Chemotherapy-induced peripheral neuropathy remains a significant side effect of cancer treatment, often requiring dose reductions or even discontinuation of therapy. Paclitaxel (PTX), a widely used chemotherapeutic agent for solid tumors, is particularly neurotoxic, and no effective treatment exists for paclitaxel-induced peripheral neuropathy (PIPN). Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone and non-histone proteins, including transcription factors and cytoskeletal components. This study evaluates the HDAC6 inhibitor ITF6475 for its potential to prevent PIPN and compares its effects with ricolinostat, a well-established HDAC6 inhibitor previously studied in cisplatin-induced neuropathy models. Female C57BL/6 mice received PTX vehicle (VEH) or PTX (70 mg/kg intravenously, once per week for four weeks), and the remaining four groups received PTX with co-treatment of either ricolinostat (50 mg/kg orally, daily) or ITF6475 (1, 6, or 12.5 mg/kg orally, daily). Neurophysiological assessments at the end of treatment showed a significant reduction in caudal sensory nerve action potential amplitude across all PTX-treated groups compared to the VEH group. At the same time, PTX treatment led to the development of mechanical allodynia. However, co-treatment with the HDAC6 inhibitor prevented significant differences compared to the VEH group. PTX-induced reduction in intraepidermal nerve fiber density was significantly prevented in the PTX + ITF6475 (1 mg/kg) group, and PTX-induced increase in neurofilament light levels was reduced in all ITF6475 co-treated groups. These findings support the potential of ITF6475 in preventing small fiber damage in a severe, chronic PIPN model.
