AUTHOR=Herbrechter Robin , Ziemba Paul M., Hoffmann Katrin M., Hatt Hanns , Werner Markus , Gisselmann Guenter 

TITLE=Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids

JOURNAL=Frontiers in Pharmacology

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2015.00130

DOI=10.3389/fphar.2015.00130

ISSN=1663-9812

ABSTRACT=<p>The traditional Japanese phytomedicine rikkunshito is traditionally used for the treatment of gastrointestinal motility disorders, cachexia and nausea. These effects indicate 5-HT<sub>3</sub> receptor antagonism, due to the involvement of these receptors in such pathophysiological processes. E.g., setrons, specific 5-HT<sub>3</sub> receptor antagonists are the strongest antiemetics, developed so far. Therefore, the antagonistic effects of the eight rikkunshito constituents at heterologously expressed 5-HT<sub>3A</sub>receptors were analyzed using the two-electrode voltage-clamp technique. The results indicate that tinctures from <italic>Aurantii</italic>, <italic>Ginseng</italic>, <italic>Zingiberis</italic>, <italic>Atractylodis</italic> and <italic>Glycyrrhiza</italic> inhibited the 5-HT<sub>3A</sub> receptor response, whereas the tinctures of <italic>Poria cocos</italic>, <italic>Jujubae</italic> and <italic>Pinellia</italic> exhibited no effect. Surprisingly, the strongest antagonism was found for <italic>Glycyrrhiza</italic>, whereas the <italic>Zingiberis</italic> tincture, which is considered to be primarily responsible for the effect of rikkunshito, exhibited the weakest antagonism of 5-HT<sub>3A</sub> receptors. Rikkunshito contains various vanilloids, ginsenosides and flavonoids, a portion of which show an antagonistic effect on 5-HT<sub>3</sub> 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 <italic>Glycyrrhiza</italic> species were found to be the most effective inhibitors of the 5-HT-induced currents in the screening. The flavonoids (-)-liquiritigenin and hesperetin from <italic>Aurantii</italic> 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-HT<sub>3A</sub> receptors. Thus, this study reveals new 5-HT<sub>3A</sub> receptor antagonists with the aid of increasing the comprehension of the complex effects of rikkunshito.</p>