Melatonin Protects Against Epirubicin-induced Ovarian Damage

The use of chemotherapy is accompanied by many side effects while increasing the survival of cancer patients.Ovarian injury is one of the main side effects of breast cancer patients receiving chemotherapy.In order to reduce the damage of chemotherapy,researchers have been actively exploring protective drugs.Epirubicin is one of the commonly used chemotherapy drugs for breast cancer patients.It belongs to anthracyclines and acts to kill tumor cells by inhibiting nucleic acid synthesis and topoisomerase activity.However,there is little known about the effect and mechanism of epirubicin on the ovary.Melatonin(N-acetyl-5-methoxytryptamine)is an indolamine hormone.Pineal gland,retina,ovary and other tissues can synthesize melatonin.Melatonin play important role in regulating seasonal rhythms and circadian rhythms,while melatonin is a potent free radical scavenger with a strong ability to scavenge reactive oxygen species.In recent years,studies have found that melatonin can reduce the damage of chemotherapy drugs to normal tissues and organs.In this study,we used 3 mg/kg epirubicin injection for 20 days to establish a mouse injury model,and found that epirubicin significantly reduced the body weight and the weight of the uterus and ovaries,as well as the litter size of the mice.The 60 mg/kg melatonin supplement reduced the effect of epirubicin on mice.We also found that melatonin can reduce the decrease in estrogen and progesterone concentrations in the serum of mice caused by epirubicin and the decrease of the number of follicles in the mouse ovary.It is mean that melatonin reduces the influences of epirubicin in ovarian function.Subsequent experiments showed that epirubicin up-regulated the transcription of the pro-apoptotic genes p53,Caspase9,and Bax in the ovary,and down-regulated the transcription of the anti-apoptotic gene Bcl-2,while melatonin supplementation significantly down-regulated p53,Caspase3,and Caspase9 and up-regulated the transcription of Bcl-2,Bcl2l1.It is mean that melatonin inhibits apoptosis in the ovary caused by epirubicin.Caspase12 and C/EBP-homologous protein(Chop)are specific molecules for apoptosis induced by endoplasmic reticulum stress.Melatonin also reduced the expression of Caspase12 and Chop induced by epirubicin.In addition,we found that epirubicin significantly up-regulated the transcription of superoxide dismutase 1(Sod1),Sod2,and peroxidase(Cat)in mouse ovaries,while melatonin supplementation significantly up-regulated the transcription of antioxidant enzymes..Subsequent detection of reactive oxygen species showed that melatonin reduced the increase in reactive oxygen species caused by epirubicin.In summary,melatonin can reduce the damage of epirubicin to the ovary.Epirubicin can induce endoplasmic reticulum stress,induce apoptosis,and ultimately affect ovarian function and the fertility by increasing the reactive oxygen species in the ovary.While melatonin can reduce the damage of epirubicin to the ovary by removing the reactive oxygen species in the ovary through its antioxidant function.