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

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.

Chemical profiling and pharmaco‐toxicological activity ofOriganum sipyleumextracts: Exploring for novel sources for potential therapeutic agents

“…Nonetheless, ethyl acetate extract revealed the highest content in flavonoids, which have been demonstrated to exert protective effects via multiple mechanisms. Actually, the blunting effects induced by ethyl acetate extract on the selected pro‐inflammatory and pro‐oxidant biomarkers could be due, albeit partially, to flavonoid‐induced inhibitory effects on LDH, COX‐2, 5‐HT3 receptor, and i‐NOS, whose upregulation have been causally related to inflammatory conditions and tissue damage (Chandel, Rawal, & Kaur, ; He et al, ; Herbrechter et al, ; Mousavizadeh et al, ; Zhang et al, ). The observed downregulating effects on the tested biomarkers could be also consistent with extract content in gentisic acid, rosmarinic acid, and phloridzin (Table ).…”

“…Overall, extracts downregulated all tested biomarkers of oxidative stress and inflammation, thus supporting a protective role in the colon. (Chandel, Rawal, & Kaur, 2018;He et al, 2018;Herbrechter et al, 2015;Mousavizadeh et al, 2009;Zhang et al, 2018). The ob-…”

Protective effects induced by alcoholic Phlomis fruticosa and Phlomis herba‐venti extracts in isolated rat colon: Focus on antioxidant, anti‐inflammatory, and antimicrobial activities in vitro

“…On the one hand, the total phenol and flavonoid contents could reduce 5-HT levels, as a result of the antioxidant activity. On the other hand, we cannot exclude a possible inhibitory effect on 5-HT activity induced by multiple components of flavonoid fraction, which could reduce 5-HT levels and release, including benzoic acid and rutin, thus antagonizing proinflammatory 5-HT3-mediated pathway (Batshaw et al, 1988;Chen, Jin, & Wu, 2002;Herbrechter et al, 2015).…”

Iron Homeostasis in Health and Disease

“…However, the ability of Fe to exchange single electrons with a number of substrates can lead to the generation of reactive oxygen species (ROS), as a result of Fe participation in the Fenton chemistry [ 3 ]. This triggers oxidative stress, lipid peroxidation, and DNA damage, which can lead to genomic instability and DNA repair defects [ 4 , 5 ] that ultimately compromise cell viability and promote programmed cell death (PCD) [ 6 ]. Under physiologic conditions these deleterious effects are prevented by fine-tuned regulatory mechanisms, which maintain systemic and cellular Fe homeostasis [ 7 ] through the cooperation of functional compartments (erythroid and proliferating cells), uptake and recycling systems (enterocytes and splenic macrophages), storage elements (hepatocytes), and mobilization processes that allow Fe trafficking through polarized cells and their corresponding organs, presumably assisted by the poly-r(C)-binding protein-1 (PCBP-1)-mediated transport [ 8 , 9 ].…”