Journal Article

DZNE-2020-00463

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Blockade of IL-6 signaling prevents paclitaxel-induced neuropathy in C57Bl/6 mice.

Huehnchen, P. ; Muenzfeld, H. ; Boehmerle, W. (Corresponding author) ; Endres, M. (Last author)DZNE*

2020
Nature Publishing Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41419-020-2239-0

Abstract: The microtubule-stabilizing agent paclitaxel frequently leads to chemotherapy-induced peripheral neuropathy (CIN), which further increases the burden of disease and often necessitates treatment limitations. The pathophysiology of CIN appears to involve both 'upstream' effects including altered intracellular calcium signaling and activation of calcium dependent proteases such as calpain as well as subsequent 'downstream' neuro-inflammatory reactions with cytokine release and macrophage infiltration of dorsal root ganglia. In this study, we aimed to investigate whether these processes are linked by the pro-inflammatory cytokine interleukin-6 (IL-6). We observed that paclitaxel exposure induced IL-6 synthesis in cultured sensory neurons from postnatal Wistar rats, which could be prevented by co-treatment with a calpain inhibitor. This suggests a calcium dependent process. We demonstrate that adult C57BL/6 mice deficient in IL-6 are protected from developing functional and histological changes of paclitaxel-induced neuropathy. Furthermore, pretreatment with an IL-6-neutralizing antibody resulted in the prevention of paclitaxel-induced neuropathy in C57BL/6 mice. Electrophysiological data from our preclinical model was adequately reflected by measurements of patients undergoing paclitaxel therapy for ovarian cancer. In this cohort, measured Il-6 levels correlated with the severity of neuropathy. Our findings demonstrate that IL-6 plays a pivotal role in the pathophysiology of paclitaxel-induced neuropathy per se and that pharmacological or genetic interference with this signaling pathway prevents the development of this potentially debilitating adverse effect. These findings provide a rationale for a clinical trial with IL-6 neutralizing antibodies to prevent dose-limiting neurotoxic adverse effects of paclitaxel chemotherapy.

Keyword(s): Animals (MeSH) ; Animals, Newborn (MeSH) ; Antibodies, Neutralizing: pharmacology (MeSH) ; Cohort Studies (MeSH) ; Female (MeSH) ; Ganglia, Spinal: pathology (MeSH) ; Humans (MeSH) ; Interleukin-6: metabolism (MeSH) ; Male (MeSH) ; Mice, Inbred C57BL (MeSH) ; Middle Aged (MeSH) ; Models, Biological (MeSH) ; Nervous System Diseases: chemically induced (MeSH) ; Nervous System Diseases: metabolism (MeSH) ; Paclitaxel: adverse effects (MeSH) ; Paclitaxel: pharmacology (MeSH) ; Rats (MeSH) ; Sensory Receptor Cells: drug effects (MeSH) ; Sensory Receptor Cells: pathology (MeSH) ; Signal Transduction: drug effects (MeSH)

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Contributing Institute(s):

1. Interdisciplinary Dementia Research (AG Endres)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2020

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