Neuronal toxicity and recovery from early bortezomib-induced neuropathy: blood-nerve barrier dysfunction without dorsal root ganglion damage.

Summary

In rats, a single bortezomib cycle caused transient tactile/cold allodynia with blood-nerve barrier leakiness and ECM/circadian/immune gene changes in nerve but only modest DRG changes. Recovery resealed the perineurial barrier, normalized axonal morphology and skin innervation, and paralleled cortactin upregulation and netrin-1 increases. In patients with persistent neuropathic pain, skin innervation was reduced and netrin-1 did not increase, implicating barrier remodeling pathways in resolution.

Key Findings

• Early bortezomib produced transient tactile and cold allodynia in rats with perineurial small-molecule leakiness that resealed during recovery.
• Nerve transcriptomics highlighted circadian, extracellular matrix, and immune gene regulation; DRG changes were modest.
• Cortactin expression in perineurium and netrin-1 levels increased with pain resolution; patients with persistent pain showed reduced skin innervation without netrin-1 increase.

Clinical Implications

Monitoring small-fiber loss and targeting perineurial barrier repair (e.g., netrin-1 pathways or ECM remodeling) may help prevent or reverse chemotherapy-induced neuropathy; anesthesiologists and pain specialists could incorporate barrier-protective strategies alongside dose management.

Limitations

• Human data were correlative and limited in sample depth; causal validation in patients is lacking.
• Temporal window focused on early toxicity; long-term remodeling and dosing regimens were not evaluated.

Future Directions

Test barrier-sealing biologics (e.g., netrin-1 agonism) and ECM-modulatory strategies in preclinical models and early-phase trials; develop biomarkers of perineurial leakiness for patient stratification.