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褪黑素通过改变雌性大鼠的类固醇生成、炎症、细胞凋亡、氧化应激以及PTEN/PI3K/Akt/mTOR/AMPK信号通路减轻顺铂诱导的卵巢功能障碍。

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

作者信息

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

机构信息

Human Anatomy & Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.

Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt.

出版信息

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

DOI:10.3390/pharmaceutics14122769
PMID:36559263
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9786155/
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.

摘要

卵巢损伤和生育能力受损是绝经前癌症患者化疗的主要副作用。顺铂是一种广泛使用的化疗药物。本研究旨在评估褪黑素作为生育力保护佐剂的改善作用。将32只成年雌性Wistar大鼠随机分为四组：对照组、褪黑素组、顺铂（CP）治疗组和CP + 褪黑素治疗组。顺铂治疗组显示体重和卵巢重量下降，血清E2和AMH降低，血清LH和FSH升高，卵巢SOD、CAT、GSH和TAC水平降低，卵巢MDA升高。顺铂治疗组的组织病理学检查显示卵巢组织内出现有害变化，表现为卵泡和黄体受损、出血、炎症浸润，透明带PAS反应微弱，卵巢胶原沉积增加，颗粒细胞、卵泡膜细胞、基质和卵母细胞中caspase-3免疫反应明显表达。同时，类固醇生成酶、IL10、AMPK、PI3K、AKT、mTOR和PTEN的mRNA表达显著下调，而TGF-β1、IL1β、IL6、TNF-α、NF-Kβ、P53、p38-MAPK、JNK和FOXO3 mRNA表达在顺铂治疗大鼠的卵巢组织中上调。顺铂治疗的大鼠与褪黑素联合给药可显著逆转这些变化。总之，褪黑素的抗氧化、抗炎和抗凋亡活性可以调节顺铂诱导的卵巢紊乱并保护生育能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/d0cb6a4fdd02/pharmaceutics-14-02769-g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/dc243c5d9f74/pharmaceutics-14-02769-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/f1acdc5ffd1a/pharmaceutics-14-02769-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/471cf78cb014/pharmaceutics-14-02769-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/a2c508ee9947/pharmaceutics-14-02769-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/336343c2c70c/pharmaceutics-14-02769-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/95e6fa4df4df/pharmaceutics-14-02769-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/ce97c590cd48/pharmaceutics-14-02769-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/d0cb6a4fdd02/pharmaceutics-14-02769-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/fa76ef6f696a/pharmaceutics-14-02769-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/b2a5d1eb864d/pharmaceutics-14-02769-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/7f63b01793f4/pharmaceutics-14-02769-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/afca3fb39ced/pharmaceutics-14-02769-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/dc243c5d9f74/pharmaceutics-14-02769-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/f1acdc5ffd1a/pharmaceutics-14-02769-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/471cf78cb014/pharmaceutics-14-02769-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/a2c508ee9947/pharmaceutics-14-02769-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/336343c2c70c/pharmaceutics-14-02769-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/95e6fa4df4df/pharmaceutics-14-02769-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/ce97c590cd48/pharmaceutics-14-02769-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b6/9786155/d0cb6a4fdd02/pharmaceutics-14-02769-g012.jpg

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