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Docetaxel‐induced peripheral neuropathy: protective effects of dihydroprogesterone and progesterone in an experimental model
Author(s) -
Roglio Ilaria,
Bianchi Roberto,
Camozzi Francesca,
Carozzi Valentina,
Cervellini Ilaria,
Crippa Donatella,
Lauria Giuseppe,
Cavaletti Guido,
Melcangi Roberto C.
Publication year - 2009
Publication title -
journal of the peripheral nervous system
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 67
eISSN - 1529-8027
pISSN - 1085-9489
DOI - 10.1111/j.1529-8027.2009.00204.x
Subject(s) - docetaxel , peripheral neuropathy , medicine , neurotoxicity , neuroprotection , neuroactive steroid , endocrinology , sciatic nerve , chemotherapy , pharmacology , toxicity , receptor , gabaa receptor , diabetes mellitus
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.