Differential Morphological and Biochemical Recovery from Chemotherapy-Induced Peripheral Neuropathy Following Paclitaxel, Ixabepilone, or Eribulin Treatment in Mouse Sciatic Nerves

B. M. Cook, K. M. Wozniak, D. A. Proctor, R. B. Bromberg, Y. Wu, Barbara Slusher, B. A. Littlefield, M. A. Jordan, L. Wilson, Stuart C. Feinstein

Research output: Contribution to journalArticle

Abstract

The reversibility of chemotherapy-induced peripheral neuropathy (CIPN), a disabling and potentially permanent side effect of microtubule-targeting agents (MTAs), is becoming an increasingly important issue as treatment outcomes improve. The molecular mechanisms regulating the variability in time to onset, severity, and time to recovery from CIPN between the common MTAs paclitaxel and eribulin are unknown. Previously (Benbow et al. in Neurotox Res 29:299–313, 2016), we found that after 2 weeks of a maximum tolerated dose (MTD) in mice, paclitaxel treatment resulted in severe reductions in axon area density, higher frequency of myelin abnormalities, and increased numbers of Schwann cell nuclei in sciatic nerves. Biochemically, eribulin induced greater microtubule-stabilizing effects than paclitaxel. Here, we extended these comparative MTD studies to assess the recovery from these short-term effects of paclitaxel, eribulin, and a third MTA, ixabepilone, over the course of 6 months. Paclitaxel induced a persistent reduction in axon area density over the entire 6-month recovery period, unlike ixabepilone- or eribulin-treated animals. The abundance of myelin abnormalities rapidly declined after cessation of all drugs but recovered most slowly after paclitaxel treatment. Paclitaxel- and ixabepilone- but not eribulin-treated animals exhibited increased Schwann cell numbers during the recovery period. Tubulin composition and biochemistry rapidly returned from MTD-induced levels of α-tubulin, acetylated α-tubulin, and end-binding protein 1 to control levels following cessation of drug treatment. Taken together, sciatic nerve axons recovered more rapidly from morphological effects in eribulin- and ixabepilone-treated animals than in paclitaxel-treated animals and drug-induced increases in protein expression levels following paclitaxel and eribulin treatment were relatively transient.

Original languageEnglish (US)
Pages (from-to)677-692
Number of pages16
JournalNeurotoxicity Research
Volume34
Issue number3
DOIs
StatePublished - Oct 1 2018

Fingerprint

eribulin
Chemotherapy
Peripheral Nervous System Diseases
Sciatic Nerve
Paclitaxel
Drug Therapy
Recovery
Microtubules
Maximum Tolerated Dose
Animals
Tubulin
Axons
Therapeutics
Schwann Cells
Myelin Sheath
Cells
Pharmaceutical Preparations
Drug therapy
ixabepilone
Biochemistry

Keywords

  • Chemotherapy-induced peripheral neuropathy
  • Eribulin
  • Ixabepilone
  • Microtubules
  • Paclitaxel
  • Sciatic nerve

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

Differential Morphological and Biochemical Recovery from Chemotherapy-Induced Peripheral Neuropathy Following Paclitaxel, Ixabepilone, or Eribulin Treatment in Mouse Sciatic Nerves. / Cook, B. M.; Wozniak, K. M.; Proctor, D. A.; Bromberg, R. B.; Wu, Y.; Slusher, Barbara; Littlefield, B. A.; Jordan, M. A.; Wilson, L.; Feinstein, Stuart C.

In: Neurotoxicity Research, Vol. 34, No. 3, 01.10.2018, p. 677-692.

Research output: Contribution to journalArticle

Cook, B. M. ; Wozniak, K. M. ; Proctor, D. A. ; Bromberg, R. B. ; Wu, Y. ; Slusher, Barbara ; Littlefield, B. A. ; Jordan, M. A. ; Wilson, L. ; Feinstein, Stuart C. / Differential Morphological and Biochemical Recovery from Chemotherapy-Induced Peripheral Neuropathy Following Paclitaxel, Ixabepilone, or Eribulin Treatment in Mouse Sciatic Nerves. In: Neurotoxicity Research. 2018 ; Vol. 34, No. 3. pp. 677-692.
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