期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 67, 期 17, 页码 3017-3034出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-010-0372-0
关键词
Anticancer drug-induced neuropathy; Biochemical mechanisms in peripheral nerves; CNPase; Cell culture; Immunohistochemistry; Neurofilament-200 kDa; Protein gene product PGP9.5; Sandwich enzyme immunoassay
资金
- Association Ti'toine (Normandie, France)
- Universite de Strasbourg (France)
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 5 alpha-dihydroprogesterone and 3 alpha,5 alpha-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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