Abstract
The traditional Japanese phytomedicine rikkunshito is traditionally used for the treatment of gastrointestinal motility disorders, cachexia and nausea. These effects indicate 5-HT3 receptor antagonism, due to the involvement of these receptors in such pathophysiological processes. E.g., setrons, specific 5-HT3 receptor antagonists are the strongest antiemetics, developed so far. Therefore, the antagonistic effects of the eight rikkunshito constituents at heterologously expressed 5-HT3Areceptors were analyzed using the two-electrode voltage-clamp technique. The results indicate that tinctures from Aurantii, Ginseng, Zingiberis, Atractylodis and Glycyrrhiza inhibited the 5-HT3A receptor response, whereas the tinctures of Poria cocos, Jujubae and Pinellia exhibited no effect. Surprisingly, the strongest antagonism was found for Glycyrrhiza, whereas the Zingiberis tincture, which is considered to be primarily responsible for the effect of rikkunshito, exhibited the weakest antagonism of 5-HT3A receptors. Rikkunshito contains various vanilloids, ginsenosides and flavonoids, a portion of which show an antagonistic effect on 5-HT3 receptors. A screening of the established ingredients of the active rikkunshito constituents and related substances lead to the identification of new antagonists within the class of flavonoids. The flavonoids (-)-liquiritigenin, glabridin and licochalcone A from Glycyrrhiza species were found to be the most effective inhibitors of the 5-HT-induced currents in the screening. The flavonoids (-)-liquiritigenin and hesperetin from Aurantii inhibited the receptor response in a non-competitive manner, whereas glabridin and licochalcone A exhibited a potential competitive antagonism. Furthermore, licochalcone A acts as a partial antagonist of 5-HT3A receptors. Thus, this study reveals new 5-HT3A receptor antagonists with the aid of increasing the comprehension of the complex effects of rikkunshito.
Highlights
The 5-HT3 receptor channels are the only ionotropic receptors within the 5-HT receptor family and belong to the cys-loop family of ligand-gated ion channels (Derkach et al, 1989; Hannon and Hoyer, 2008)
The inhibition obtained with the rikkunshito tincture (33.7 ± 1.5%) was close to that calculated by the addition of the effects of the tinctures of the eight constituents with regard to their mass distribution in the decoction (27.5%) (Supplementary Table 1)
Rikkunshito is a Japanese herbal medicine that shows orexigen and antiemetic effects (Takeda et al, 2008; Fujitsuka and FIGURE 2 | 5-HT3A receptor inhibition by the substances and the unsweetened licorice tincture (A) and original traces of the antagonistic effect of hesperetin and (-)-liquiritigenin (B). (A) Of the tested substances, the flavonoids exhibited the strongest inhibition with hesperetin and rutin from Aurantii and licochalcone A and (-)-liquiritigenin from Glycyrrhiza species
Summary
The 5-HT3 receptor channels are the only ionotropic receptors within the 5-HT receptor family and belong to the cys-loop family of ligand-gated ion channels (Derkach et al, 1989; Hannon and Hoyer, 2008). Other 5-HT3 receptor expressing structures are the nucleus tractus solitarius and the area postrema (Boess and Martin, 1994), which are parts of the vomiting center that trigger nausea and vomiting. Many plant compounds act as 5-HT3 receptor antagonists. Alkaloids, such as nicotine (Schreiner et al, 2014), hot substances and terpenes, e.g., bilobalide and ginkgolide B (Thompson et al, 2011), gingerols (Walstab et al, 2013) and many others, were reviewed by Walstab et al (2010)
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