Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats

Amal Al-Shahat; Mohey A E Hulail; Nada M M Soliman; Tarek Khamis; Liana Mihaela Fericean; Ahmed Hamed Arisha; Rania S Moawad

doi:10.3390/pharmaceutics14122769

Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats

Pharmaceutics. 2022 Dec 10;14(12):2769. doi: 10.3390/pharmaceutics14122769.

Authors

Amal Al-Shahat¹, Mohey A E Hulail¹, Nada M M Soliman¹, Tarek Khamis^{2

3}, Liana Mihaela Fericean⁴, Ahmed Hamed Arisha^{5

6}, Rania S Moawad¹

Affiliations

¹ Human Anatomy & Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.
² Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt.
³ Laboratory of Biotechnology, Faculty of Veterinary 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 (BUC), Badr City 11829, Egypt.
⁶ Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt.

Abstract

Ovarian damage and fertility impairment are major side effects of chemotherapy in pre-menopausal cancer patients. Cisplatin is a widely used chemotherapeutic drug. The present study was designed to assess the ameliorative effects of melatonin as an adjuvant for fertility preservation. Thirty-two adult female Wistar rats were divided randomly into four equal groups: Control, Melatonin, Cisplatin (CP) treated, and CP + Melatonin treated. The cisplatin-treated group showed decreased body and ovarian weights, decreased serum E2 and AMH, increased serum LH and FSH, reduced ovarian levels of SOD, CAT, GSH, and TAC, and increased ovarian MDA. The histopathological examination of the cisplatin-treated group showed deleterious changes within ovarian tissue in the form of damaged follicles and corpus luteum, hemorrhage, and inflammatory infiltrates with faint PAS reaction in zona pellucida, increased ovarian collagen deposition, and marked expression of caspase-3 immune reaction in granulosa and theca cells, stroma, and oocytes. Alongside, there was a significant downregulation in the mRNA expression of steroidogenic enzymes, IL10, AMPK, PI3K, AKT, mTOR, and PTEN, while TGF-β1, IL1β, IL6, TNF-α, NF-Kβ, P53, p38-MAPK, JNK, and FOXO3 mRNA expressions were upregulated in cisplatin-treated rats' ovarian tissue. Coadministration of cisplatin-treated rats with melatonin reversed these changes significantly. In conclusion, melatonin's antioxidant, anti-inflammatory, and anti-apoptotic activities could modulate ovarian disturbances induced by cisplatin and preserve fertility.

Keywords: cisplatin; melatonin; ovarian impairment; ovary; oxidative stress; steroidogenesis.

Grants and funding

This research received no external funding, and The APC was funded by the own research funds of the University of Life Sciences “King Mihai I” from Timisoara, Aradului St. 119, Timisoara, 300645, Romania.