Tu2085 Rikkunshito Prevents Levodopa-Inhibited Gastric Motility in Fasted Rats

Abstract

Background: The most commonly used drug for Parkinson disease (PD) therapy, levodopa (L-dopa) induces delayed gastric emptying (GE) in PD patients and healthy controls. We previously reported that ghrelin could prevent L-dopa-inhibited GE in rats. Rikkunshito is a kampo medicine that increases ghrelin in humans and mice and used clinically in Japan to treat functional and chemotherapy-induced dyspepsia, and post-operative gastric ileus. Aim: To investigate whether rikkunshito mimics ghrelin effect to improve gastric motility in L-dopa-treated rats. Methods: In overnight fasted rats, rikkunshito (Gastroenterology 2008, 143:2004), or vehicle (distilled water) was administered by orogastic gavage (og) 170 min before L-dopa/carbidopa (LD/CD, og), 10 min later followed by a meal (methylcellulose/ phenol red or 40% powder meal in water with 50% glass bead, og), and GE was assessed 20 min (non-nutrient solution) or 60 min (nutrient meal) thereafter. The ghrelin antagonist, D-[Lys3]-GHRP-6 was injected IP at the same time as rikkunshito and GE was determined 20 min after og LD/CD or vehicle. Strain gauge transducer was implanted in the rat antrum. After 6 days, overnight food restricted rats were treated with rikkunshito or vehicle and 170 min later with L-dopa or vehicle (IP) and then 10 min later, the powder meal solution was gavaged and antral motility was recorded for 60 min. Food intake was monitored after rikkunshito and LD/CD gavage in overnight fasted rats. Results: LD/CD (15/1.5, 20/2 and 50/5 mg/kg, og) dose-dependently inhibited GE of nutrient meal (58.1±4.1%, 41.9±5.8%*, 28.9±5.6%* vs. vehicle 72.9±5.2%, respectively, *:p,0.05). In vehicle pretreated rats, LD/ CD (20/2 mg/kg, og) decreased GE of a non-nutrient meal compared to vehicles (12.1±7.4% vs. 49.3±7.0%, p,0.05). Rikkunshito (0.5 or 1.0 g/kg, og) prevented dose-dependently the LD/CD inhibitory effect on GE (36.9±7.4% and 46.6±4.8% respectively, p,0.05 vs. vehicle plus LD/CD) while having no effect alone (56.6±8.5%). Likewise, rikkunshito (1.0 g/kg) blocked LD/CD reduced GE of the nutrient meal (61.4±4.1% vs. 43.0±5.0%, p ,0.05) compared to vehicles (71.5±5.0%). L-dopa (15 mg/kg)-induced reduction of antral motility (motility index 78.3±3.4 vs. vehicle 103.3±6.7, p,0.05) was blocked by rikkunshito (1.0 g/kg; motility index 102.0±5.4). D-[Lys3]-GHRP-6 (1 mg/kg) partially reversed rikkunshito effect on LD/CD-inhibited GE. There was no significant difference in cumulative food intake response to a fast at 1, 2, 4 and 24 h after og rikkunshito (1.0 g/kg) plus LD/CD (20/2 mg/ kg). Conclusions: Rikkunshito exerts a gastroprokinetic effect under conditions of levodopainhibited gastric motor function that may be in part mediated by ghrelin. Rikkunshito may have therapeutic application to improve gastric transit in levodopa treated-PD patients. Supported by Tsumura & Co. and NIDDK 41303 (animal core)