Activation of membrane-located Ca2+ channels by hop beta acids and their tricyclic transformation products

Abstract

Beta-bitter acids of hops (lupulones) revealed sedative and antidepressant-like effects in animal studies. Transformation of β-acids during beer brewing leads to the formation of tricyclic transformation products, which have a close structural analogy to hyperforin. The latter compound is responsible for the antidepressant activity of St. John's wort by activation of TRPC6 cation channels in neuronal-like cells leading to Ca²⁺ influx. In this study, nortricyclolupones, dehydrotricyclolupones, and tricyclolupones were isolated from a wort-boiling model and their structures were elucidated by UHPLC-DAD, UHPLC-ESI^--MS/MS and 1D/2D-NMR spectroscopy. Beta-bitter acids and their transformation products induced Ca²⁺ influx in PC12 cells to the same extent as hyperforin. Application of a Ca²⁺-free environment abolished the Ca²⁺ elevation, indicating that the increase is mediated by influx across the plasma membrane. Thus, activation of neuronal-like Ca²⁺-channels by lupulones and tricyclolupones represent a novel mechanism contributing to the antidepressant activity of hops.

Keywords: Antidepressant; Ca(2+) influx; Hops; Lupulones; Neuronal-like cells; Tricyclolupones; β-bitter acids.