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

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.

The effect of Usnea longissima extract on chemotherapy-associated multi-organ damage in rats

“…Despite their antitumor activity, studies showed that they have toxic effects on non-targeted organs such as ovary, heart, liver and kidney [9,13,14,24]. The mechanism of action of adverse side effects of doxorubicin and cisplatin is not well understood however it is thought to be the result of reactive oxygen radicals [8,25].…”

“…Cisplatin is one of the most potent and commonly used drugs in the treatment of various solid neoplasms like testicular, endometrial, head and neck, bladder, lung, and cervix malignancies, melanoma and lymphoma [13]. However, cisplatin can cause nephrotoxicity, ototoxicity, hepatotoxicity, gastrointestinal toxicity, cardiotoxicity and reproduction function anomalies [13][14][15]. It has been reported that oxidative damage that is caused by metabolisation of these drugs play an important role in various organ toxicities.…”

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

“…Then, the rats were anesthetized by intraperitoneal injection of thiopental (75 mg/kg BW) and subjected to cervical dislocation, the abdomen was then opened to collect both testes outside the body, weighted and then divided into three parts; the first part was collected on 10% neutral buffered formalin for histopathological and immunohistochemical examination, the second part (30 mg) was removed directly on liquid nitrogen and then kept at −80 °C to be used for total RNA extraction and the third part (1 g) was homogenized to be used for different biochemical tests. After being dissected, the hypothalamus and pituitary gland were stored in liquid nitrogen and kept there at −80 °C until total RNA extraction as previously described [ 97 ].…”

Interleukin-35 and Thymoquinone nanoparticle-based intervention for liver protection against paracetamol-induced liver injury in rats

“…Hepatic inflammatory related genes including TNF-α, TGF-β, IL1β, IL10, Bax, Bcl2 and Casps-3 was examined using qRT-PCR as early described ( Al-Shahat et al, 2022 ). Extraction of RNA from hepatic tissues was achieved using Trizol reagent (Invitrogen; USA).…”

“…Following the extraction, the quality of RNA was evaluated by a NanoDrop® ND-1000 Spectrophotometer (NanoDrop Technologies, Delaware, USA). Subsequently, synthesis of cDNA was achieved through using the HiSenScript™ RH (-) cDNA Synthesis kit (iNtRON Biotechnology Co., South Korea) ( Al-Shahat et al, 2022 , Saber et al, 2022 ). Analysis of gene expression was conducted using qRT-PCR (Agilent Stratagene, USA) by 5x HOT FIRE Pol EvaGreen qPCR Mix Plus (Solis BioDyne, Tartu, Estonia), according to supplier's directions.…”