Emoghrelin, a unique emodin derivative in Heshouwu, stimulates growth hormone secretion via activation of the ghrelin receptor

Ethnopharmacological relevance: Heshouwu, the root of Polygonum multiflorum, is an anti-aging Chinese traditional medicine. Fresh (raw) Heshouwu is commonly converted to processed Heshouwu by specialized heating to alleviate its side effects of diarrhea presumably caused by anthraquinones. However, raw Heshouwu has been noted to be better than processed Heshouwu regarding anti-aging effects. The therapeutic effects of raw Heshouwu on aging-related diseases were somehow similar to the anti-aging effects of growth hormone release induced by ghrelin Materials and methods: Major ingredients in the methanol extract from raw Heshouwu were separated and identified. Emodin-8-O-(6'-O-malonyl)-glucoside, a unique anthraquinone glycoside known to be completely eliminated in the conversion process of Heshouwu was isolated. This emodin derivative, tentatively named emoghrelin, was examined for its cytotoxicity and capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. Moreover, molecular modeling of emoghrelin docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket. Results: No apparent cytotoxicity was observed for emoghrelin of 10(-7)-10(-4) M. Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, emoghrelin was demonstrated to stimulate growth hormone secretion of rat primary anterior pituitary cells in a dose dependent manner, and the stimulation was inhibited by [D-Arg(1), D-Phe(5), D-Trp(79), Leu(11)]-substance P. an antagonist of the ghrelin receptor. Molecular modeling and docking showed that emoghrelin as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor. Conclusion: The results suggest that emoghrelin is a key ingredient accounting for the anti-aging effects of Heshouwu, and possesses great potential to be a promising non-peptidyl analog of ghrelin. (C) 2014 Elsevier Ireland Ltd. All rights reserved.