Protective properties of glycogen synthase kinase-3 inhibition against doxorubicin-induced oxidative damage to mouse ovarian reserve

A. In response to doxorubicin-induced stress conditions, the cell responds by activating the adaptive defense system, thereby triggering the phosphorylation of GSK-3β at serine 9, resulting in an increase in the inhibition of GSK-3. The inhibited GSK-3 rescues Nrf2 from proteasomal degradation by suppressing the ubiquitination of Nrf2. The rescued Nrf2 is then translocated into the nucleus to activate the transcription of antioxidant genes, which prevents the generation of reactive oxygen species, leading to an increase in cell survival, a decrease in ovarian tissue damage and the maintenance of ovarian function. B. When the doxorubicin-induced toxicity is not reversed or is prolonged, the cellular adaptive defense mechanism against oxidative stress becomes decompensated by the exhaustion of the serine 9 phosphorylation of GSK-3β, resulting in a decrease in inactive GSK-3, followed by the ubiquitination and proteasomal degradation of Nrf2, a reduction in the Nrf2 that is translocated into the nucleus, a decrease in the transcription of antioxidant genes, an increase in the accumulation of reactive oxygen species, eventually leading to oxidative ovarian tissue damage and to a subsequent decrease in ovarian function •The inhibition of GSK-3 attenuates the DOX-induced increase in oxidative stress markers.•The inhibition of GSK-3 recovers low Nrf2 protein from DOX toxicity in the mouse ovary.•The inhibition of GSK-3 abrogates DOX toxicity on ovarian folliculogenesis.•The inhibition of GSK-3 protects the ovarian follicle pool against DOX-induced apoptosis. Chemotherapy induces ovarian failure in female children and young female cancer survivors. It has been shown that doxorubicin (DOX), an antitumor drug of the anthracycline group, causes gonadotoxicity via the stimulation of oxidative stress. The inhibition of glycogen synthase kinase-3 (GSK-3) was reported to be able to regulate oxidative stress. The present study assessed whether GSK-3 inhibition confers protection to the ovary against DOX-induced oxidative stress damage. An intraperitoneal injection of DOX was used to induce oxidative damage in the mouse ovary, while the inhibition of GSK-3 was achieved by the administration of SB216763, a small and potent GSK-3 inhibitor. DOX increased the mRNA expression levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the antioxidant genes heme-oxygenase-1 (HO-1) and catalase (CAT), while reducing the levels of glutathione peroxidase (GSH-Px) and superoxi