title: Neurosteroid 3α-androstanediol efficiently counteracts paclitaxel-induced peripheral neuropathy and painful symptoms.
abstract: Painful peripheral neuropathy belongs to major side-effects limiting cancer chemotherapy. Paclitaxel, widely used to treat several cancers, induces neurological symptoms including burning pain, allodynia, hyperalgesia and numbness. Therefore, identification of drugs that may effectively counteract paclitaxel-induced neuropathic symptoms is crucial. Here, we combined histopathological, neurochemical, behavioral and electrophysiological methods to investigate the natural neurosteroid 3α-androstanediol (3α-DIOL) ability to counteract paclitaxel-evoked peripheral nerve tissue damages and neurological symptoms. Prophylactic or corrective 3α-DIOL treatment (4 mg/kg/2 days) prevented or suppressed PAC-evoked heat-thermal hyperalgesia, cold-allodynia and mechanical allodynia/hyperalgesia, by reversing to normal, decreased thermal and mechanical pain thresholds of PAC-treated rats. Electrophysiological studies demonstrated that 3α-DIOL restored control values of nerve conduction velocity and action potential peak amplitude significantly altered by PAC-treatment. 3α-DIOL also repaired PAC-induced nerve damages by restoring normal neurofilament-200 level in peripheral axons and control amount of 2',3'-cyclic-nucleotide-3'-phosphodiesterase in myelin sheaths. Decreased density of intraepidermal nerve fibers evoked by PAC-therapy was also counteracted by 3α-DIOL treatment. More importantly, 3α-DIOL beneficial effects were not sedation-dependent but resulted from its neuroprotective ability, nerve tissue repairing capacity and long-term analgesic action. Altogether, our results showing that 3α-DIOL efficiently counteracted PAC-evoked painful symptoms, also offer interesting possibilities to develop neurosteroid-based strategies against chemotherapy-induced peripheral neuropathy. This article shows that the prophylactic or corrective treatment with 3α-androstanediol prevents or suppresses PAC-evoked painful symptoms and peripheral nerve dysfunctions in rats. The data suggest that 3α-androstanediol-based therapy may constitute an efficient strategy to explore in humans for the eradication of chemotherapy-induced peripheral neuropathy.
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Faculté de Médecine, Strasbourg, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Meyer
authors.forename: Christine
authors.initials: C
authors.lastname: Patte-Mensah
authors.forename: Omar
authors.initials: O
authors.lastname: Taleb
authors.forename: Ayikoe Guy
authors.initials: AG
authors.lastname: Mensah-Nyagan
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D015113:Androstane-3,17-diol / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects; D009437:Neuralgia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017239:Paclitaxel / Q000009:adverse effects*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018696:Neuroprotective Agents; D015113:Androstane-3,17-diol; D017239:Paclitaxel