Hyperforin and Miquelianin from St. Johnʼs Wort Attenuate Gene Expression in Neuronal Cells After Dexamethasone-Induced Stress

Abstract

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis plays an important part in the development of depressive symptoms. In this study, the effects of a commercial St. John's wort extract (STW3-VI), hyperforin, miquelianin, and the selective serotonin reuptake inhibitor citalopram on the expression of genes relevant to HPA axis function were investigated in human neuronal cells. SH-SY5Y cells were treated with STW3-VI (20 µg/mL), hyperforin (1 µM), miquelianin (10 µM), or citalopram (10 µM) in the presence of the glucocorticoid receptor agonist dexamethasone (DEX,10 µM) for 6 h and 48 h, respectively. Quantitative real-time polymerase chain reaction was used to determine the expression of FKBP5 (FK506 binding protein 51), CREB (cAMP responsive element binding protein), GRIK4 (glutamate ionotropic receptor kainate type subunit 4), VEGF (vascular endothelial growth factor), NET (norepinephrine transporter), and ARRB (-arrestins), promising biomarkers of antidepressant therapy. Using DEX to mimic stress conditions, it was shown that the gene expression pattern of FKBP5, CREB, GRIK4, VEGF, NET, and ARRB2 in SH-SY5Y cells is time- and treatment-dependent. Most pronounced effects were observed for FKBP5: after 6 h of co-incubation, only STW3-VI could reverse the DEX-induced increase in FKBP5 expression, and after 48 h, citalopram, miquelianin, and hyperforin also reversed the glucocorticoid-induced increase in FKBP5 mRNA expression. The effects observed on FKBP5, CREB, GRIK4, VEGF, NET, and ARRB2 are in good correlation with published data, suggesting that this model could be used to screen the responsiveness of antidepressants under stress conditions.

Clinical relevance of St. John's wort drug interactions revisited

“…• Verjee, Weston, Kolb, Kalbhenn-Aziz, and Butterweck (2018) showed in recent in vitro experiments that the SSRI citalopram as well as a commercial SJW extract could antagonize the dexamethasone stress-induced increase in expression of the mRNA for FK506-binding protein 51 (FKBP5). FKBP5 is a co-chaperone involved in the translocation of the glucocorticoid receptor (GR).…”

“…Short‐ and long‐term administration of an SJW extract to rats reduced the expression of genes that are involved in the regulation of the hypothalamic–pituitary–adrenal axis and lowered plasma adrenocorticotropic hormone and corticosterone levels. Verjee, Weston, Kolb, Kalbhenn‐Aziz, and Butterweck () showed in recent in vitro experiments that the SSRI citalopram as well as a commercial SJW extract could antagonize the dexamethasone stress‐induced increase in expression of the mRNA for FK506‐binding protein 51 (FKBP5). FKBP5 is a co‐chaperone involved in the translocation of the glucocorticoid receptor (GR).…”

Aktueller Forschungsstand zum pflanzlichen Antidepressivum Johanniskrautextrakt

“…Daher wurden neben den anerkannten pharmakodynamischen Eigenschaften inzwischen weitere Mechanismen untersucht, die das Verständnis der Wirkweise von SJW ergänzen. [13]. Die Stressachse umfasst allerdings auch nicht neuronale Zellen, beispielsweise in der Hypophyse.…”

“…Auf zellulärer Ebene bewirkt SJW eine rasche Senkung der Aktivität des Glukokortikoidrezeptors. Zusätzlich wird die Expression des Stressgens FKBP5 gesenkt, wie im Tiermodell gezeigt wurde [12,13]. Klinische Studien werden zeigen müssen, ob dieser epigenetische Risikofaktor mitilfe von SJW auch vergleichbar im Menschen minimiert werden kann.…”

Hypericum Genus as a Natural Source for Biologically Active Compounds

“…Hypericin and hyperforin are the most well-known compounds, and they originated from the Hypericum species as a source of natural products. Hyperforin regulates the expressions of genes related to depressive states, while hypericin actively reduces stress-induced behaviors and increases the extracellular brain concentrations of glutamate and acetylcholine [ 15 , 16 , 17 ]. Hyperforin also has antimicrobial activity against microorganisms, such as Staphylococcus aureus , Streptococcus pyogenes, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa [ 18 ].…”