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. 2019 Apr 17:2019:4029694.
doi: 10.1155/2019/4029694. eCollection 2019.

Prophylactic Repetitive Treatment with the Herbal Medicine Kei-kyoh-zoh-soh-oh-shin-bu-toh Attenuates Oxaliplatin-Induced Mechanical Allodynia by Decreasing Spinal Astrocytes

Tsugunobu Andoh  1 , Daisuke Fukutomi  1 , Daisuke Uta  1 , Yasushi Kuraishi  1
Affiliations

Prophylactic Repetitive Treatment with the Herbal Medicine Kei-kyoh-zoh-soh-oh-shin-bu-toh Attenuates Oxaliplatin-Induced Mechanical Allodynia by Decreasing Spinal Astrocytes

Tsugunobu Andoh et al. Evid Based Complement Alternat Med. .

Abstract

Chemotherapeutic drugs typically induce peripheral neuropathy, which is a major dose-limiting side effect of these drugs and is difficult to manage. In this study, we examined whether the traditional herbal formulation Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT) could relieve the mechanical allodynia induced by chemotherapeutic drugs (oxaliplatin, paclitaxel, vincristine, and bortezomib) in mice. A single intraperitoneal injection of oxaliplatin, paclitaxel, vincristine, and bortezomib was used to induce mechanical allodynia, which peaked on days 10, 14, 14, and 12 after the injection, respectively. A single oral administration of KSOT did not inhibit mechanical allodynia after any of the treatments. However, prophylactic repetitive oral administrations of KSOT inhibited the exacerbation of mechanical allodynia induced by oxaliplatin but were not effective for allodynia induced by the other drugs. A single intraperitoneal injection of oxaliplatin did not alter the mRNA expression of the NMDA receptor NR2B in the spinal cord and that of neuregulin-1 in the sciatic nerve. In addition, the number of microglia in spinal dorsal horn did not increase in oxaliplatin-treated mice. However, the number of reactivated astrocytes in the spinal dorsal horn increased, which could be inhibited by repetitive administration of KSOT. These results suggest that prophylactic repetitive treatment of KSOT attenuates oxaliplatin-induced mechanical allodynia by decreasing the number of spinal astrocytes.

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Figures

Figure 1
Figure 1
Development of mechanical allodynia induced by a single injection of chemotherapeutic agents. Mice were given a single injection of (a) oxaliplatin (OXP, 3 mg/kg, i.p.), (b) paclitaxel (PTX, 5 mg/kg, i.p.), (c) vincristine (VCN, 0.1 mg/kg, i.p.), (d) bortezomib (BTZ, 0.3 mg/kg, i.v.) or the corresponding vehicle (VH) on day 0. Mechanical allodynia was evaluated using a fine von Frey filament (0.69 mN strength). Data are presented as mean ± standard errors of the mean (n = 6). ∗P < 0.05 vs. VH (Holm-Šidák multiple comparisons). i.p.: intraperitoneal injection, i.v.: intravenous injection.
Figure 2
Figure 2
Effect of a single oral administration of Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT) on the mechanical allodynia induced by chemotherapeutic agents. Mice were given a single injection of (a) oxaliplatin (OXP, 3 mg/kg, i.p.), (b) paclitaxel (PTX, 5 mg/kg, i.p.), (c) vincristine (VCN, 0.1 mg/kg, i.p.), or (d) bortezomib (BTZ, 0.3 mg/kg, i.v.) on day 0. KSOT or the vehicle (VH) was orally administered on day 10 (for OXP-treated mice), day 14 (for PTX- or VCN-treated mice), or day 12 (for BTZ-treated mice) after the injection. Mechanical allodynia was evaluated using a fine von Frey filament (0.69 mN strength). Data are presented as mean ± standard errors of the mean (n = 6). i.p.: intraperitoneal injection, i.v.: intravenous injection.
Figure 3
Figure 3
Effect of prophylactic repetitive oral administration of Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT) on the mechanical allodynia induced by chemotherapeutic agents. Mice were given a single injection of (a) oxaliplatin (OXP, 3 mg/kg, i.p.), (b) paclitaxel (PTX, 5 mg/kg, i.p.), (c) vincristine (VCN, 0.1 mg/kg, i.p.), (d) bortezomib (BTZ, 0.3 mg/kg, i.v.) or the corresponding vehicles (VH1) on day 0. KSOT or the vehicle (VH2) orally administered once daily from the day after a single injection of chemotherapeutic agent or the corresponding vehicle (VH1). Mechanical allodynia was evaluated using a fine von Frey filament (0.69 mN strength). Data are presented as mean ± standard errors of the mean (n = 6). ∗P < 0.05 vs. OXP + VH2 (Holm-Šidák multiple comparisons). i.p.: intraperitoneal injection, i.v.: intravenous injection.
Figure 4
Figure 4
Effect of prophylactic repetitive oral administration of Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT) on cold dysesthesia induced by oxaliplatin. Mice were given a single injection of oxaliplatin (OXP, 3 mg/kg, i.p.) or the corresponding vehicle (VH1) on day 0. KSOT or the vehicle (VH2) was orally administered once daily, starting the day after a single injection of oxaliplatin or the corresponding vehicle (VH1). Cold dysesthesia was evaluated using acetone test. Data are presented as mean ± standard errors of the mean (n = 6). ∗P < 0.05 vs. VH1 + VH2 (Holm-Šidák multiple comparisons). i.p.: intraperitoneal injection.
Figure 5
Figure 5
Effect of prophylactic repetitive oral administration of Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT) on the expression of NMDA receptor 2B (NR2B) and neuregulin-1 (NRG1) in oxaliplatin-treated mice. Mice were given a single injection of oxaliplatin (OXP, 3 mg/kg, i.p.) or the corresponding vehicle (VH1) on day 0. KSOT or the vehicle (VH2) was orally administered once daily, starting the day after a single injection of OXP or the corresponding vehicle (VH1). The spinal cord for NR2B (a) and the sciatic nerve for NRG1 (b) were isolated on day 10 after OXP injection and the proteins were extracted for Western blotting. The expression level of NR2B or NRG1 in each sample was normalized to that of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and further normalized to its expression level of the vehicle control (VH1+VH2). (a) A typical example of the expression levels of NR2B or NRG1 and GAPDH. (b) The expression level of NR2B or NRG1, normalized with that of GAPDH. Data are presented as mean ± standard errors of the mean (n = 6 for NR2B; n = 3 for NRG1).
Figure 6
Figure 6
Distribution of microglia in the spinal dorsal horn of oxaliplatin-treated mice and the effect of Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT). Mice were given a single injection of oxaliplatin (OXP, 3 mg/kg, i.p.) or the corresponding vehicles (VH1) on day 0. KSOT or the vehicle (VH2) was orally administered once daily, starting the day after a single injection of OXP or the corresponding vehicle (VH1). The spinal cords were isolated on day 10 after OXP injection. Typical examples of the distribution of Iba-1-immunoreactive microglia in mouse spinal dorsal horn: (a) VH1+VH2, (b) OXP + VH2, and (c) OXP+ KSOT. Scale bar = 100 μm. (d) The number of Iba-1-immunoreactive microglia. Data are presented as mean ± standard errors of the mean (n = 4). i.p.: intraperitoneal injection.
Figure 7
Figure 7
Distribution of astrocytes in the spinal dorsal horn of oxaliplatin-treated mice and the effect of Kei-kyoh-zoh-soh-oh-shin-bu-toh (KSOT). Mice were given a single injection of oxaliplatin (OXP, 3 mg/kg, i.p.) or the corresponding vehicles (VH1) on day 0. KSOT or the vehicle (VH2) was orally administered once daily, starting from the day after a single injection of OXP or the corresponding vehicle (VH1). The spinal cords were isolated on day 10 after OXP injection. Typical examples of the distribution of GFAP-immunoreactive astrocytes in mouse spinal dorsal horn: (a) VH1+VH2, (b) OXP + VH2, and (c) OXP+ KSOT. Scale bar = 100 μm. (d) The number of GFAP-immunoreactive astrocytes. Data are presented as mean ± standard errors of the mean (n = 4). ∗P < 0.05 (Holm-Šidák multiple comparisons). i.p.: intraperitoneal injection.
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