Gastrodin alleviates bortezomib-induced peripheral neuropathy by inhibiting NF-κB/NLRP3 pathway-mediated microglial inflammation.

Background: Multiple chemotherapeutic agents exhibit neurotoxicity. For example, bortezomib (BTZ)-induced peripheral neuropathy (BIPN) is characterized by sensory abnormalities and pain, and effective treatment strategies are currently lacking. This study aimed to investigate the alleviating effects of gastrodin (GAS) on BIPN and its potential mechanisms. Methods: Behavioral tests were used to assess changes in pain thresholds across all groups of mice. Hematoxylin-eosin staining, transmission electron microscopy, and immunofluorescence were used to evaluate peripheral nerve injury and the activation of spinal glial cells. ELISA was used to measure the levels of inflammatory cytokines. Proteins associated with the NF-κB/NLRP3 pathway were examined using Western blot. Results: GAS significantly improved thermal and mechanical hyperalgesia in BIPN mice. Moreover, BTZ can cause loss of intraepidermal nerve fibers, microstructural damage to the dorsal root ganglia, a disorganized arrangement of sciatic nerve fibers, and demyelination, all of which were effectively reversed by GAS treatment. Further investigation revealed that GAS significantly suppressed the upregulation of IBA-1 and GFAP in the spinal cord of BIPN mice, and the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were concurrently reduced. IBA-1/IL-1β and IBA-1/TNF-α double-labeled positive cells were significantly increased in BIPN mice, and GAS intervention reduced the number of these double-labeled cells. In addition, GAS significantly inhibited aberrant NF-κB signaling and upregulation of NLRP3 inflammasome-related proteins of BIPN mice. Conclusions: GAS may alleviate BIPN by suppressing microglia-mediated neuroinflammatory responses, and the NF-κB/NLRP3 inflammasome signaling pathway appears to be involved in this process.