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Neurofilament light chain: a specific serum biomarker of axonal damage severity in rat models of Chemotherapy-Induced Peripheral Neurotoxicity

  • Organ Toxicity and Mechanisms
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Abstract

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a severe and long-lasting side effect of anticancer therapy, which can severely impair patients’ quality of life. It is a sensory and length-dependent neuropathy, which predominantly affects large myelinated fibers. Easy and reliable monitoring of CIPN in patients is still an unmet clinical need. Since increasing clinical evidence supports the potential use of neurofilament light chain (NfL) as a biomarker of axonal injury, in this study we measured serum NfL levels in animals chronically treated with cisplatin (CDDP) and paclitaxel (PTX), two antineoplastic drugs with different neuronal targets. Wistar rats were treated with CDDP (2 mg/kg i.p. twice/week for 4 weeks) or PTX (10 mg/kg i.v. once/week for 4 weeks). Repeated serum NfL quantification was obtained using the Single Molecule Array (Simoa) technology. The onset and progression of peripheral neurotoxicity were evaluated through neurophysiology, morphological assessments and intraepidermal nerve fibers density quantification. Our results showed that serum NfL measurements correlated with the severity of axonal damage. In fact, both treatments induced serum NfL increase, but higher levels were evidenced in PTX-treated animals, compared with CDDP-treated rats, affected by a milder neurotoxicity. Notably, also the timing of the NfL level increase was associated with the severity of morphological and functional alterations of axonal structure. Therefore, NfL could be a useful biomarker for axonal damage in order to follow the onset and severity of axonal degeneration and possibly limit the occurrence of serious PNS disease.

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Acknowledgements

GC is a recipient of a research grant from Associazione Italiana Ricerca sul Cancro (AIRCProgettoIG2016Id.18631), and GC and CM are supported by the Italian PRIN Grant (# 2017ZFJCS3). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931) and the UK Dementia Research Institute at UCL.

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Author notes

  1. Cristina Meregalli and Giulia Fumagalli authors contributed equally to this work.

Authors and Affiliations

  1. Experimental Neurology Unit, School of Medicine and Surgery; NeuroMI (Milan Center for Neuroscience), University of Milano-Bicocca, Monza, MB, Italy

    Cristina Meregalli, Giulia Fumagalli, Paola Alberti, Annalisa Canta, Alessia Chiorazzi, Laura Monza, Eleonora Pozzi, Valentina Alda Carozzi, Guido Cavaletti & Paola Marmiroli

  2. Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

    Kaj Blennow & Henrik Zetterberg

  3. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    Kaj Blennow & Henrik Zetterberg

  4. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK

    Henrik Zetterberg

  5. UK Dementia Research Institute at UCL, London, UK

    Henrik Zetterberg

Authors
  1. Cristina Meregalli
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  2. Giulia Fumagalli
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  3. Paola Alberti
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  5. Alessia Chiorazzi
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  6. Laura Monza
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Contributions

All authors made substantial contributors to design, and/or acquisition of data, and/or analysis and interpretation of data. Individual contributors: conceived of study and design: CM, GF, GC, PM. Performed research: all authors. Acquisition, analysis and interpretation data: CM, GF, KB, HZ. Manuscript writing: CM, GF, GC, PM and HZ. Revising the manuscript for important intellectual content: all authors.

Corresponding author

Correspondence to Guido Cavaletti.

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Conflict of interest

HZ has served at scientific advisory boards for Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. The other authors declare that they have no conflict of interest.

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Meregalli, C., Fumagalli, G., Alberti, P. et al. Neurofilament light chain: a specific serum biomarker of axonal damage severity in rat models of Chemotherapy-Induced Peripheral Neurotoxicity. Arch Toxicol 94, 2517–2522 (2020). https://doi.org/10.1007/s00204-020-02755-w

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  • DOI: https://doi.org/10.1007/s00204-020-02755-w

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