Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat

Guido Cavaletti, Alessandra Gilardini, Annalisa Canta, Laura Rigamonti, Virginia Rodriguez-Menendez, Cecilia Ceresa, Paola Marmiroli, Mario Bossi, Norberto Oggioni, Maurizio D'Incalci, Roland De Coster

Research output: Contribution to journalArticle

Abstract

Bortezomib is a new proteasome inhibitor with a high antitumor activity, but also with a potentially severe peripheral neurotoxicity. To establish a preclinical model and to characterize the changes induced on the peripheral nerves, dorsal root ganglia (DRG) and spinal cord, bortezomib was administered to Wistar rats (0.08, 0.15, 0.20, 0.30 mg/kg/day twice [2q7d] or three times [3q7d] weekly for a total of 4 weeks). At baseline, on days 14, 21 and 28 after the beginning the treatment period and during a 4-week follow-up period sensory nerve conduction velocity (SNCV) was determined in the tail of each animal. Sciatic nerve, DRG and spinal cord specimens were processed for light and electron microscope observations and morphometry. At the maximum tolerated dose bortezomib induced a significant reduction in SNCV, with a complete recovery at the end of the follow-up period. Sciatic nerve examination and morphometric determinations demonstrated mild to moderate pathological changes, involving predominantly the Schwann cells and myelin, although axonal degeneration was also observed. Bortezomib-induced changes were also observed in DRG and they were represented by satellite cell intracytoplasmatic vacuolization due to mitochondrial and endoplasmic reticulum damage, closely resembling the changes observed in sciatic nerve Schwann cells. Only rarely did the cytoplasm of DRG neurons has a dark appearance and clear vacuoles occurring in the cytoplasm. Spinal cord was morphologically normal. This model is relevant to the neuropathy induced by bortezomib in the treatment of human malignancies and it could be useful in increasing our knowledge regarding the mechanisms underlying bortezomib neurotoxicity.

Original languageEnglish
Pages (from-to)317-325
Number of pages9
JournalExperimental Neurology
Volume204
Issue number1
DOIs
Publication statusPublished - Mar 2007

Fingerprint

Spinal Ganglia
Sciatic Nerve
Spinal Cord
Schwann Cells
Neural Conduction
Cytoplasm
Neurons
Proteasome Inhibitors
Maximum Tolerated Dose
Myelin Sheath
Vacuoles
Peripheral Nerves
Endoplasmic Reticulum
Bortezomib
Tail
Wistar Rats
Electrons
Light
Neoplasms

Keywords

  • Bortezomib
  • Dorsal root ganglia
  • Experimental
  • Peripheral neuropathy
  • Proteasome inhibitors
  • Rat

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

Cavaletti, G., Gilardini, A., Canta, A., Rigamonti, L., Rodriguez-Menendez, V., Ceresa, C., ... De Coster, R. (2007). Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat. Experimental Neurology, 204(1), 317-325. https://doi.org/10.1016/j.expneurol.2006.11.010

Bortezomib-induced peripheral neurotoxicity : A neurophysiological and pathological study in the rat. / Cavaletti, Guido; Gilardini, Alessandra; Canta, Annalisa; Rigamonti, Laura; Rodriguez-Menendez, Virginia; Ceresa, Cecilia; Marmiroli, Paola; Bossi, Mario; Oggioni, Norberto; D'Incalci, Maurizio; De Coster, Roland.

In: Experimental Neurology, Vol. 204, No. 1, 03.2007, p. 317-325.

Research output: Contribution to journalArticle

Cavaletti, G, Gilardini, A, Canta, A, Rigamonti, L, Rodriguez-Menendez, V, Ceresa, C, Marmiroli, P, Bossi, M, Oggioni, N, D'Incalci, M & De Coster, R 2007, 'Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat', Experimental Neurology, vol. 204, no. 1, pp. 317-325. https://doi.org/10.1016/j.expneurol.2006.11.010
Cavaletti G, Gilardini A, Canta A, Rigamonti L, Rodriguez-Menendez V, Ceresa C et al. Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat. Experimental Neurology. 2007 Mar;204(1):317-325. https://doi.org/10.1016/j.expneurol.2006.11.010
Cavaletti, Guido ; Gilardini, Alessandra ; Canta, Annalisa ; Rigamonti, Laura ; Rodriguez-Menendez, Virginia ; Ceresa, Cecilia ; Marmiroli, Paola ; Bossi, Mario ; Oggioni, Norberto ; D'Incalci, Maurizio ; De Coster, Roland. / Bortezomib-induced peripheral neurotoxicity : A neurophysiological and pathological study in the rat. In: Experimental Neurology. 2007 ; Vol. 204, No. 1. pp. 317-325.
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