Influence of hyperoside and hyperforin on the regulation of β1-adrenergic receptors on living C6 glioblastoma cells: A new postsynaptic approach for the mode of action of St. John's wort
In depressive disorders hyperactivity of the hypothalamic-pituitary-adrenal axis is one of the most consistent findings which can be corrected with standard antidepressant drugs. One of the receptors involved in mediating the effects of antidepressants is the β1-adrenergic receptor (β1-AR). It was shown that pretreatment of C6-cells (overexpressing the β1-AR-GFP) with 1µM of hyperforin or hyperoside from St. John's wort extract, led to β1-AR downregulation , the same holds true for desipramine (DMI) and was explained by inhibition of receptor recycling . Here we investigated the effects of preincubation with 1µM of DMI, hyperforin and hyperoside on cAMP-levels of C6-cells. Compared to non-treated control cells, both hyperforin and DMI decreased the basal cAMP-level, while hyperoside did not show any effect. In contrast, under stimulating conditions hyperoside reduced the dobutamine (selective β1-agonist) mediated increase in cAMP formation significantly, whereas stimulation of the remaining β1-AR seemed to be unaffected after both DMI and hyperforin preincubation. Although pretreatment of C6-cells with DMI, hyperforin and hyperoside under stimulating conditions led to a similar reduction in cAMP formation, apparently different modes of action are responsible for this effect. Remarkably, reduction in β1-adrenergic sensitivity of C6-cells with hyperforin and hyperoside from St. John's wort extracts was found without the need of increased presynaptic neurotransmitter release and downstream regulatory processes. Thus, the direct influence of hyperforin and hyperoside on the regulation of postsynaptic β1-adrenergic receptors is a novel contribution to the mode of action of St. John's wort extracts in the treatment of mild to moderate cases of depression.
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