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Cellular and functional evidence for a protective action of neurosteroids against vincristine chemotherapy-induced painful neuropathy

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Abstract

Painful neuropathy is a major side-effect limiting cancer chemotherapy. Therefore, novel strategies are required to suppress the neuropathic effects of anticancer drugs without altering their chemotherapeutic effectiveness. By combining biochemical, neuroanatomical/neurochemical, electrophysiological and behavioral methods, we demonstrated that progesterone-derived neurosteroids including 5α-dihydroprogesterone and 3α,5α-tetrahydroprogesterone suppressed neuropathic symptoms evoked in naive rats by vincristine. Neurosteroids counteracted vincristine-induced alterations in peripheral nerves including 2′,3′-cyclic nucleotide 3′-phosphodiesterase, neurofilament-200 kDa and intraepidermal nerve fiber repression, nerve conduction velocity, and pain transmission abnormalities (allodynia/hyperalgesia). In skin-tumor rats generated with carcinosarcoma-cells, vincristine, which suppressed the skin tumor and restored normal blood concentration of vascular endothelial growth factor (VEGF), reproduced neuropathic side-effects. Administered alone, neurosteroids did not affect the tumor and VEGF level. Combined with vincristine, neurosteroids preserved vincristine anti-tumor action but counteracted vincristine-induced neural side-effects. Together, these results provide valuable insight into the cellular and functional mechanisms underlying anticancer drug-induced neuropathy and suggest a neurosteroid-based strategy to eradicate painful neuropathy.

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Acknowledgments

This work was supported by grants from Association Ti’toine (Normandie, France) and Université de Strasbourg (France). L.M. was a postdoctoral fellow supported by Association Ti’toine (Normandie, France).

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  1. Equipe Stéroïdes, Neuromodulateurs et Neuropathologies, Bâtiment 3 de la Faculté de Médecine, EA-4438 Université de Strasbourg, 11 rue Humann, 67000, Strasbourg, France

    Laurence Meyer, Christine Patte-Mensah, Omar Taleb & Ayikoe Guy Mensah-Nyagan

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  1. Laurence Meyer
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  2. Christine Patte-Mensah
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Correspondence to Ayikoe Guy Mensah-Nyagan.

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Meyer, L., Patte-Mensah, C., Taleb, O. et al. Cellular and functional evidence for a protective action of neurosteroids against vincristine chemotherapy-induced painful neuropathy. Cell. Mol. Life Sci. 67, 3017–3034 (2010). https://doi.org/10.1007/s00018-010-0372-0

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