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Peripheral neurotoxicity is a frequent complication limiting docetaxel chemotherapy in patients with cancer. We developed an experimental model that closely mimics the course of neuropathy in patients, aiming to investigate both the mechanisms of neurotoxicity at biochemical, functional and morphological levels and the potential neuroprotective role of neuroactive steroids. We demonstrated that treatment with dihydroprogesterone (DHP) or progesterone (P) counteracts docetaxel-induced neuropathy, preventing nerve conduction and thermal threshold changes, and degeneration of skin nerves in the foodpad. Neuroactive steroids also counteract the changes in gene expression of several myelin proteins and calcitonin gene-related peptide induced by docetaxel in sciatic nerve and lumbar spinal cord, respectively. Most nerve abnormalities observed during the treatment with docetaxel spontaneously recovered after drug withdrawal, similarly to what occurs in patients. However, results of midterm follow-up experiments indicated that animals cotreated with DHP or P have a faster recovery of the neuropathy compared with docetaxel-treated rats. Our study confirmed that neuroactive steroids exert a protective effect on peripheral nerves at different levels, suggesting that they might represent a new therapeutic frontier for patients with chemotherapy-induced neuropathy.

Original publication

DOI

10.1111/j.1529-8027.2009.00204.x

Type

Journal article

Journal

J Peripher Nerv Syst

Publication Date

03/2009

Volume

14

Pages

36 - 44

Keywords

20-alpha-Dihydroprogesterone, Analysis of Variance, Animals, Body Weight, Disease Models, Animal, Gene Expression Regulation, Male, Myelin Basic Protein, Myelin P0 Protein, Myelin Proteins, Nerve Fibers, Neural Conduction, Neuroprotective Agents, Pain Threshold, Peripheral Nervous System Diseases, Progesterone, Rats, Rats, Inbred F344, Sciatic Nerve, Taxoids