Pyrvinium pamoate ameliorates cyclosporin A- induced hepatotoxicity via the modulation of Wnt/β-catenin signaling and upregulation of PPAR-γ.

Autor: Faheem SA; Pharmacology and Toxicology department, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt., El-Sayed NM; Pharmacology and Toxicology department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt. Electronic address: Norhan.ms@pharm.suez.edu.eg., Moustafa YM; Pharmacology and Toxicology department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University, Cairo, Egypt., Saeed NM; Pharmacology and Toxicology department, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt., Hazem RM; Pharmacology and Toxicology department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2022 Mar; Vol. 104, pp. 108538. Date of Electronic Publication: 2022 Jan 21.
DOI: 10.1016/j.intimp.2022.108538
Abstrakt: Background: Cyclosporin A (CsA) is an immunosuppressive agent that can be used to treat autoimmune diseases. Despite its hepatotoxicity, CsA is a backbone in organ transplantation. Pyrvinium pamoate (PP) is an inhibitor of Wnt signaling approved by the U.S. Food and Drug Administration for its anthelmintic properties.
Aim: The goal of this investigation was to determine whether PP could protect against CsA-induced hepatotoxicity.
Method: Five groups of 50 albino male mice were selected and divided into five groups; group 1 was the control, groups 2 to 4 were subjected to daily CsA (25 mg/kg, i.p), in which groups 3 and 4 were treated with graded dose of PP (0.25, 0.5 mg/kg), and group 5 was treated with PP (0.5 mg/ kg) for 21 days. The mice were sacrificed under anesthesia, and their livers were removed for histological and biochemical assessment.
Results: CsA was found to cause a striking increase in liver enzymes, total bilirubin, and malondialdehyde levels while significantly decreasing the levels of albumin, glutathione, and antioxidant enzymes in the treated groups. The tissue levels of tumor necrosis factor-α, interleukin-1β, and NFКB were also significantly higher with CsA treatment. Moreover, CsA triggered a notable increase in the levels of apoptotic marker P53. CsA activated the Wnt/β-catenin pathway by increasing WNT3a expression, frizzled receptor-7, β-catenin, and c-myc. On the other hand, the levels of PPAR-γ decreased significantly with CsA. CsA-induced alterations in the previously stated parameters were greatly reduced by PP, indicating its antioxidant, anti-inflammatory, and antiapoptotic properties.
Conclusions: PP may be considered as a promising agent to prevent CsA hepatotoxicity.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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