Merck
  • Home
  • Search Results
  • Toxic effects of bortezomib on primary sensory neurons and Schwann cells of adult mice.

Toxic effects of bortezomib on primary sensory neurons and Schwann cells of adult mice.

Neurotoxicity research (2015-01-16)
Albert Alé, Jordi Bruna, Mireia Herrando, Xavier Navarro, Esther Udina
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Potassium, chunks (in mineral oil), 98% trace metals basis
Sigma-Aldrich
Ethylenediaminetetraacetic acid, 99.995% trace metals basis
Sigma-Aldrich
Potassium hydride, 30 wt % dispersion in mineral oil
Sigma-Aldrich
Ethylenediaminetetraacetic acid, ≥98.0% (KT)
Sigma-Aldrich
Ethylenediaminetetraacetic acid, BioUltra, ≥99.0% (KT)
Sigma-Aldrich
Ethylenediaminetetraacetic acid disodium salt solution, BioUltra, for molecular biology, pH 8.0, ~0.5 M in H2O
Sigma-Aldrich
Osmium tetroxide solution, suitable for electron microscopy, 2% in H2O
Sigma-Aldrich
Osmium tetroxide solution, suitable for electron microscopy, 4% in H2O
Sigma-Aldrich
Sucrose, puriss., meets analytical specification of Ph. Eur., BP, NF
Millipore
Sucrose, ACS reagent, suitable for microbiology, ≥99.0%
Sigma-Aldrich
Sucrose, BioUltra, for molecular biology, ≥99.5% (HPLC)
Sigma-Aldrich
Toluidine Blue, for microscopy (Hist., Vit.)
Sigma-Aldrich
Sucrose, meets USP testing specifications
Sigma-Aldrich
Sucrose, BioXtra, ≥99.5% (GC)
Sigma-Aldrich
Sucrose, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥99.5% (GC)
Sigma-Aldrich
Sucrose, Grade I, suitable for plant cell culture
Sigma-Aldrich
Sucrose, Grade II, suitable for plant cell culture
Sigma-Aldrich
Ethylenediaminetetraacetic acid solution, 0.02% in DPBS (0.5 mM), sterile-filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
L-(−)-Dithiothreitol, ≥95%
Sigma-Aldrich
Ethylenediaminetetraacetic acid, ACS reagent, 99.4-100.6%, powder
Sigma-Aldrich
Ethylenediaminetetraacetic acid, anhydrous, crystalline, BioReagent, suitable for cell culture
Sigma-Aldrich
Ethylenediaminetetraacetic acid, purified grade, ≥98.5%, powder
Sigma-Aldrich
Ethylenediaminetetraacetic acid, BioUltra, anhydrous, ≥99% (titration)
Sigma-Aldrich
Sucrose, ≥99.5% (GC)
Sigma-Aldrich
Sucrose, ACS reagent
Sigma-Aldrich
Sucrose, for molecular biology, ≥99.5% (GC)
Sigma-Aldrich
Sucrose, ≥99.5%
Supelco
Sucrose, analytical standard, for enzymatic assay kit SCA20
Sigma-Aldrich
Potassium, cubes (in mineral oil), 99.5% trace metals basis
Sigma-Aldrich
Potassium hydride, in paraffin