title: [6]-gingerol and [6]-shogaol, active ingredients of the traditional Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced pain via action on Na+channels.
abstract: The traditional Japanese herbal medicine hangeshashinto (HST) has beneficial effects for the treatment of oral ulcerative mucositis (OUM) in cancer patients. However, the ingredient-based mechanism that underlies its pain-relieving activity remains unknown. In the present study, to clarify the analgesic mechanism of HST on OUM-induced pain, we investigated putative HST ingredients showing antagonistic effects on Na+channels in vitro and in vivo. A screen of 21 major ingredients using automated patch-clamp recordings in channel-expressing cells showed that [6]-gingerol and [6]-shogaol, two components of a Processed Ginger extract, considerably inhibited voltage-activated Na+currents. These two ingredients inhibited the stimulant-induced release of substance P and action potential generation in cultured rat sensory neurons. A submucosal injection of a mixture of [6]-gingerol and [6]-shogaol increased the mechanical withdrawal threshold in healthy rats. In a rat OUM model, OUM-induced mechanical pain was alleviated 30min after the swab application of HST despite the absence of anti-bacterial and anti-inflammatory actions in the OUM area. A swab application of a mixture of [6]-gingerol and [6]-shogaol induced sufficient analgesia of OUM-induced mechanical or spontaneous pain when co-applied with a Ginseng extract containing abundant saponin. The Ginseng extract demonstrated an acceleration of substance permeability into the oral ulcer tissue without an analgesic effect. These findings suggest that Na+channel blockage by gingerol/shogaol plays an essential role in HST-associated analgesia of OUM-induced pain. This pharmacological mechanism provides scientific evidence supporting the use of this herbal medicine in patients suffering from OUM-induced pain.
authors.affiliation: Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Suzuro
authors.initials: S
authors.lastname: Hitomi
authors.affiliation: Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan. Electronic address: ono@kyu-dent.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ono
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Terawaki
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Chinami
authors.initials: C
authors.lastname: Matsumoto
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan; Division of Dental Anesthesiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Imai
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Omiya
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kase
authors.affiliation: Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Inenaga
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000494:pharmacology*; D057809:HEK293 Cells; D029001:Herbal Medicine / Q000379:methods; D006801:Humans; D008297:Male; D008518:Medicine, East Asian Traditional / Q000379:methods; D052016:Mucositis / Q000150:complications*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D059408:Pain Management / Q000379:methods; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000493:pharmacokinetics*
chemical_list: D000700:Analgesics; D002396:Catechols; D004365:Drugs, Chinese Herbal; D005233:Fatty Alcohols; D010936:Plant Extracts; D015222:Sodium Channels; C088236:hange-shashinto; C040115:shogaol; C007845:gingerol
keywords: Gingerol; Oral ulcerative mucositis; Shogaol; Traditional Japanese (Kampo) medicine; Voltage-dependent Na(+) channels; [6]-gingerol (PubChem CID: 442793); [6]-shogaol (PubChem CID: 5281794)