Cancer is a critical health problem, and chemotherapy administration is mandatory for its eradication. However, chemotherapy like doxorubicin (Dox) has serious side-effects including cognitive impairment or chemo brain. Melatonin is a neuroprotective agent that has antioxidant, and anti-inflammatory effects. We aimed to explore melatonin's effect on Dox-induced chemo brain to discover new mechanisms associated with Dox-induced neurotoxicity and try to prevent its occurrence. Thirty-two male albino rats had been equally divided into four groups; control, melatonin-administrated, Dox-induced chemo brain, and melatonin + Dox treated. On the 9th day, brain had been excised after scarification and had been assessed for reactive oxygen species measurement, histopathological analysis, immunohistochemical, gene and protein expressions for the nuclear factor erythroid 2-related factor 2 (Nrf2), p53 and Silent information regulator 2 homolog 1 (SIRT1). Our results show that melatonin coadministration diminished Dox induced hippocampal and prefrontal cortex (PFC) cellular degeneration. It alleviated Nitric Oxide (NO) level and reversed the decline of antioxidant enzyme activities. It also upregulated Nrf2, SIRT1 and downregulated p53 gene expression in rats receiving Dox. Moreover, melatonin elevated the protein expression level of Nrf2, SIRT1 and reduced p53 corresponding to immunohistochemical results. The data suggested that melatonin can mitigate Dox-induced neurotoxicity by aggravating the endogenous antioxidants and inducing neurogenesis through activation of Nrf2/p53–SIRT1signaling pathway in adult rats' PFC. These effects were associated with Nrf2, SIRT1 activation and p53 inhibition. This could be guidance to add melatonin as an adjuvant supplement to Dox regimens to limit its adverse effect on the brain function.

Cisplatin (cis-diamminedichloroplatinum II) (CDDP) is an FDA approved anticancer therapy that is commonly used in women’s cancer treatment protocols, such as breast, cervical, endometrial, and gestational trophoblastic cancers. Premature ovarian insufficiency/failure is a well-known long-term risk of chemotherapy including CDDP in women. Granulosa cells (GCs) are an essen-tial ovarian cell type that promotes oocyte growth and is crucial for ovarian reproductive function. Many types of chemotherapeutic agents, such as CDDP, could induce GCs apoptosis, which could result in ovarian failure. Hyperoside (HYP) is a flavonoid known for its beneficial phar-macological properties, including anti-inflammatory and antiapoptotic effects. Hence the current work aimed to evaluate the potential cytoprotective impact of HYP on CDDP-induced cytotoxicity in a human ovarian GCs cell line model. Forty-eight-hour exposure to 5-10µM CPPD resulted in reduction of GCs viability in a dose-dependent manner. HYP (40µM) was found to ameliorate this CPPD-induced effect on GCs viability. CPPD in a concentration-dependent way, dramatically reduced cellular ATP, mitochondrial activities, cellular progesterone, and estradiol secretion. It also increased oxidative stress markers, Akt kinase activity, cytochrome c levels, caspase -3.-8.-9, and Bax/Bcl2 ratio. These cytotoxic effects of CDDP on the treated GCs, were mitigated to varying degrees by HYP (40 µM). In conclusion, CDDP-induced cytotoxic effects on GCs seem to be the possible underlying cellular and molecular mechanisms of CDDP-induced ovarian insufficien-cy/failure. The study also demonstrated the therapeutic potential of HYP in mitigating CDDP-induced ovarian injury. Further studies are warranted to investigate the potential benefit of HYP as an adjuvant to CDDP treatment protocols to avoid adverse ovarian effects.