Preventive effect of rikkunshito on gastric motor function inhibited by l-dopa in rats

Abstract

We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson’s disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2 mg kg−1) decreased significantly GE to 26.3 ± 6.0% compared to 61.2 ± 3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9 ± 5.8% compared to 72.9 ± 5.2% in og vehicle monitored 60 min after a nutrient meal. Rikkunshito (0.5 or 1.0 g kg−1) reduced the LD/CD (20/2 mg kg−1) inhibition of GE of non-nutrient meal (36.9 ± 7.4% and 46.6 ± 4.8% respectively vs. 12.1 ± 7.4% in og vehicle plus LD/CD) while having no effect alone (56.6 ± 8.5%). The ghrelin antagonist, [d-Lys3]-GHRP-6 (1 mg kg−1) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD-inhibited GE. Rikkunshito (1.0 g kg−1) blocked LD/CD (20/2 mg kg−1)-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson’s disease rat model, rikkunshito (1.0 g kg−1, og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naïve and PD rat model in part through ghrelin-related mechanisms.

New ghrelin agonist, HM01 alleviates constipation and L‐dopa‐delayed gastric emptying in 6‐hydroxydopamine rat model of Parkinson's disease

“…The reason for the difference is not clear and could involve different GE methods and our use of desipramine before the microinjection to prevent the uptake of 6‐OHDA into noradrenergic neurons . We further demonstrated that L‐dopa combined with carbidopa‐inhibited GE similarly in 6‐OHDA and control rats, consistent with clinical studies in PD patients, healthy human volunteers and naïve rats …”

Standardized herbal treatments on functional bowel disorders: moving from putative mechanisms of action to controlled clinical trials

“…In additional studies in rats, RKT and its active ingredient hesperidin dose‐dependently improved gastric emptying delayed by a 5‐HT3 agonist, with an effect comparable to the 5‐HT3 antagonist ondansetron . Pretreatment with RKT reduced the inhibitory effects of levodopa–carbidopa on gastric emptying in rats, with no effect on emptying rate when administered alone . These observations suggest the gastroprokinetic effects of RKT are mediated via multiple pathways.…”

“…6 Pretreatment with RKT reduced the inhibitory effects of levodopa-carbidopa on gastric emptying in rats, with no effect on emptying rate when administered alone. 7 These observations suggest the gastroprokinetic effects of RKT are mediated via multiple pathways.…”

Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis

“…Very little attention, however, has been focused on the GI dysfunctions in models of toxin-mediated parkinsonian-like neurodegeneration in rats. Most of the studies have focused on the effects of neurotoxins on the ENS (4,12,15,33,38,41,51,56,57,61), and, essentially, limited information has been generated linking CNS neurodegeneration with parkinsonian gastric dysmotility. Relatively recent studies by Zheng and colleagues (58,59) show that degeneration of nigral neurons, as obtained either with administration of 6-OHDA or lipopolysaccharide in the SNpc, decreases antral motility, possibly via alterations of the neurochemical phenotype of DMV neurons; the model, however, used bilateral microinjections in the SNpc, which may limit severely the relevance of the observation because of the large array of behavioral side effects induced by the bilateral damage of SNpc (33).…”