Identification of molecular mechanisms that may contribute to the antidepressant effect of St. John's wort extract Ze 117

Abstract

Chronic stress is one of the factors that contribute to the development and maintenance of depression. Previous studies have shown that the treatment of cultured cells with the natural stress hormone cortisol, but also with synthetic relatives such as dexamethasone, led to a change in their plasma membrane fluidity. Furthermore, it is assumed that this can result in altered properties of membrane receptors that are suspected to be responsible for the development of depression and thus represent targets for its treatment. St. John's wort extract (SJW) Ze 117 has long been used as an alternative to synthetic antidepressants to treat mild to moderate depression. It has also been shown to counteract the glucocorticoid mediated effect on the plasma membrane fluidity of various cell types. Part of its molecular mode of action may therefore be due to an effect on the cellular lipid composition and thus on the properties of plasma membranes and receptor systems embedded within. The prior aim of the present work was to identify cellular target structures that may contribute to the antidepressant effect of Ze 117 using C6 and HEK cell based assays, including fluorescence anisotropy, RT-qPCR, proteomics, lipid analysis, β-arrestin 2 recruitment, and single particle tracking (SPT). <br /> The results show that dexamethasone has an increasing effect on the fluidity of C6 cell plasma membranes which was counteracted by the co-treatment with Ze 117. The performed experiments revealed that this is not due to an effect on the enzyme stearoyl-CoA-desaturase (SCD) but rather on cellular cholesterol synthesis. This was reflected in changed cellular cholesterol contents. While Ze 117 increased the cholesterol content by 42.5 %, dexamethasone reduced cholesterol levels similar to simvastatin. It was also shown that alterations in cholesterol levels affect the interaction of the intracellular protein β-arrestin 2 with the membranous G protein-coupled receptor (GPCR) 5-HT_1A. Moreover, SPT experiments revealed that Ze 117 and other membrane fluidity affecting treatments alter the diffusion state occupancy of SNAP-tagged 5-HT_1A receptor. <br /> In summary, Ze 117 affects membrane fluidity through cholesterol metabolism, impacting 5-HT_1A receptor signal transduction and mobility, suggesting a new antidepressant mechanism.