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. 2022 Jan 15:289:120218.
doi: 10.1016/j.lfs.2021.120218. Epub 2021 Dec 8.

Protective role of irbesartan against cyclophosphamide-induced testicular damage in rats via up-regulating PPAR-γ signaling and ameliorating NF-κB/NLRP3/IL-18 inflammatory axis

Sally E Abu-Risha  1 , Mai A Mousa  2 , Alaa E Elsisi  1
Affiliations

Protective role of irbesartan against cyclophosphamide-induced testicular damage in rats via up-regulating PPAR-γ signaling and ameliorating NF-κB/NLRP3/IL-18 inflammatory axis

Sally E Abu-Risha et al. Life Sci. .

Abstract

Background: Cancer and its therapies can impact fertility in various ways, and therefore a growing number of cancer survivors face fertility as a significant concern. The cytotoxic alkylating agent cyclophosphamide (CP) is commonly used as an antineoplastic agent; unfortunately, its use is significantly associated with male infertility and damage to the reproductive system.

Aim: The present study aimed to assess the possible beneficial effects of Irbesartan (IRB) in a rat model of CP-induced testicular toxicity.

Main methods: The effects of treatment were assessed by measuring peroxisome proliferator-activated receptor gamma (PPAR-γ) expression via qRT-PCR, the immunohistochemical (IHC) assessment of apoptotic markers, NOD-like receptor protein 3 (NLRP3), and nuclear factor-κB (NF-κB), determination of the count and viability of epididymal sperm, oxidative stress markers via biochemical analysis, serum testosterone, caspase-1, and interleukin-18 (IL-18) levels via ELISA, histopathological assessment, and fibrosis by Masson's trichrome (MT) stain.

Key findings: There was a significant increase in malondialdehyde (MDA), caspase-1, and IL-18 contents, NF-κB, NLRP3, Bcl-2-associated X protein (Bax), caspase-3, and MT staining in testicular tissue after CP administration compared to the normal control group. Whereas reduced glutathione (GSH), superoxide dismutase (SOD), PPAR-γ expression, B-cell lymphoma-2 (Bcl-2) staining, serum testosterone, and the count and viability of epididymal sperm were decreased compared to the normal control group. The IRB treatment has reversed CP-induced testicular toxicity.

Significance: It is possible to conclude that IRB revealed a significant testicular protective effect against CP via antioxidant, anti-apoptotic, and anti-inflammatory effects.

Keywords: Apoptosis; Cyclophosphamide; Irbesartan; NLRP3; Oxidative stress; PPAR-γ; Testicular toxicity.

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