkylating; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D001713:Biphenyl Compounds; D018836:Inflammation Mediators; D047495:PPAR gamma; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D003520:Cyclophosphamide; D005640:Follicle Stimulating Hormone; D000077405:Irbesartan
keywords: IL-10; Rad-51; caspase-3; cyclophosphamide; irbesartan; ovarian tissue; p53