Cellular and functional evidence for a protective action of neurosteroids against vincristine chemotherapy-induced painful neuropathy.
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 5alpha-dihydroprogesterone and 3alpha,5alpha-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.
Meyer
Laurence
L
Equipe Stéroïdes, Neuromodulateurs et Neuropathologies, Bâtiment 3 de la Faculté de Médecine, EA-4438 Université de Strasbourg, 11 rue Humann, 67000, Strasbourg, France.
Patte-Mensah
Christine
C
Taleb
Omar
O
Mensah-Nyagan
Ayikoe Guy
AG
D043582:5-alpha-Dihydroprogesterone / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D045744:Cell Line, Tumor; D004594:Electrophysiology; D006908:Hydroxyprogesterones / Q000494:pharmacology / Q000627:therapeutic use; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D008297:Male; D009431:Neural Conduction / Q000502:physiology; D009437:Neuralgia / Q000139:chemically induced* / Q000188:drug therapy*; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010147:Pain Measurement; D010525:Peripheral Nerves / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014750:Vincristine / Q000009:adverse effects*
D000972:Antineoplastic Agents, Phytogenic; D006908:Hydroxyprogesterones; D018377:Neurotransmitter Agents; D042461:Vascular Endothelial Growth Factor A; D014750:Vincristine; D043582:5-alpha-Dihydroprogesterone