Abstract
BackgroundRikkunshito is a traditional Japanese herbal medicine that is used to treat appetite loss associated with cancer and other disorders. The formulation contains various constituents that influence cell signaling, and rikkunshito may accordingly affect human homeostasis through multiple regulatory pathways, including those governed by the endocrine system. We investigated the actions of rikkunshito on catecholamine release from PC12 cells, an adrenal chromaffin cell line.MethodsThe actions of rikkunshito on PC12 cells were evaluated by measuring intracellular cAMP levels, tyrosine hydroxylase (TH) and vasoactive intestinal peptide (VIP) mRNA expression levels, and catecholamine levels in the culture medium. The transcriptional activation of VIP gene by rikkunshito was assessed by using a VIP promoter-driven reporter gene assay.ResultsRikkunshito dose-dependently enhanced forskolin-induced elevations in cAMP in PC12 cells, and also increased the gene expression of TH and VIP. The transcriptional activation of VIP gene by rikkunshito was confirmed. Norepinephrine and dopamine secretion into the culture medium of PC12 cells were also dose-dependently augmented by rikkunshito and/or forskolin, but experiments with a protein kinase C (PKC) activator and a phosphodiesterase inhibitor revealed that the effects of rikkunshito were not simply due to the modulation of PKC or phosphodiesterase activity.ConclusionsThese findings suggest that rikkunshito enhances the release of catecholamines by a novel mechanism involving cAMP.
Highlights
Rikkunshito is a traditional Japanese herbal medicine that is used to treat appetite loss associated with cancer and other disorders
We report that rikkunshito stimulates the release of norepinephrine and dopamine from PC12 cells via a novel mechanism involving cAMP
Effects of rikkunshito on vasoactive intestinal peptide (VIP) promoter activity To confirm that the increased mRNA levels corresponding to the cAMP-responsive tyrosine hydroxylase (TH) and VIP genes were due to enhanced transcription, VIP gene promoter activity was measured in PC12 cells expressing the β-galactosidase reporter gene driven by the VIP gene promoter (PC12-VG cells)
Summary
Rikkunshito is a traditional Japanese herbal medicine that is used to treat appetite loss associated with cancer and other disorders. (w/w)), Poria (poria sclerotium, 18.6%), Ginseng radix (ginseng, 18.6%), Pinelliae tuber (pinellia tuber, 18.6%), Aurantii nobilis pericarpium (citrus unshiu peel, 9.3%), Zizyphi fructus (jujube, 9.3%), Zingiberis rhizoma (ginger, 2.3%), and Glycyrrhizae radix (glycyrrhiza, 4.7%). Because many of these herbal constituents influence cell signaling, rikkunshito may affect human homeostasis through multiple regulatory pathways, including the endocrine system. PC12 cells are often used as a model of the adrenal medulla in pharmacological studies [9] These cells contain endogenous catecholamines that are released in response to distinct stimuli, including various herbal medicine components
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