Dose-Dependent Neuroprotective Effect of Hesperidin Against Vincristine-Induced Neuropathy

Abstract Background Vincristine-induced peripheral neuropathy (VIPN) is a common, dose-limiting complication of chemotherapy for which no effective preventive treatment currently exists. Oxidative stress is a key mechanism underlying vincristine neurotoxicity, and hesperidin, a citrus-derived flavonoid with well-documented antioxidant and neuroprotective properties, represents a promising candidate for its prevention. Objective This study evaluated the dose-dependent preventive effects of hesperidin on VIPN in mice, assessed through thermal nociceptive behavior and serum oxidative stress biomarkers. Methods Fifty male mice were randomly divided into five groups (n = 10/group): vehicle + saline, vehicle + vincristine (0.1 mg/kg/day, i.p., 10 days), and vincristine co-administered with hesperidin (25, 50, or 100 mg/kg/day, i.p.). Thermal nociceptive latency was assessed using the Hot Plate test at baseline and on days 6, 10, 15, and 19. Serum malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured at the end of the protocol, and body weight was monitored throughout. Results Vincristine administration induced significant thermal hyperalgesia from day 10 onward, accompanied by significantly elevated serum MDA and reduced TAC compared with controls ( P < 0.001). Hesperidin at 25 and 50 mg/kg did not significantly modify these outcomes; however, hesperidin at 100 mg/kg significantly preserved nociceptive latency and normalized serum MDA and TAC levels relative to the vincristine-only group ( P < 0.001). No significant differences in body weight gain were observed among the experimental groups. Conclusion Hesperidin exerts a dose-dependent protective effect against vincristine-induced peripheral neuropathy, with 100 mg/kg being the most effective dose, likely mediated through attenuation of oxidative stress. These findings support further investigation of hesperidin as a candidate adjunct for the prevention of chemotherapy-induced peripheral neuropathy.