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. 2016 Nov;17(11):1206-1212.
doi: 10.1080/15384047.2016.1210742.

An effective therapeutic approach for oxaliplatin-induced peripheral neuropathy using a combination therapy with goshajinkigan and bushi

Keita Mizuno  1 , Keisuke Shibata  2 , Ryohei Komatsu  2 , Yuji Omiya  1 , Yoshio Kase  1 , Schuichi Koizumi  2
Affiliations

An effective therapeutic approach for oxaliplatin-induced peripheral neuropathy using a combination therapy with goshajinkigan and bushi

Keita Mizuno et al. Cancer Biol Ther. 2016 Nov.

Abstract

Oxaliplatin-induced peripheral neuropathy (OIPN) occurs at extraordinarily high frequency, but no effective treatment for this disorder has been established. Goshajinkigan (GJG), a traditional Japanese medicine known as Kampo, is known to reduce OIPN in both basic and clinical studies. However, its molecular mechanisms remain largely unknown. Here, we elucidate the mechanisms underlying the therapeutic effects of GJG against OIPN and the therapeutic benefits of combining GJG with bushi, a herbal medicine derived from the processed Aconiti tuber. Oxaliplatin (4 mg/kg) was injected into mice twice a week for up to 4 and 3 weeks, respectively. OIPN was assessed using pain behavioral tests, such as those testing cold hypersensitivity, thermal hyperalgesia, and mechanical allodynia, as well as a reduction of the current perception threshold (CPT). GJG (0.3 or 1 g/kg) and bushi (0.1 or 0.3 g/kg) were orally administered 5 times a week for 4 weeks. Behavioral analysis was performed 24 h after the final dose. Oxaliplatin induced cold hypersensitivity and mechanical allodynia but not thermal hyperalgesia and reduced CPT of Aδ- and Aβ-fibers but not C-fibers. All these effects were counteracted by GJG. Bushi, an ingredient of GJG that shows analgesic effect, reduced oxaliplatin-induced cold hypersensitivity but had no effect on oxaliplatin-induced mechanical allodynia. However, bushi significantly accentuated the effects of GJG when co-administered with GJG. GJG reduces OIPN by counteracting the sensitization of Aδ- and Aβ-fibers and shows analgesic effects against cold hypersensitivity and mechanical allodynia. These effects are potentiated by bushi. The combination of GJG with bushi has high potential for preventing OIPN.

Keywords: Analgesic effect; bushi; combination therapy; goshajinkigan; oxaliplatin; peripheral neuropathy; traditional Japanese medicine.

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Figures

Figure 1.
Figure 1.
Goshajinkigan inhibits oxaliplatin-induced cold hypersensitivity and mechanical allodynia but not thermal hyperalgesia in mice. Oxaliplatin (4 mg/kg) was injected intraperitoneally twice a week for 4 weeks. Goshajinkigan (GJG) (0.3 or 1 g/kg) was administered orally, immediately after the injection of oxaliplatin, 5 times a week for 4 weeks. The acetone test was performed at the indicated periods (A) and on day 3 (E) to assess the effects of GJG on oxaliplatin-induced cold allodynia. The cold plate (B) and hot plate (C) tests were performed at the indicated periods. The latency of the withdrawal response against each thermal stimulus was measured. The von Frey test was performed to assess mechanical allodynia at the indicated periods (D) and on day 18 (F). The paw withdrawal response to the tactile stimulus was evaluated. d; days after oxaliplatin treatment; **P < 0.01 compared with the control group; #P < 0.05, ##P < 0.01 compared with the oxaliplatin-treated group. Data are expressed as the mean ± standard error of the mean. n = 5–6 per group.
Figure 2.
Figure 2.
The oxaliplatin-induced hyperactivation of Aδ- and Aβ-fibers, and its inhibition by goshajinkigan. The sensitivities of different types of peripheral neurons (C-, Aδ-, and Aβ-fibers) were assessed using a neurometer test. The thresholds of paw withdrawal responses to electrical stimuli with 5 Hz (C-fibers, (A)and B), 250 Hz (Aδ-fibers, (C)and D), and 2000 Hz (Aβ-fibers, (E)and F) were measured. (A), (C), and (E) shows the time courses of sensitization of C-, Aδ-, and Aβ-fibers, respectively. (B), (D), and (F) show the concentration dependence of the effects of goshajinkigan on the sensitivity of C-, Aδ-, and Aβ-fibers, respectively on day 19. d, days after oxaliplatin treatment; *P < 0.05, **P < 0.01 compared with the control group; ##P < 0.01 compared with the oxaliplatin-treated group. Data are expressed as the mean ± standard error of the mean. n = 5–6 per group.
Figure 3.
Figure 3.
Bushi potentiates the ameliorating effects of goshajinkigan against oxaliplatin-induced peripheral neuropathy. Goshajinkigan (GJG) (0.3 g/kg) and/or bushi (0.1 or 0.3 g/kg) were administered orally, immediately after the injection of oxaliplatin, 5 times a week for 3 weeks. The acetone test was performed on day 3 ((A)and C). The von Frey test was performed on day 18 ((B) and D). **P < 0.01 compared with the control group; #P < 0.05, ##P < 0.01 compared with the oxaliplatin-treated group. $P < 0.05, $$P < 0.01 compared with the oxaliplatin + GJG group. Data are expressed as the mean ± standard error of the mean. n = 10 per group.
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References

    1. De GA, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, et al.. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:2938-47; PMID:10944126 - PubMed
    1. Engstrom PF, Arnoletti JP, Benson AB 3rd, Chen YJ, Choti MA, Cooper HS, Covey A, Dilawari RA, Early DS, Enzinger PC, et al.. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: colon cancer. J Natl Compr Canc Netw 2009; 7:778-831; PMID:19755046 - PubMed
    1. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zanillnelli M, Clingan P, Bridgewater J, et al.. Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343-51; PMID:15175436; http://dx.doi.org/1498173810.1056/NEJMoa032709 - DOI - PubMed
    1. Lehky TJ, Leonard GD, Wilson RH, Grem JL, Floeter MK. Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve 2004; 29:387-92; PMID:14981738; http://dx.doi.org/10.1002/mus.10559 - DOI - PubMed
    1. Pasetto LM, D'Andrea MR, Rossi E, Monfardini S. Oxaliplatin-related neurotoxicity: how and why? Crit Rev Oncol Hemato 2006; 59:159-68; PMID: 16806962; http://dx.doi.org/1588039510.1016/j.critrevonc.2006.01.001 - DOI - PubMed

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