Protective effect of roflumilast on cyclophosphamide-induced ovarian toxicity in rats: role of SIRT1/Nrf2/nF-ĸB pathway.

OBJECTIVE

This study aimed to investigate the possible protective effect of roflumilast (RFL) on cyclophosphamide (CP)-induced ovarian toxicity as well as the possible underlying mechanism.

MATERIAL AND

METHODS

Female Wistar rats received the vehicle (n = 6) or CP (200 mg/kg, i.p.). The other 2 groups (n = 6 for each) were orally pretreated with RFL at dosages of 0.5 and 1 mg/kg, respectively, for 14 days and then after one hour of RFL administration on the 14th day, rats were intraperitoneally administered a single dose of CP. Serum and tissue samples were collected. Biochemical, real-time polymerase chain reaction, histopathological and immunohistopathological examination were carried out.

RESULTS

RFL significantly elevated serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) compared to the CP group. RFL remarkably elevated ovarian contents of Sirtuin-1 (SIRT1), heme oxygenase-1 (HO-1), and reduced nuclear factor-kappa B (NF-ĸb) p65/NF-ĸB ratio as compared to control CP group. Compared to the CP group, RFL significantly elevated Nrf2 gene expression, reduced malondialdehyde (MDA), and elevated the reduced glutathione (GSH) ovarian content. It also reduced the protein expression of TNF-α and caspase-3.

CONCLUSION

It can be concluded that RFL (0.5 and 1 mg/kg) protected rats against CP-induced ovarian toxicity via altering the SIRT1/Nrf2/NF-ĸB pathway, ameliorating histopathological changes in addition to its anti-apoptotic effect.