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. 2010 Sep;67(17):3017-34.
doi: 10.1007/s00018-010-0372-0. Epub 2010 Apr 30.

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

Laurence Meyer  1 , Christine Patte-Mensah, Omar Taleb, Ayikoe Guy Mensah-Nyagan
Affiliations

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

Laurence Meyer et al. Cell Mol Life Sci. 2010 Sep.

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.

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Figures

Fig. 1
Fig. 1
a Effect of vincristine treatment on the mechanical nociceptive thresholds of naive rats. The curves (mean + SEM) were obtained with mechanical stimulations (g), which induced more than 70% withdrawal responses in each animal before or after drug administrations (n = 10 per group). b, c Time-course of mechanical allodynia (b) and hyperalgesia (c) induced by vincristine treatment. Graphs show the mean + SEM of the percentages of paw withdrawal responses to mechanical stimulation by Von Frey filament 4 g (b) or 15 g (c). d Effect of vincristine treatment on the thermal nociceptive thresholds of naive rats assessed by the Plantar test. Each point represents the mean + SEM of six observations in each of ten rats. *p < 0.05, **p < 0.01, ***p < 0.005. e Vincristine effect on nerve conduction velocity. Typical traces of rat sciatic NAP recorded from rats treated with NaCl (dashed curve) or vincristine (filled curve). The nerve was stimulated with a supra-maximal pulse potential as illustrated by the protocol trace (lower trace). The arrows1–3 indicate the beginning of the stimulation artifact (1) and the onset of NAP in control (2) and vincristine (3) conditions giving a calculated NAP CVlatency in this case of 77.5 and 33.2 m/s for control and vincristine, respectively. Each NAP trace was obtained by averaging 50 consecutive original NAPs
Fig. 2
Fig. 2
a–f Photomicrographs of sagittal sections of sciatic nerves (a–d) and hind paw skins (e, f) dissected from NaCl- (a, c, e) and vincristine-treated (b, d, f) rats. The nerve sections were labeled with the monoclonal anti-CNPase revealed with Alexa-488-conjugated donkey anti-mouse. The skin sections were labeled with the polyclonal anti-PGP9.5 revealed with FITC-conjugated goat anti-rabbit. Scale bar 100 μm. Comparative analysis of the numbers of CNPase-positive Schwann cell bodies detected (g) and the density of NF200-immunolabeling (h) in sciatic nerve sections dissected from NaCl- and vincristine-treated rats (n = 6 per group). Each value is expressed as percent (+SEM) of CNPase-positive cells bodies (g) or NF200-immunolabeling density (h) detected in sciatic nerve sections of control (NaCl-treated) rats. i Comparative analysis of IENF density measured in hind paw skin sections dissected from NaCl- and vincristine-treated rats (n = 4 per group). *p < 0.05, ***p < 0.001
Fig. 3
Fig. 3
Effect of progesterone (4 mg/kg per 2 days) prophylactic (a, c, e) or corrective (b, d, f) treatment on vincristine-induced neuropathic pain symptoms. a, b Chart bars (mean + SEM) were obtained with mechanical stimulations (g), which induced more than 70% withdrawal responses in each animal before or after drug administrations (n = 6 per group). c–f Antagonistic effect of progesterone against vincristine-induced mechanical allodynia (c, d) and hyperalgesia (e, f). Chart bars show the mean + SEM of the percentages of paw withdrawal responses to mechanical stimulation by Von Frey filament 4 g (c, d) or 15 g (e, f). *p < 0.05, **p < 0.01, ***p < 0.005. Asterisk versus NaCl + CDEX, Hash versus VINC + CDEX. g Effects of progesterone, 5α-DHP and 3α,5α-THP on vincristine-induced conduction velocity (CV) decrease in sciatic nerves. All mean CV and SEM values obtained from rats treated as indicated in the histogram were calculated as % of the mean CV obtained from vehicle treated rats. *p < 0.05, **p < 0.001, ***p < 0.0001
Fig. 4
Fig. 4
a–l Photomicrographs of sagittal sections of sciatic nerves (a–h) or hind paw skins (i–l) dissected from NaCl + CDEX (a, e, i)-, NaCl + PROG (c, g, k)-, VINC + CDEX (b, f, j)- or VINC + PROG (d, h, l)-treated rats. Scale bar 100 μm. m–t Neuroprotective effects of prophylactic (m, o, q, s) or corrective (n, p, r, t) neurosteroid treatment against vincristine-induced alterations in sciatic nerves and intraplantar skin. m–pChart bars show the numbers of CNPase-immunoreactive Schwann cell bodies detected in sciatic nerve sections dissected from NaCl + CDEX-, VINC + CDEX-, NaCl + PROG (m, n)-, VINC + PROG (m, n)-, NaCl + DHP (o, p)-, VINC + DHP (o, p)-, NaCl + THP (o, p)- or VINC + THP (o, p)-treated rats (n = 6 per group). Each value is expressed as percent (+SEM) of CNPase-positive cell bodies counted in sciatic nerve sections of control (NaCl + CDEX-treated) rats. *p < 0.05 versus NaCl + CDEX, #p < 0.01 versus VINC + CDEX. q–tGraphs show NF200 expression in sciatic nerve sections (q, r) or IENF density in intraplantar skin sections (s, t) dissected from NaCl + CDEX-, VINC + CDEX-, NaCl + PROG-, VINC + PROG-, NaCl + DHP-, VINC + DHP-, NaCl + THP- or VINC + THP-treated rats. q, r Each value is expressed as percent (+SEM) of NF200-immunolabeling density detected in sciatic nerve sections of NaCl + CDEX-treated rats (n = 6 per group). *p < 0.01 versus NaCl + CDEX, #p < 0.001 versus VINC + CDEX. s, t Each value is expressed as mean (+SEM) of IENF density counted in hind paw skin sections (n = 4 per group). *p < 0.05 versus NaCl + CDEX, #p < 0.05 versus VINC + CDEX
Fig. 5
Fig. 5
Effects of finasteride (inhibitor of progesterone conversion into 5α-metabolites) or progesterone + finasteride on vincristine-induced painful neuropathy in naive rats. a The curves (mean + SEM) were obtained with mechanical stimulations (g), which induced more than 70% withdrawal responses in each animal before or after drug administrations (n = 6 per group). b, c Absence of action of finasteride (Fin) or progesterone + finasteride on vincristine-induced mechanical allodynia (b) and hyperalgesia (c). Graphs show the mean + SEM of the percentages of paw withdrawal responses to mechanical stimulation by Von Frey filament 4 g (b) or 15 g (c). *p < 0.05, **p < 0.01, ***p < 0.005 at each time point from D12 to D32 (a, c) or from D14 to D32 (b). Asterisk NaCl + CDEX versus VINC + CDEX; Plus NaCl + CDEX versus NaCl + PROG; Hash VINC + CDEX versus VINC + PROG; Dollar NaCl + Fin versus VINC + Fin; Ampersand NaCl + PROG + Fin versus VINC + PROG + Fin. d Effects of Fin (25 mg/kg) alone or progesterone (4 mg/kg) + Fin on the numbers of CNPase-positive Schwann cell bodies detected in sciatic nerve sections dissected from NaCl + CDEX-, VINC + CDEX-, NaCl + PROG-, VINC + PROG-, NaCl + Fin-, VINC + Fin-, NaCl + PROG + Fin-, or VINC + PROG + Fin-treated rats (n = 6 per group). Each value is expressed as percent (+SEM) of CNPase-positive cell bodies counted in sciatic nerve sections of control (NaCl + CDEX-treated) rats. *p < 0.05, ***p < 0.001
Fig. 6
Fig. 6
Effects of prophylactic (a, c, e) or corrective (b, d, f) treatment with 5α-DHP or 3α,5α-THP (4 mg/kg per 2 days) on vincristine-induced painful neuropathy. a, b Chart bars (mean + SEM) were obtained with mechanical stimulations (g), which induced more than 70% withdrawal responses in each animal before or after drug administrations (n = 6 per group). c–f Antagonistic effect of 5α-DHP or 3α,5α-THP against vincristine-induced mechanical allodynia (c, d) and hyperalgesia (e, f). Chart bars show the mean + SEM of the percentages of paw withdrawal responses to mechanical stimulation by Von Frey filament 4 g (c, d) or 15 g (e, f). *p < 0.01 versus NaCl + CDEX, # p < 0.01 versus VINC + CDEX
Fig. 7
Fig. 7
Effects of vincristine, progesterone, 5α-DHP or 3α,5α-THP on tumor volume and VEGF serum level in tumor-bearing (TB) rats. a–f External (a, c, e) and internal (b, d, f) views of the posterior right flanks of TB and control rats 34 days after W256 carcinosarcoma cells or PBS inoculation. a, b Photomicrographs of the external (a) or internal (b) skin in the right flank of control animals (injected with PBS) showing the absence of tumor. c, d Photomicrographs of the external (c) or internal (d) skin in the right flank of tumor-bearing animals injected with W256 cells. The black circle shows the tumor location. e, f Treatment of skin cancer rats with vincristine completely suppressed the tumor, which disappeared on the external (e) and internal (f) sides. g Vincristine treatment alone or associated with progesterone, 5α-DHP or 3α,5α-THP (4 mg/kg) completely suppressed the tumor while the administration of progesterone, 5α-DHP, or 3α,5α-THP alone did not affect the tumor volume. Each bar represents the mean (+SEM) of six tumor volumes. ***p < 0.001; Hash a significant difference compared to control rats inoculated with PBS. h Vincristine treatment alone or associated with progesterone, 5α-DHP or 3α,5α-THP (4 mg/kg) restored baseline/physiological values of VEGF serum levels, which increased significantly in TB rats. Injections of progesterone, 5α-DHP, or 3α,5α-THP alone did not modify increased or baseline levels of VEGF detected in TB or control rats, respectively. Each bar represents the mean level (+SEM) of four dosages performed in duplicate. ***p < 0.001; Hash a significant difference compared to control rats inoculated with PBS
Fig. 8
Fig. 8
Effects of neurosteroids on vincristine-induced pain symptoms and cellular alterations (CNPase and NF200 repression as well as IENF density decrease) in peripheral nerves of tumor-bearing (TB) rats. Progesterone, 5α-DHP, 3α,5α-THP (4 mg/kg) or the vehicle CDEX was administered every 2 days to vincristine- and NaCl-treated TB rats. a The curves (mean + SEM) were obtained with mechanical stimulations (g), which induced more than 70% withdrawal responses in each animal before or after drug administrations (n = 6 per group). b, c Antagonistic effects of progesterone, 5α-DHP, or 3α,5α-THP against vincristine-induced mechanical allodynia (b) and hyperalgesia (c) in TB rats. Graphs show the mean + SEM of the percentages of paw withdrawal responses to mechanical stimulation by Von Frey filament 4 g (b) or 15 g (c). *p < 0.05, ***p < 0.01 at each time point from D14 to D34 (a, c) or from D20 to D34 (b). Asterisk TB-NaCl + CDEX versus TB-VINC + CDEX; Plus TB-NaCl + CDEX versus TB-NaCl + PROG; Ampersand TB-NaCl + CDEX versus TB-NaCl + DHP; Dollar TB-NaCl + CDEX versus TB-NaCl + THP; Hash TB-VINC + CDEX versus TB-VINC + PROG; Sect TB-VINC + CDEX versus TB-VINC + DHP; Pound TB-VINC + CDEX versus TB-VINC + THP. d, e Effect of progesterone, 5α-DHP, or 3α,5α-THP (4 mg/kg) on the numbers of CNPase-positive Schwann cell bodies (d) or on NF200 expression (e) detected in sciatic nerve sections dissected from NaCl + CDEX-, VINC + CDEX-, NaCl + PROG-, VINC + PROG-, NaCl + DHP-, VINC + DHP-, NaCl + THP- or VINC + THP-treated TB rats (n = 6 per group). Each value is expressed as percent (+SEM) of CNPase-positive cell bodies counted (d) or of NF200-immunolabeling density detected (e) in sciatic nerve sections of control (NaCl + CDEX-treated) TB rats. *p < 0.05, **p < 0.01, ***p < 0.005. f Comparative analysis of IENF density measured in hind paw skin sections dissected from NaCl + CDEX-, VINC + CDEX-, NaCl + PROG-, VINC + PROG-, NaCl + DHP-, VINC + DHP-, NaCl + THP- or VINC + THP-treated TB rats (n = 4 per group). Each value is expressed as mean (+SEM) of IENF density counted in hind paw skin sections. *p < 0.05, **p < 0.01
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