title: An effective therapeutic approach for oxaliplatin-induced peripheral neuropathy using a combination therapy with goshajinkigan and bushi.
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.
authors.affiliation: a Tsumura Research Laboratories , Kampo Scientific Strategies Division, Tsumura & Co., Yoshiwara, Ami-machi , Inashiki-gun, Ibaraki , Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: b Department of Neuropharmacology , Interdisciplinary Graduate School of Medicine, University of Yamanashi , Shimokato, Chuo, Yamanashi , Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shibata
authors.affiliation: b Department of Neuropharmacology , Interdisciplinary Graduate School of Medicine, University of Yamanashi , Shimokato, Chuo, Yamanashi , Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Komatsu
authors.affiliation: a Tsumura Research Laboratories , Kampo Scientific Strategies Division, Tsumura & Co., Yoshiwara, Ami-machi , Inashiki-gun, Ibaraki , Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Omiya
authors.affiliation: a Tsumura Research Laboratories , Kampo Scientific Strategies Division, Tsumura & Co., Yoshiwara, Ami-machi , Inashiki-gun, Ibaraki , Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kase
authors.affiliation: b Department of Neuropharmacology , Interdisciplinary Graduate School of Medicine, University of Yamanashi , Shimokato, Chuo, Yamanashi , Japan.
authors.forename: Schuichi
authors.initials: S
authors.lastname: Koizumi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D056587:Cryopyrin-Associated Periodic Syndromes / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009413:Nerve Fibers, Myelinated / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D010936:Plant Extracts / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D009944:Organoplatinum Compounds; D010936:Plant Extracts; C568891:bushi; C119642:gosha-jinki-gan; D000077150:Oxaliplatin
keywords: Analgesic effect; bushi; combination therapy; goshajinkigan; oxaliplatin; peripheral neuropathy; traditional Japanese medicine