In Vitro Effects of the Dicyclohexylammonium Salt of Hyperforin on Interleukin-6 Release in Different Experimental Models

Abstract

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. [³ H]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.

References

• 1 Linde K, Mulrow C D. St John’s wort for depression. Cochrane Database Syst Rev 2000 CD000448
• 2 Greeson J M, Sanford B, Monti D A. St. John’s wort (Hypericum perforatum): a review of the current pharmacological, toxicological, and clinical literature.  Psychopharmacology (Berl). 2001;  153 402-14
• 3 Nahrstedt A, Butterweck V. Biologically active and other chemical constituents of the herb of Hypericum perforatum L.  Pharmacopsychiatry. 1997;  30 (Suppl 2) 129-34
• 4 Butterweck V, Jurgenliemk G, Nahrstedt A, Winterhoff H. Flavonoids from Hypericum perforatum show antidepressant activity in the forced swimming test.  Planta Medica. 2000;  66 3-6
• 5 Butterweck V, Christoffel V, Nahrstedt A, Petereit F, Spengler B, Winterhoff H. Step by step removal of hyperforin and hypericin: activity profile of different Hypericum preparations in behavioral models.  Life Sciences. 2003;  73 627-39
• 6 Butterweck V, Petereit F, Winterhoff H, Nahrstedt A. Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test.  Planta Medica. 1998;  64 291-4
• 7 Chatterjee S S, Bhattacharya S K, Wonnemann M, Singer A, Muller W E. Hyperforin as a possible antidepressant component of Hypericum extracts.  Life Sciences. 1998;  63 499-510
• 8 Gambarana C, Tolu P L, Masi F, Rinaldi M, Giachetti D, Morazzoni P. et al . A study of the antidepressant activity of Hypericum perforatum on animal models.  Pharmacopsychiatry. 2001;  34 (Suppl 1) S42-4
• 9 Cervo L, Rozio M, Ekalle-Soppo C B, Guiso G, Morazzoni P, Caccia S. Role of hyperforin in the antidepressant-like activity of Hypericum perforatum extracts.  Psychopharmacology. 2002;  164 423-8
• 10 Gobbi M, Dalla Valle F, Ciapparelli C, Diomede L, Morazzoni P, Verotta L. et al . Hypericum perforatum L. extract does not inhibit 5-HT transporter in rat brain cortex.  Naunyn-Schmiedebergs Archives of Pharmacology. 1999;  360 262-9
• 11 Gobbi M, Mennini T. Is St John’s wort a ‘Prozac-like’ herbal antidepressant?.  Trends in Pharmacological Sciences. 2001;  22 557-9
• 12 Butterweck V, Nahrstedt A, Evans J, Hufeisen S, Rauser L, Savage J. et al . In vitro receptor screening of pure constituents of St. John’s wort reveals novel interactions with a number of GPCRs.  Psychopharmacology. 2002;  162 193-202
• 13 Butterweck V, Winterhoff H, Herkenham M. St John’s wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term and long-term administration in normal and stressed rats.  Mol Psychiatry. 2001;  6 547-64
• 14 Fiebich B L, Hollig A, Lieb K. Inhibition of substance P-induced cytokine synthesis by St. John’s wort extracts.  Pharmacopsychiatry. 2001;  34 (Suppl. 1) S26-8
• 15 Stout S C, Owens M J, Nemeroff C B. Neurokinin(1) receptor antagonists as potential antidepressants.  Annual Review of Pharmacology and Toxicology. 2001;  41 877-906
• 16 Dantzer R, Wollman E E, Yirmiya R. Cytokines and depression: an update.  Brain, Behaviour and Immunology. 2002;  16 501-2
• 17 Besedovsky H O, del Rey A. Immune-neuro-endocrine interactions: facts and hypotheses.  Endocr Rev. 1996;  17 64-102
• 18 Thiele B, Brink I, Ploch M. Modulation of cytokine expression by Hypericum extract.  Journal of Geriatric Psychiatry and Neurology. 1994;  7 (Suppl 1) S60-2
• 19 Biber A, Fischer H, Romer A, Chatterjee S S. Oral bioavailability of hyperforin from Hypericum extracts in rats and human volunteers.  Pharmacopsychiatry. 1998;  31 (Suppl 1) 36-43
• 20 Calapai G, Crupi A, Firenzuoli F, Inferrera G, Ciliberto G, Parisi A. et al . Interleukin-6 involvement in antidepressant action of Hypericum perforatum .  Pharmacopsychiatry. 2001;  34 (Suppl 1) S8-10
• 21 Verotta L, Appendino G, Belloro E, Bianchi F, Sterner O, Lovati M. et al . Synthesis and biological evaluation of hyperforin analogues. Part I. Modification of the enolized cyclohexanedione moiety.  J Nat Prod. 2002;  65 433-8
• 22 Palma C, Nardelli F, Manzini S. Correlation between binding characteristics and functional antagonism in human glioma cells by tachykinin NK1 receptor antagonists.  European Journal of Pharmacology. 1999;  374 435-43