Hesperidin Mitigates Cyclophosphamide-Induced Testicular Dysfunction via Altering the Hypothalamic Pituitary Gonadal Axis and Testicular Steroidogenesis, Inflammation, and Apoptosis in Male Rats

Tarek Khamis; Abdelmonem Awad Hegazy; Samaa Salah Abd El-Fatah; Eman Ramadan Abdelfattah; Marwa Mohamed Mahmoud Abdelfattah; Liana Mihaela Fericean; Ahmed Hamed Arisha

doi:10.3390/ph16020301

Hesperidin Mitigates Cyclophosphamide-Induced Testicular Dysfunction via Altering the Hypothalamic Pituitary Gonadal Axis and Testicular Steroidogenesis, Inflammation, and Apoptosis in Male Rats

Pharmaceuticals (Basel). 2023 Feb 15;16(2):301. doi: 10.3390/ph16020301.

Authors

Tarek Khamis¹, Abdelmonem Awad Hegazy^{2

3}, Samaa Salah Abd El-Fatah³, Eman Ramadan Abdelfattah³, Marwa Mohamed Mahmoud Abdelfattah³, Liana Mihaela Fericean⁴, Ahmed Hamed Arisha^{5

6}

Affiliations

¹ Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt.
² Anatomy and Embryology, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan.
³ Human Anatomy & Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.
⁴ Biology Department, Faculty of Agriculture, University of Life Sciences "King Michael I of Romania" from Timisoara, Aradului St. 119, 300645 Timisoara, Romania.
⁵ Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt.
⁶ Department of Physiology, Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt.

Abstract

Cyclophosphamide (CP) is a cytotoxic, cell cycle, non-specific, and antiproliferative drug. This study aimed to address the toxic effects of CP on male fertility and the possible ameliorative role of hesperidin (HSP). Thirty-two adult albino rats were randomly divided into four groups, namely, the negative control, HSP, CP-treated, and CP+HSP-treated groups. The CP-treated rats showed a significant reduction in the levels of serum LH, FSH, testosterone, prolactin, testicular glutathione peroxidase (GPx), and total antioxidant capacity (TAC) with an elevation in levels of malondialdehyde (MDA), and p53, and iNOS immune expression, compared to the control group. A significant downregulation in hypothalamic KISS-1, KISS-1r, and GnRH, hypophyseal GnRHr, and testicular mRNA expression of steroidogenesis enzymes, PGC-1α, PPAR-1, IL10, and GLP-1, as well as a significant upregulation in testicular mRNA of P53 and IL1β mRNA expression, were detected in the CP-treated group in comparison to that in the control group. The administration of HSP in CP-treated rats significantly improved the levels of serum LH, FSH, testosterone, prolactin, testicular GPx, and TAC, with a reduction in levels of MDA, and p53, and iNOS immune expression compared to the CP-treated group. A significant upregulation in hypophyseal GnRHr, and testicular mRNA expression of CYP19A1 enzymes, PPAR-1, IL10, and GLP-1, as well as a significant downregulation in testicular mRNA of P53 and IL1β mRNA expression, were detected in the CP+HSP-treated group in comparison to that in the CP-treated group. In conclusion, HSP could be a potential auxiliary agent for protection from the development of male infertility.

Keywords: P53; apoptosis; cyclophosphamide; hesperidin; iNOS; oxidative stress.

Grants and funding

This research received no external funding, and the APC was funded by the project 6PFE of the University of Life Sciences “King Mihai I” from Timisoara and Research Institute for Biosecurity and Bioengineering from Timisoara, Romania.