Effects of Rikkunshi-To on the donepezil-induced gastrointestinal symptoms in mice

Donepezil is used for treatment of Alzheimer's disease, but it is associated with increased risk for gastrointestinal (GI) symptoms, such as anorexia, nausea, and vomiting. Their insufficient control affects the ability to continue the donepezil therapy. Rikkunshi-To (RKT), a traditional herbal Japanese medicine, has been prescribed for patients with various GI symptoms because it improves the GI function via the potentiation of ghrelin signaling pathway. In this study, we investigated the effects of RKT on the prevention of donepezil-induced anorexia, nausea, and vomiting in mice and the involvement of ghrelin in its therapeutic effect. We have reported that donepezil (5mg/kg, i.p.) induced anorexia and pica, kaolin ingestion behavior, could be used to evaluate nausea and vomiting in mice fed the normal diet. Mice fed the diet supplemented with RKT (1%) did not show donepezil-induced anorexia and pica, and this therapeutic effect was antagonized by pretreatment with the ghrelin receptor antagonist. Donepezil significantly suppressed the intestinal motility in mice fed the normal diet; however, RKT recovered the motility delay. Furthermore, the ghrelin receptor antagonist reduced the effect of RKT to improve the intestinal motility. These findings suggest that RKT is a candidate for the treatment of donepezil induced anorexia, nausea, and vomiting in human patients, and that the enhancement of ghrelin signaling is involved in its therapeutic effect.