ArticleBritish journal of anaesthesia2026
Neuronal toxicity and recovery from early bortezomib-induced neuropathy: blood-nerve barrier dysfunction without dorsal root ganglion damage.
Article in British journal of anaesthesia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundUse of the first in class proteasome inhibitor bortezomib (BTZ) is highly effective in the treatment of multiple myeloma. However, its long-term use is limited by the fact that most treated patients develop painful polyneuropathy. In some of the treated patients, pain resolves with time; in others, it persists, with the underlying mechanisms poorly understood. One prerequisite for neural toxicity is the ability of a drug to penetrate the blood-nerve barrier.
methodsWe analysed the pathways involved in early BTZ-induced polyneuropathy development and its resolution in rats and in patients with myeloma using pain behaviour, barrier analysis, transcriptomics, immunohistochemistry, and clinical data.
resultsOne cycle of BTZ elicited transient tactile and cold allodynia in rats. Transcriptomic signature and network analysis revealed regulation of circadian, extracellular matrix, and immune genes within the nerve and modest changes in the dorsal root ganglia. Recovery processes resealed the small molecule leakiness of the perineurial barrier, reversed axonal swelling, and normalised fibre density in the skin. Expression of the microtubule-associated cytoskeletal protein cortactin matched this process in the perineurium. Netrin-1 as a known barrier sealer was also upregulated in pain resolution in nerve and skin. In patients with painful BTZ-induced polyneuropathy, skin innervation was reduced and netrin-1 was unchanged, compatible with the persistence of pain.
conclusionsIn summary, our data demonstrate that early bortezomib toxicity targets mainly peripheral nerves and indicate that pain resolution could be supported by protective growth factors such as netrin-1 for remodelling of the extracellular matrix and neuronal barriers. CLINICAL
trial registrationDRKS00025422.
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