Effects of Rikkunshi-To, a Japanese kampo medicine, on donepezil- induced gastrointestinal side effects in mice

Donepezil, an acetylcholinesterase inhibitor, is associated with gastrointestinal symptoms, such as nausea, vomiting, and anorexia, which may affect adherence to continuous therapy. Since Rikkunshi-To, a Japanese herbal medicine, activates the ghrelin signaling pathway and promotes gastrointestinal func-tion, it is administered to prevent gastrointestinal symptoms. We herein investigated whether donepezil-induced gastrointestinal side effects in mice are ameliorated by Rikkunshi-To and if its therapeutic ef-ficacy is mediated by ghrelin. Since pica behavior, the ingestion of kaolin, correlates with nausea and vomiting in humans, donepezil was intraperitoneally administered with or without Rikkunshi-To daily to mice, and food and kaolin intakes were monitored. The effects of donepezil on intestinal motility and a ghrelin receptor antagonist on donepezil-induced pica behavior, anorexia, and changes in intestinal motility were examined in mice treated with Rikkunshi-To. Pica behavior and anorexia were significantly induced by donepezil and significantly inhibited by Rikkunshi-To. Intestinal motility was significantly suppressed by donepezil and promoted by Rikkunshi-To. Furthermore, the therapeutic effects of Rikkunshi-To were antagonized by the ghrelin receptor antagonist. The present results support the therapeutic efficacy of Rikkunshi-To against donepezil-induced gastrointestinal side effects. (c) 2022 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).