LCZ696 (sacubitril/valsartan) mitigates cyclophosphamide-induced premature ovarian failure in rats; the role of TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway.

Autor: Khallaf WAI; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: waleed.khallaf@pharm.bsu.edu.eg., Sharata EE; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt. Electronic address: ehab.essam@deraya.edu.eg., Attya ME; Department of Pathology, Faculty of Medicine, Minia University, Minia 61519, Egypt. Electronic address: mena.ezzat@mu.edu.eg., Abo-Youssef AM; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: amira.abouyousif@pharm.bsu.edu.eg., Hemeida RAM; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minia 61111, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut branch, Assiut 71524, Egypt. Electronic address: ramadan.hemeida@deraya.edu.eg.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2023 Aug 01; Vol. 326, pp. 121789. Date of Electronic Publication: 2023 May 17.
DOI: 10.1016/j.lfs.2023.121789
Abstrakt: Aim: Cyclophosphamide (CP) is used to treat a variety of cancers and autoimmune illnesses. CP has been found to frequently cause premature ovarian failure (POF). The study's objective was to assess LCZ696's potential for protection against CP-induced POF in a rat model.
Main Methods: Rats were randomly assigned into seven groups as follows: control, valsartan (VAL), LCZ696, CP, CP + VAL, CP + LCZ696, and CP + triptorelin (TRI). Ovarian malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-18 (IL-18), IL-1β, and tumor necrosis factor-alpha (TNF-α) were assessed using ELISA. Serum anti-mullerian hormone (AMH), estrogen, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also measured using ELISA. The expression of NLRP3/Caspase-1/GSDMD C-NT and TLR4/MYD88/NF-B P65 proteins was estimated using western blot assay. The histopathology of the ovaries was also investigated. The estrous cycle, body, and ovarian weights were also monitored.
Key Findings: CP treatment significantly elevated levels of MDA, IL-18, IL-1β, TNF-α, FSH, LH, and up-regulated TLR4/NF-κB/NLRP3/Caspase-1 proteins, as compared to the control group, however, ovarian follicles count, and levels of GSH, SOD, AMH, and estrogen were reduced with CP administration. All the aforementioned biochemical and histological abnormalities were considerably alleviated by the LCZ696 therapy compared to valsartan alone.
Significance: LCZ696 effectively mitigated CP-induced POF, offering promising protection that could be related to its suppression power on NLRP3-induced pyroptosis and TLR4/NF-B P65 pathway.
Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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