In vitro effects of the dicyclohexylammonium salt of hyperforin on interleukin-6 release in different experimental models

Cytokine hypersecretion might be involved in the onset and maintenance of depressive disorders and it has been suggested that St. John's wort extracts (Hypericum perforatum, SJW) might exert their antidepressant-like effects by affecting peripheral interleukin-6 (IL6) expression. We found that hyperforin, one putative active principle of SJW, and its dicyclohexylammonium salt (hyperforin-DCHA), inhibited the substance P (SP)-induced IL6 release in human astrocytoma cells (U373MG) with an IC₅₀ of 1.6 μM, indicating that hyperforin is likely to account for the inhibitory effect previously found in the same experimental model with SJW extracts. [³H]SP binding experiments in parallel on the same intact cells indicate that hyperforin-DCHA does not interact with neurokinin-1 receptors but very likely interacts with some intracellular steps leading to the synthesis and/or release of IL6. Hyperforin-DCHA also inhibited, with a similar IC₅₀, the IL6 release induced in U373MG cells by two other classic proinflammatory stimuli, IL1β and lipopolysaccharide (LPS), as well as the LPS-induced IL6 release in whole rat blood. Hyperforin-DCHA was less active in whole human blood. The concentrations required in vitro to inhibit LPS-induced IL6 release from rat and human whole blood are about one order of magnitude higher than the hyperforin levels measured in the plasma of rats or humans treated with pharmacologically active doses of SJW or hyperforin-DCHA.