Toxic Effects of Bortezomib on Primary Sensory Neurons and Schwann Cells of Adult Mice

Albert Alé, Jordi Bruna, Mireia Herrando, Xavier Navarro, Esther Udina

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

© 2015, Springer Science+Business Media New York. The proteasome inhibitor bortezomib is nowadays first line treatment for multiple myeloma. One of the most significant adverse events is peripheral neuropathy, mainly involving sensory nerve fibers that can lead to withdrawal of treatment. Here we develop an in vitro model to compare the effects of bortezomib on primary sensory neurons and Schwann cells of adult mice. We observed that sensory neurons were more susceptible to bortezomib, and their viability was reduced at a concentration of 6 nM, that only affected Schwann cell proliferation but not survival. At concentration higher than 8 nM Schwann cell viability was also compromised. Already at low concentrations, surviving neurons presented alterations in neurite outgrowth. Neurites were shorter and had dystrophic appearance, with alterations in neurofilament staining. However, neurites were able to regrow after removing bortezomib from the medium, thus indicating reversibility of the neurotoxicity. We confirmed in vivo that bortezomib produced alterations in neurofilaments at early stages of the treatment. After an accumulated dose of 2 mg/kg bortezomib, dorsal root ganglia neurons of treated animals showed accumulation of neurofilament in the soma. To evaluate if this accumulation was related with alterations in axonal transport, we tested the ability of sensory neurons to retrogradely transport a retrotracer applied at the distal nerve. Treated animals showed a lower amount of retrotracer in the soma 24 h after its application to the tibial nerve, therefore suggesting that axonal transport was affected by bortezomib.
Original languageEnglish
Pages (from-to)430-440
JournalNeurotoxicity Research
Volume27
DOIs
Publication statusPublished - 1 May 2015

Keywords

  • Axonal transport
  • Bortezomib
  • Neuron
  • Proteasome inhibition
  • Schwann cell

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