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

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

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 adu...

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Bibliographic Details
Published in:Pharmaceutics Vol. 14; no. 12; p. 2769
Main Authors: Al-Shahat, Amal, Hulail, Mohey A E, Soliman, Nada M M, Khamis, Tarek, Fericean, Liana Mihaela, Arisha, Ahmed Hamed, Moawad, Rania S
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 01-12-2022
MDPI
Subjects:
Apoptosis
Cancer therapies
Causes of
Cell cycle
Chemotherapy
Cisplatin
Complications and side effects
Dosage and administration
Drug dosages
Drug therapy
Ethanol
Females
Fertility
Infertility
Inflammation
Laboratory animals
Melatonin
Ovarian diseases
ovarian impairment
Ovaries
ovary
Oxidative stress
Stains & staining
steroidogenesis
Testing
Egypt
United States > US
steroidogenesis
ovary
cisplatin
melatonin
oxidative stress
ovarian impairment
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Summary: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.
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ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics14122769