REPURPOSING CENOBAMATE FOR CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY: A PRECLINICAL COMPARISON WITH GABAPENTIN

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity of cisplatin (CIS) with limited treatment options. We hypothesized that cenobamate (CEN), through dual action on voltage-gated sodium channels and GABAA receptors, would produce analgesic and motor-restorative effects compared with gabapentin (GBP) in a CIS-induced peripheral neuropathy model. Male Sprague-Dawley rats (n=30) received CIS (3 mg/kg, ip) weekly for five weeks to induce peripheral neuropathy, then rats were allocated to four groups: Control, CIS only, CIS+CEN (CEN; 10 mg/kg), and CIS+GBP (GBP; 30 mg/kg). Treatments were administered daily; days 37 to 45. Peripheral neuropathy was reassessed at baseline and on days 35, 37, 45, and 52 using mechanical plantar test, acetone drop test, thermal plantar test, rotarod performance, and footprint analysis. On day 59, rats were euthanized to collect DRG for histopathological and immunohistochemical (Caspase 3, eNOS, IL-1β) evaluation. CIS induced significant mechanical and thermal hypersensitivity on day 35 (p<0.01). CEN reversed mechanical allodynia (on days 37 and 45; p<0.001 vs CIS only and CIS+GBP), improved thermal hyperalgesia acutely (on day 37; p<0.05 vs. CIS+GBP), and restored motor coordination in rotarod (on day 45; p<0.05 vs. day 35). GBP showed mild, delayed relief of mechanical allodynia and minimal motor improvement. Neither drug affected cold allodynia. CEN demonstrated greater acute and subacute efficacy than GBP in alleviating sensory impairments and partial improvement of immunohistochemical markers. These findings highlight CEN’s potential for repurposing in CIPN, though long-term and translational studies are warranted.Supported by Eskisehir Osmangazi University “Scientific Research Projects” Commission (TDK-2024-3115).