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: Laurence Meyer, Christine Patte-Mensah, Omar Taleb, Ayikoe Guy Mensah-Nyagan
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e80915 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24260511 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Neuroprotective Agents
• Androstane-3,17-diol
• Paclitaxel

Topics

• Action Potentials (drug effects)
• Androstane-3,17-diol (analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (adverse effects)
• Hyperalgesia (chemically induced, physiopathology, prevention & control)
• Male
• Nerve Fibers (drug effects, pathology)
• Neural Conduction (drug effects)
• Neuralgia (chemically induced, physiopathology, prevention & control)
• Neuroprotective Agents (pharmacology)
• Paclitaxel (adverse effects)
• Pain (chemically induced, physiopathology, prevention & control)
• Pain Measurement
• Peripheral Nerves (drug effects, pathology)
• Peripheral Nervous System Diseases (chemically induced, physiopathology, prevention & control)
• Rats
• Rats, Sprague-Dawley