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,Yasushi Kuraishi,Daisuke Fukutomi,Daisuke Uta

doi:10.1155/2019/4029694

Tsugunobu Andoh, Yasushi Kuraishi + Show 2 more

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https://doi.org/10.1155/2019/4029694

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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.

Highlights

Most cancer patients receive anticancer drugs such as the platinum-based drug oxaliplatin, the taxane paclitaxel, the vinca alkaloid vincristine, and the proteasome holoenzyme inhibitor bortezomib
A single intraperitoneal injection of oxaliplatin (0.3 mg/kg, i.p.) (Figure 1(a)), paclitaxel (5 mg/kg, i.p.) (Figure 1(b)), vincristine (0.1 mg/kg, i.p.) (Figure 1(c)), or bortezomib (0.3 mg/k, i.p.) (Figure 1(d)) was used to induce mechanical allodynia, which peaked on days 10, 14, 14 or 12 after the injection, respectively (Figure 1)
Mechanical allodynia almost subsided on days 30, 35, 35 or 32 after the injection of oxaliplatin, paclitaxel, vincristine, or bortezomib, respectively (Figure 1)

Summary

Introduction

Most cancer patients receive anticancer drugs such as the platinum-based drug oxaliplatin, the taxane paclitaxel, the vinca alkaloid vincristine, and the proteasome holoenzyme inhibitor bortezomib These anticancer drugs induce peripheral neuropathy, which is a major dose-limiting side effect and is characterized by dysesthesias, including allodynia and cold hypersensitivity [1,2,3,4]. In rodents (rats and mice), herbal medicine Cinnamomi cortex Zingiberis rhizoma Ziziphi fructus Glycyrrhizae radix Ephedrae herba Asiasari radix Aconiti Tuber. KSOT inhibits hyperalgesia induced by repeated cold stress or adjuvant prepared with heat-killed Mycobacterium tuberculosis [7, 8] It is unknown whether KSOT is effective against chemotherapy-induced mechanical allodynia. In this study, we investigated the effects of KSOT on mechanical allodynia induced by chemotherapeutic drugs (oxaliplatin, paclitaxel, vincristine, and bortezomib) in mice. We investigated the mechanisms underlying the antiallodynic action of KSOT

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