Ginkgoghrelins, unique acylated flavonoid diglycosides in Folium Ginkgo, stimulate growth hormone secretion via activation of the ghrelin receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: Folium Ginkgo, the dried leaf of Ginkgo biloba L. is a traditional Chinese medicine listed in the Pharmacopoeia of the People's Republic of China with several therapeutic effects, including prevention of aging. It is used as herbal medicine for the treatment of several aging-related diseases. The therapeutic effects of Folium Ginkgo on aging-related diseases are suspected to be similar to the anti-aging effects of growth hormone release induced by ghrelin.

MATERIALS AND METHODS: Candidate components responsible for the anti-aging effects via the ghrelin receptor-activated pathway were searched from the known compounds found in Folium Ginkgo. Two acylated flavonoid diglycosides, tentatively named ginkgoghrelins in this study, were selected and isolated from the methanol extract of Folium Ginkgo, and their chemical structures were confirmed by spectroscopic analysis. These two compounds were examined for their capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. The major metabolites of ginkgoghrelins in rat bile were detected after intravenous injection and structurally analyzed by mass spectroscopy. Molecular modeling of ginkgoghrelins docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket.

RESULTS: Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, ginkgoghrelins were 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(7,9), Leu(11)]-substance P, an inverse agonist of the ghrelin receptor. Putative metabolites of ginkgoghrelins via glucuronidation and methylation were detected in bile of rats after intravenous injection. Molecular modeling and docking showed that ginkgoghrelins as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor.

CONCLUSION: The results suggest that ginkgoghrelins are putative components partly accounting for the anti-aging effects of Folium Ginkgo possibly via activation of the ghrelin receptor, and possess great potential to be developed as non-peptidyl analogs of ghrelin.