Use of ginkgolide B and a ginkgolide-activated response element to control gene transcription: example of the adrenocortical peripheral-type benzodiazepine receptor.
Identification of the molecular switch controlling glucocorticoid synthesis might facilitate the development of pharmacological tools to control circulating cortisol levels. The transport of cholesterol from intracellular sources to the inner mitochondrial membrane represents the rate-determining step in the cascade of reactions leading to cortisol synthesis. A key element in this step is the peripheral-type benzodiazepine receptor (PBR). Several studies have indicated the beneficial effects of Ginkgo biloba on memory and stress control. Using pharmacological, biochemical and proteomic methods, we demonstrated that the standardized Ginkgo biloba extract EGb 761 and its isolated component ginkgolide B (GKB) inhibit PBR ligand binding and protein expression, resulting in decreased serum corticosterone levels. We further demonstrated that EGb 761- and GKB-induced inhibition of PBR protein is preceded by a decrease in mRNA-levels due to transcriptional suppression of PBR gene expression. Further studies indicated that the action of GKB is mediated by a transcription factor binding to the PBR gene promoter, thereby regulating PBR gene expression. These data indicate that EGb 761-induced inhibition of glucocorticoid production is due to specific transcriptional suppression of the adrenal PBR gene by GKB, and suggest that EGb 761 and GKB might serve as pharmacological tools to control excess glucocorticoid formation.
Amri
Hakima
H
Department of Cell Biology, Georgetown University Medical Center, Washington, DC, USA.
Drieu
Katy
K
Papadopoulos
Vassilios
V
D000818:Animals; D004224:Diterpenes; D005786:Gene Expression Regulation / Q000187:drug effects; D046934:Ginkgolides; D007783:Lactones / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D020218:Response Elements / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*
D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D018696:Neuroprotective Agents; D010936:Plant Extracts; D011963:Receptors, GABA-A; C045856:ginkgolide B