Experimental epothilone B neurotoxicity: Results of in vitro and in vivo studies

Alessia Chiorazzi, Gabriella Nicolini, Annalisa Canta, Norberto Oggioni, Roberta Rigolio, Giacomo Cossa, Raffaella Lombardi, Ilaria Roglio, Ilaria Cervellini, Giuseppe Lauria, Roberto Cosimo Melcangi, Roberto Bianchi, Donatella Crippa, Guido Cavaletti

Research output: Contribution to journalArticlepeer-review

Abstract

Epothilones are a novel class of microtubule-targeting anticancer agents that are neurotoxic. In this study, we investigated the epothilone B toxic effect in vitro and we characterized in vivo the general and neurological side effects of epothilone B administration in Wistar and Fischer rats. The in vitro experiments made it possible to explore a wide concentration range (0.1 nM-1 μM) and evidenced a dose-dependent effect of epothilone B exposure on neuron neurite elongation. This dose-dependent neurotoxic effect was confirmed in both in vivo studies performed on two different rat strains at the neurophysiological, behavioral and pathological levels in the dose range 0.25-1.5 mg/kg iv weekly × 4 weeks and tubulin hyper-polymerization was demonstrated in sciatic nerve specimens. These are the first studies of the neurological effects of epothilone B and they can provide a basis for extending pre-clinical investigation to other members of the epothilone family.

Original languageEnglish
Pages (from-to)270-277
Number of pages8
JournalNeurobiology of Disease
Volume35
Issue number2
DOIs
Publication statusPublished - Aug 2009

Keywords

  • Epothilone B
  • In vitro
  • In vivo
  • Peripheral neuropathy
  • Toxicity
  • Tubulin

ASJC Scopus subject areas

  • Neurology

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