Effects of Hesperidin and Naringenin on Apoptotic Markers in Cisplatin-Induced Nephrotoxicity in Male Wistar Albino Rats

Cisplatin is a widely used platinum-based chemotherapeutic agent for the treatment of several solid malignancies, including testicular, ovarian, bladder, lung, and head-and-neck cancers. However, its clinical use is frequently limited by nephrotoxicity, a major dose-limiting adverse effect affecting approximately 20–30% of patients. This study evaluated the protective effects of hesperidin and naringenin on apoptotic markers in cisplatin-induced nephrotoxicity in male Wistar rats. Thirty-six male Wistar rats were randomly allocated into six groups (n = 6): normal control, cisplatin control, vitamin C reference control (200 mg/kg), hesperidin-treated (200 mg/kg), naringenin-treated (200 mg/kg), and combined hesperidin–naringenin-treated (200 mg/kg each). Treatments were administered orally for 28 days, and nephrotoxicity was induced in Groups B–F by a single intraperitoneal injection of cisplatin (20 mg/kg) on day 28. Renal apoptotic markers, including caspase-3, caspase-9, Bax, and Bcl-2, were assessed. Cisplatin significantly increased renal caspase-3, caspase-9, and Bax levels while significantly reducing Bcl-2 expression compared with the normal control group (p < 0.05), indicating activation of mitochondrial apoptosis. Pretreatment with hesperidin, naringenin, and their combination significantly reduced caspase-3, caspase-9, and Bax expression and restored Bcl-2 levels relative to the cisplatin control group (p < 0.05). The combined treatment produced the most pronounced protective effect. Hesperidin and naringenin effectively attenuated cisplatin-induced nephrotoxicity by suppressing pro-apoptotic markers and enhancing the anti-apoptotic protein Bcl-2 (p < 0.05). Their protective actions, particularly when combined, suggest potential utility as adjunctive agents for mitigating cisplatin-associated renal toxicity through inhibition of mitochondrial-dependent apoptosis. Keywords: Cisplatin; Nephrotoxicity; Hesperidin; Naringenin; Apoptosis; Oxidative Stress.