FISETIN AMELIORATES SENSORY AND MOTOR DEFICITS IN CISPLATIN-INDUCED PERIPHERAL NEUROPATHY: THE ROLE OF PI3K/AKT PATHWAY

Cisplatin (Cis) is a chemotherapeutic agent used to treat solid organ tumors. The dose-limiting side effect of cisplatin is chemotherapy-induced peripheral neuropathy (CIPN). Fisetin (F) is a naturally occurring flavonoid with antioxidant, anti-inflammatory, and neuroprotective effects. Previous studies have shown controversial results regarding the effect of Fisetin on the PI3K/Akt pathway. This study aimed to explore the protective effects of Fisetin in CIPN and the role of the PI3K/Akt pathway in this effect.
Forty-two male Sprague-Dawley rats were divided into 6 groups: Control, Cis, Cis+F (10, 20, and 40 mg/kg) and Cis+F20+ANT (LY294002, 0.3 mg/kg). CIPN was induced by i.p. administrations of cisplatin (3 mg/kg/week for 5 weeks). Body weight, mechanical allodynia, and cold allodynia assessments were conducted at baseline (before drug administration) and on the 6th day following each drug administration. Rotarod was performed at baseline and at the end of the drug administration period.
Cisplatin administration significantly impaired motor coordination and increased mechanical and cold sensitivity compared to control on day 21 and onward. Fisetin treatment improved those deficits in a dose-dependent effect with 20 mg/kg being the optimal dose. The protective effect of Fisetin (20 mg/kg) was partially reversed with LY294002, demonstrating the involvement of the PI3K/Akt pathway in the protective effects of Fisetin. These findings suggest that Fisetin has therapeutic potential for CIPN via the PI3K/Akt pathway. Supported by Eskisehir Osmangazi University “Scientific Research Projects” Commission (TTU-2025-3312).