Empagliflozin beyond antidiabetic effect: Amelioration of cyclophosphamide-induced testicular toxicity in rats: Orchestrating klotho/Nrf-2/PPAR-γ/NF-κB/Bax/Bcl-2 cues.

Gonadal toxicity is one of the most serious adverse effects associated with chemotherapy, thus affecting patient quality of life. This work aimed to investigate the pleiotropic effects of empagliflozin (EMPA) against testicular toxicity induced by cyclophosphamide (CP) apart from its antidiabetic activity. Rats were distributed among four groups, each 6 animals. Rats in group I received the vehicles, while in group II, animals received CP (100 mg/kg/day; i.p.) starting from day nine and continued for seven days to act as the model group. Furthermore, animals in groups III and IV were administered EMPA either at doses of 10 or 20 mg/kg/day, orally for 15 days, and CP as in group II. EMPA ameliorated testicular damage-related markers elicited by CP with prominent effects to the high dose. EMPA improved testis index, beside modulating serum sex hormones' levels, sperm count, motility, and histopathological alterations, besides, Johnsen's score. Additionally, EMPA upregulated klotho, nuclear factor erythroid 2-related factor 2 (Nrf-2), and hemeoxygenase-1(HO-1), hence modulating oxidative stress status. Likewise, EMPA increased peroxisome proliferator-activated receptor gamma (PPAR-γ) content with suppressing inflammatory axis viz., nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) as well as interleukin (IL)-1β and 6, while increasing IL-10. Furthermore, EMPA enhanced testicular tissue survival by decreasing Bcl-2-associated X (Bax) protein, while elevating B-cell lymphoma 2 (Bcl-2) protein, thus reducing caspase-3 expression. Consequentially, EMPA, through antioxidant, anti-inflammatory, and anti-apoptotic effects, could be nominated as a promising candidate against CP-induced gonadal toxicity.