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

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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.

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Acknowledgements

We are grateful to Ben Lopez, Mary Raven, Nichole LaPointe, Jennifer Smith, Sarah Benbow, and Rebecca Best for their valuable discussions. We also acknowledge the use of the NRI-MCDB Microscopy Facility and the Spectral Laser Scanning Confocal supported by the Office of the Director, National Institutes of Health of the NIH under award no. S10OD010610.

Funding

These studies were supported by grants from EISAI (to SCF, BSS, MAJ, and LW) and NIH grant no. R01CA161056 (to B.S. Slusher).

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Authors and Affiliations

  1. Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, 93106, USA

    B. M. Cook, M. A. Jordan, L. Wilson & Stuart C. Feinstein

  2. Department of Biomolecular Sciences and Engineering, University of California Santa Barbara, Santa Barbara, CA, 93016, USA

    B. M. Cook

  3. Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    K. M. Wozniak, Y. Wu & B. S. Slusher

  4. Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, 93016, USA

    D. A. Proctor, R. B. Bromberg, M. A. Jordan, L. Wilson & Stuart C. Feinstein

  5. Scientific Administration, Eisai Research Institute, Andover, MA, 01810, USA

    B. A. Littlefield

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Correspondence to Stuart C. Feinstein.

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Experimental protocols were approved by the Institutional Animal Care and Use Committee of John Hopkins University and adhered to all applicable institutional and governmental guidelines for humane treatment set forth in the Guide for the Care and Use of Laboratory Animals (Office of Laboratory Animal Welfare, NIH).

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Cook, B.M., Wozniak, K.M., Proctor, D.A. et al. Differential Morphological and Biochemical Recovery from Chemotherapy-Induced Peripheral Neuropathy Following Paclitaxel, Ixabepilone, or Eribulin Treatment in Mouse Sciatic Nerves. Neurotox Res 34, 677–692 (2018). https://doi.org/10.1007/s12640-018-9929-8

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