Ivy leaves dry extract EA 575® mediates biased β-adrenergic receptor signaling.

BACKGROUND

β-adrenergic receptor (β-AR) stimulation activates the G protein/cAMP pathway, which is opposed by the GRK2/β-arrestin 2 pathway. The latter is undesirable in the treatment of respiratory diseases.

HYPOTHESIS/PURPOSE: EA 575® is capable of mediating a biased β-adrenergic signaling pathway.

METHODS

The impact of the ivy leaves dry extract EA 575® on β-adrenergic signaling was tested in a dynamic mass redistribution assay in HEK wild-type and in HEK β-arrestin knock-out cells. cAMP formation and recruitment of β-arrestin 2 were investigated using GloSensor™ and PathHunter® assays, respectively. NFκB transcriptional activity was determined in both HEK wild-type as well as HEK β-arrestin knock-out cells.

RESULTS

EA 575® inhibits the recruitment of β-arrestin 2 and thereby enhances G protein/cAMP signaling under β-stimulating conditions, as evidenced by a corresponding increase in cAMP formation. While β-AR-mediated inhibition of NFκB transcriptional activity is β-arrestin-dependent, EA 575® leads to significant inhibition of NFκB transcriptional activity in β-arrestin knock-out cells and thus via a β-arrestin-independent signaling pathway.

CONCLUSION

EA 575® is the first active phytopharmaceutical ingredient for which biased β-adrenergic activation has been described. This shift towards G protein/cAMP signaling provides the molecular basis for the clinically proven efficacy of EA 575® in the treatment of lower respiratory tract diseases. In this light, EA 575® could potentially reduce β-arrestin-mediated adverse effects in new combinatorial therapeutic approaches.