Cellular and functional evidence for a protective action of neurosteroids against vincristine chemotherapy-induced painful neuropathy

Abstract

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.

Neuroactive steroids and the peripheral nervous system: An update

“…Indeed, as reported in different experimental models, Ttype calcium channels, GABA-A channels, P2X3 receptors, voltage-gated sodium channels and bradykinin signaling, which exert a role in neuropathic pain, are also affected by different kinds of neuroactive steroids [84][85][86][87][88][89]. In particular, metabolites of PROG (i.e., DHP and THP) suppress neuropathic symptoms (allodynia/hyperalgesia) evoked by antineoplastic drugs such as vincristine [90] or oxaliplatin [91]. Moreover, metabolites of T have been recently demonstrated as potential agents for the treatment of diabetic neuropathic pain [92].…”

Levels and actions of progesterone and its metabolites in the nervous system during physiological and pathological conditions

“…PROG metabolites exert a beneficial effect also on this component, since both DHP and 3a-THP suppress neuropathic symptoms (allodynia/hyperalgesia) evoked by antineoplastic drugs, such as vincristine (Meyer et al, 2010) or oxaliplatin (Meyer et al, 2011).…”

Novel small molecule alpha9 alpha10 nicotinic receptor antagonist prevents and reverses chemotherapy evoked neuropathic pain in rats

“…32 For example, the nAChR agonist, ABT-594 9 and selective Ttype calcium channel blocker, ethosuximide, 20 reversed vincristine-induced neuropathy in a dose-dependent manner. The positive effects were noted with anticonvulsant, 33,34 neurosteroids, 35 cannabinoids, 36 and drugs that enhance mitochondrial function. 26 Mixed results were demonstrated with common analgesic drugs such as opioids and nonsteroidal antiinflammatory drugs.…”