Histone Deacetylase 6 Inhibitors: Mitigators Of Chemotherapy Induced Peripheral Neuropathy Via The NMNAT2/SARM1 Pathway Modulation

Chemotherapy-induced peripheral neuropathy (CIPN) affects up to 70% of cancer patients during or after treatment, with few neuroprotective therapies available. Histone deacetylase 6 (HDAC6), a cytoplasmic enzyme regulating microtubule stability via non-histone deacetylation, is a promising target for neuroprotection. As a matter of fact, HDAC6 inhibitors (HDAC6i) have shown potential in reducing chemotherapy-induced neurotoxicity. Our in vitro study investigated how HDAC6i protect against neurotoxicity caused by Bortezomib, Oxaliplatin, Paclitaxel, and Vincristine, focusing on the NMNAT2/SARM1 pathway, a possible crossroad in the mechanisms underlying CIPN and neurite degeneration. The effects of HDAC6 inhibitors (Ricolinostat, SW-100, Tubastatin A) were tested in vitro using adult mouse primary sensory neurons to assess neuronal viability and neurite length. Neurons were treated with HDAC6i alone or in combination with Bortezomib, Oxaliplatin, Paclitaxel, and Vincristine at varying concentrations. Non-interference of HDAC6i with the antitumor effects of these drugs was confirmed using MTT assays in various cancer cell lines. Protein expression of NMNAT2 and SARM1 was analyzed by Western blotting, acetylated SARM1 levels were assessed via immunoprecipitation, and SARM1 activity was measured using NAD+/NADH assays. Ricolinostat demonstrated to have the most neuroprotective effects against Bortezomib and Paclitaxel, whilst Tubastatin had the most promising results against Oxaliplatin. No HDAC6i showed to be neuroprotective against Vincristine. Furthermore, no HDAC6i showed interference with their antitumor activity in cancer cell lines. Bortezomib, Oxaliplatin and Paclitaxel reduced NMNAT2 levels, while Vincristine showed no significant effect. More significantly, HDAC6i treatment, alone or combined with chemotherapeutics, increased SARM1 acetylation, potentially contributing to its inhibition and reduced activity. This study shows that HDAC6 inhibitors effectively reduce neurotoxicity caused by Bortezomib, Oxaliplatin, and Paclitaxel, but not Vincristine. HDAC6i increased NMNAT2 levels, reduced SARM1 levels and activity, and enhanced SARM1 acetylation, suggesting modulation of the NMNAT2/SARM1 pathway as a key mechanism of their neuroprotective effects.