Search of anti-allodynic compounds from Plantaginis Semen, a crude drug ingredient of Kampo formula “Goshajinkigan”
- 20 Downloads
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the dose-limiting side effects of cancer chemotherapy. Although the control of CIPN is important, it is difficult to manage with currently available therapeutic drugs. Therefore, there is a need for novel therapeutic agents for treating CIPN. Goshajinkigan (GJG) is a Kampo formula composed of ten crude drugs. While GJG has been used for the treatment of CIPN, the active constituents of GJG and their underlying mechanisms of pharmacological effects are still unknown. Our previous study revealed that repetitive oral administration of the water extract of Plantaginis Semen, a crude drug ingredient of GJG, inhibited the mechanical allodynia induced by an intraperitoneal injection of paclitaxel in mice. To elucidate the active compounds of Plantaginis Semen, activity-guided separation of the water extract of Plantaginis Semen was performed. From the active fraction, four iridoids (1–4) were identified. Repetitive oral administration of aucubin (1) at 100 or 30 mg/kg and 100 mg/kg of the fraction crude 3 [primarily comprised of pedicularis-lactone (3)], showed anti-allodynic activity, suggesting 1 and 3 could be some of the active compounds responsible for the anti-allodynic property of Plantaginis Semen and GJG. Our study establishes that oral administration of 1 has potent anti-allodynic effect in addition to the activity of intraperitoneally administered 1 reported previously. Identification of active anti-allodynic compounds found in Kampo formulations will support the development of novel therapies for the management of CIPN in cancer patients.
KeywordsPlantaginis Semen Plantago asiatica Allodynia Peripheral neuropathy Iridoids Goshajinkigan
This study was supported in part by a Grant-in-Aid for the Cooperative Research Project from Institute of Natural Medicine, University of Toyama in 2016 and 2017, JSPS KAKENHI Grant Number 15K07993 and 18K06728, Wakanyaku-Biotechnology Research Grant from Toyama prefecture, and JSPS Core-to-Core Program, Asia-Africa Science Platforms. The authors would like to thank Tsumura & Co. and Nippon funmatsu yakuhin Co., LTD, for providing the samples.
Compliance with ethical standards
Conflict of interest
The authors declare that they are no conflict of interest.
- 3.Department of Pharmacognosy, Phytochemistry and Narcotics (DPPN), National Institute of Health Sciences (NIHS) of Japan and National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN). Standards of Reporting Kampo Products (STORK) (http://mpdb.nibiohn.go.jp/stork/)
- 4.Institute of Natural Medicine, University of Toyama. Traditional Medical & Pharmaceutical Database (http://dentomed.toyama-wakan.net/en/medical_information_on_kampo_formulas/goshajinkigan/SCP000052)
- 7.Yamamoto T, Murai T, Ueda M, Katsuura M, Oishi M, Miwa Y, Okamoto Y, Uejima E, Taguchi T, Noguchi S, Kurokawa N (2009) Clinical features of paclitaxel-induced peripheral neuropathy and role of Gosya-jinki-gan. Gan To Kagaku Ryoho 36:89–92 (Article in Japanese) Google Scholar
- 9.Suzuki T, Miyamoto K, Yokoyama N, Sugi M, Kagioka A, Kitao Y, Adachi T, Ohsawa M, Mizukami H, Makino T (2016) Processed aconite root and its active ingredient neoline may alleviate oxaliplatin-induced peripheral neuropathic pain. J Ethnopharmacol 186:44–52. https://doi.org/10.1016/j.jep.2016.03.056 CrossRefGoogle Scholar
- 11.Andoh T, Kato M, Kitamura R, Mizoguchi S, Uta D, Toume K, Komatsu K, Kuraishi Y (2016) Prophylactic administration of an extract from Plantaginis Semen and its major component aucubin inhibits mechanical allodynia caused by paclitaxel in mice. J Tradit Complement Med 6:305–308. https://doi.org/10.1016/j.jtcme.2015.12.001 CrossRefGoogle Scholar
- 16.Kawamura T, Hisata Y, Okuda K, Hoshino S, Noro Y, Tanaka T, Kodama A, Nishibe S (1998) Pharmacognostical Study of Plantaginis Herba (13) Constituents of Seeds of Plantago sp. and Commercial Plantago Seeds. Nat Med 52:5–9Google Scholar
- 19.Peng QH, Han ZZ, Tong RC, Hu XQ, Yang QM, Qi M, Shi YH, Wang ZT, Yang L (2017) Chemical constituents from hypoglycemic active part of Plantaginis Semen. Zhongguo Zhong Yao Za Zhi 42:4150–4153. https://doi.org/10.19540/j.cnki.cjcmm.20170905.009 (Article in Chinese) Google Scholar
- 23.Andoh T, Uta D, Kato M, Toume K, Komatsu K, Kuraishi Y (2017) Prophylactic administration of aucubin inhibits paclitaxel-induced mechanical allodynia via the inhibition of endoplasmic reticulum stress in peripheral schwann cells. Biol Pharm Bull 40:473–478. https://doi.org/10.1248/bpb.b16-00899 CrossRefGoogle Scholar
- 24.Bahar MA, Andoh T, Ogura K, Hayakawa Y, Saiki I, Kuraishi Y (2013) Herbal medicine goshajinkigan prevents paclitaxel-induced mechanical allodynia without impairing antitumor activity of paclitaxel. Evid Based Complement Altern Med 2013:849754. https://doi.org/10.1155/2013/849754 CrossRefGoogle Scholar
- 29.Nagata Y, Watanabe T, Nagasaka K, Yamada M, Murai M, Takeuchi S, Murase M, Yazaki T, Murase T, Komatsu K, Kaizuka M, Sano M, Asano K, Ando C, Taniuchi N (2016) Total dosage of gardenia fruit used by patients with mesenteric phlebosclerosis. BMC Complement Altern Med 16:207. https://doi.org/10.1186/s12906-016-1182-1 CrossRefGoogle Scholar
- 30.Hiramatsu K, Sakata H, Horita Y, Orita N, Kida A, Mizukami A, Miyazawa M, Hirai S, Shimatani A, Matsuda K, Matsuda M, Ogino H, Fujinaga H, Terada I, Shimizu K, Uchiyama A, Ishizawa S, Abo H, Demachi H, Noda Y (2012) Mesenteric phlebosclerosis associated with long-term oral intake of geniposide, an ingredient of herbal medicine. Aliment Pharmacol Ther 36:575–586. https://doi.org/10.1111/j.1365-2036.2012.05221 CrossRefGoogle Scholar
- 31.Ohtsu K, Matsui T, Nishimura T, Hirai F, Ikeda K, Iwashita A, Yorioka M, Hatakeyama S, Hoashi T, Koga Y, Sakurai T, Miyaoka M (2014) Association between mesenteric phlebosclerosis and Chinese herbal medicine intake. Nihon Shokakibyo Gakkai Zasshi 111:61–68 (Article in Japanese) Google Scholar
- 33.Zhou Q, Lu W, Niu Y, Liu J, Zhang X, Gao B, Akoh CC, Shi H, Yu L (2013) Identification and quantification of phytochemical composition and anti-inflammatory, cellular antioxidant, and radical scavenging activities of 12 Plantago species. J Agric Food Chem 61:6693–6702. https://doi.org/10.1021/jf401191q CrossRefGoogle Scholar