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The mechanisms of action of St. John’s wort: an update

Die Wirkmechanismen von Johanniskraut – Ein Update

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Summary

Pharmacological research confirms and supports the clinically observed antidepressant efficacy of St. John’s wort (Hypericum perforatum L., SJW). This contribution is an update of a former review by the authors in 2007. Positive evidence of antidepressant effects has been found with SJW preparations, extract fractions, and single constituents. The efficacy of SJW is obviously defined by a range of parallel mechanisms of action, triggered by different constituents. In vitro research showed, among other tests, positive effects in neurotransmitter regulation (in beta adrenergic systems and glutamate receptors) and ion channel conductance. Antidepressant effects were confirmed in typical in vivo models such as the forced swimming test, the open field test, the tail suspension test, or a model of stress-impaired memory. The overall effect cannot be attributed to a single constituent or fraction. SJW is therefore an outstanding example of the total extract being defined as the active constituent of herbal medicines.

Zusammenfassung

Die pharmakologische Forschung bestätigt und unterstützt die klinisch beobachtete antidepressive Wirksamkeit von Johanniskraut (Hypericum perforatum L.). Dieser Beitrag ist ein Update eines früheren Reviews der Autoren aus dem Jahr 2007. Positive Evidenz für antidepressive Effekte wurde für Johanniskrautzubereitungen, Extraktfraktionen und isolierte Inhaltstoffe gefunden. Die Wirksamkeit von Johanniskraut beruht offenbar auf einer Reihe paralleler Wirkmechanismen, die ihrerseits von verschiedenen Inhaltstoffen ausgelöst werden. Die in vitro-Forschung ergab unter Anderem positive Effekte in der Regulation von Neurotransmitters (betraadrenerge Systeme und Glutamat-Rezeptor) sowie von Ionenkanälen. Eine Bestätigung antidepressiver Effekte fand sich auch in vivo in typischen Modellen wie Forced Swimming Test, Open Field Test, Tail Suspension Test oder einem Modell Stress-bedingt eingeschränkter Gedächtnisleistung. Der Gesamteffekt kann nicht einem einzelnen Inhaltstoff oder einer einzelnen Fraktion zugeordnet werden. Johanniskraut ist damit ein besonders anschauliches Beispiel dafür, dass bei Phytopharmaka der Gesamtextrakt als Wirkstoff zu betrachten ist.

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References

  1. Anon. Community Herbal Monograph on Hypericum perforatum L. Herba (Well-established Medicinal Use). EMA/HMPC/101304/2008. London: European Medicines Agency; 2009.

    Google Scholar 

  2. Anon. Assessment Report on Hypericum perforatum L., Herba. EMA/HMPC/101303/2008. London: European Medicines Agency; 2009.

    Google Scholar 

  3. Bennett DA Jr., Phun L, Polk JF, Voglino SA, Zlotnik V, Raffa RB. Neuropharmacology of St. John’s wort (Hypericum). Ann Pharmacother. 1998;32(11):1201–8.

    Article  PubMed  Google Scholar 

  4. Nathan P. The experimental and clinical pharmacology of St John’s wort (Hypericum perforatum L.). Mol Psychiatry. 1999;4(4):333–8.

    Article  CAS  PubMed  Google Scholar 

  5. Greeson JM, Sanford B, Monti DA. St. John’s wort (Hypericum perforatum): a review of the current pharmacological, toxicological, and clinical literature. Psychopharmacology (Berl). 2001;153(4):402–14.

    Article  CAS  Google Scholar 

  6. Grundmann O, Lv Y, Kelber O, Butterweck V. Mechanism of St. John’s wort extract (STW3-VI) during chronic restraint stress is mediated by the interrelationship of the immune, oxidative defense, and neuroendocrine system. Neuropharmacology. 2010;58(4–5):767–73.

    Article  CAS  PubMed  Google Scholar 

  7. Butterweck V, Schmidt M. St. John’s wort: role of active compounds for its mechanism of action and efficacy. Wien Med Wochenschr. 2007;157(13–14):356–61.

    Article  PubMed  Google Scholar 

  8. Kiyan HT, Demirci B, Baser KH, Demirci F. The in vivo evaluation of anti-angiogenic effects of Hypericum essential oils using the chorioallantoic membrane assay. Pharm Biol. 2014;52(1):44–50.

    Article  CAS  PubMed  Google Scholar 

  9. Billard C, Merhi F, Bauvois B. Mechanistic insights into the antileukemic activity of hyperforin. Curr Cancer Drug Targets. 2013;13(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  10. Zaher M, Tang R, Bombarda I, Merhi F, Bauvois B, Billard C. Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa. Int J Oncol. 2012;40(1):269–76.

    CAS  PubMed  Google Scholar 

  11. Novelli M, Beffy P, Menegazzi M, De Tata V, Martino L, Sgarbossa A, et al. St. John’s wort extract and hyperforin protect rat and human pancreatic islets against cytokine toxicity. Acta Diabetol. 201 4;51: 113–121.

  12. Zeng KW, Wang XM, Ko H, Kwon HC, Cha JW, Yang HO. Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid beta-protein via the PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway. Eur J Pharmacol. 2011;672(1–3):45–55.

    Article  CAS  PubMed  Google Scholar 

  13. Hofrichter J, Krohn M, Schumacher T, Lange C, Feistel B, Walbroel B, et al. Reduced Alzheimer’s disease pathology by St. John’s wort treatment is independent of hyperforin and facilitated by ABCC1 and microglia activation in mice. Curr Alzheimer Res. 2013;10(10):1057–69.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Kraus B, Wolff H, Heilmann J, Elstner EF. Influence of Hypericum perforatum extract and its single compounds on amyloid-beta mediated toxicity in microglial cells. Life Sci. 2007;81(11):884–94.

    Article  CAS  PubMed  Google Scholar 

  15. Saddiqe Z, Naeem I, Maimoona A. A review of the antibacterial activity of Hypericum perforatum L. J Ethnopharmacol. 2010;131(3):511–21.

    Article  CAS  PubMed  Google Scholar 

  16. Xiuying P, Jianping L, Ruofeng S, Liye Z, Xuehong W, Yan L. Therapeutic efficacy of Hypericum perforatum L. extract for mice infected with an influenza A virus. Can J Physiol Pharmacol. 2012;90(2):123–30.

    Article  PubMed  Google Scholar 

  17. Esposito F, Sanna C, Del Vecchio C, Cannas V, Venditti A, Corona A, et al. Hypericum hircinum L. components as new single-molecule inhibitors of both HIV-1 reverse transcriptase-associated DNA polymerase and ribonuclease H activities. Pathog Dis. 2013;68(3):116–24.

    Article  CAS  PubMed  Google Scholar 

  18. Huang N, Singh N, Yoon K, Loiacono CM, Kohut ML, Birt DF. The immuno-regulatory impact of orally-administered Hypericum perforatum extract on Balb/C mice inoculated with H1n1 influenza A virus. PLoS One. 2013;8(9):e76491.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. De Marchis GM, Bürgi S, Kientsch U, Honegger UE. Vitamin E reduces antidepressant-related beta-adrenoceptor down-regulation in cultured cells. Comparable effects on St. John’s wort and tricyclic antidepressant treatment. Planta Med. 2006;72(15):1436–7.

    Article  PubMed  Google Scholar 

  20. Prenner L, Sieben A, Zeller K, Weiser D, Haberlein H. Reduction of high-affinity beta2-adrenergic receptor binding by hyperforin and hyperoside on rat C6 glioblastoma cells measured by fluorescence correlation spectroscopy. Biochemistry. 2007;46(17):5106–13.

    Article  CAS  PubMed  Google Scholar 

  21. Jakobs D, Hage-Hülsmann A, Prenner L, Kolb C, Weiser D, Häberlein H. Downregulation of β1 -adrenergic receptors in rat C6 glioblastoma cells by hyperforin and hyperoside from St John’s wort. J Pharm Pharmacol. 2013;65(6):907–15.

    Article  CAS  PubMed  Google Scholar 

  22. Chang Y, Wang SJ. Hypericin, the active component of St. John’s wort, inhibits glutamate release in the rat cerebrocortical synaptosomes via a mitogen-activated protein kinase-dependent pathway. Eur J Pharmacol. 2010;634(1–3):53–61.

    Article  CAS  PubMed  Google Scholar 

  23. Leuner K, Li W, Amaral MD, Rudolph S, Calfa G, Schuwald AM, et al. Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca(2+) -permeable TRPC6 channels. Hippocampus. 2013;23(1):40–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Gibon J, Deloulme JC, Chevallier T, Ladeveze E, Abrous DN, Bouron A. The antidepressant hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner. Int J Neuropsychopharmacol. 2013;16(1):189–98.

    Article  CAS  PubMed  Google Scholar 

  25. Bouron A, Lorrain E. Effets cellulaires et moléculaires de l’hyperforine, un antidépresseur végétal: revue de la littérature. L’Encephale. 2013;40(2):108–113.

  26. Trofimiuk E, Holownia A, Braszko JJ. Activation of CREB by St. John’s wort may diminish deletorious effects of aging on spatial memory. Arch Pharm Res. 2010;33(3):469–77.

    Article  CAS  PubMed  Google Scholar 

  27. Crupi R, Abusamra YA, Spina E, Calapai G. Preclinical data supporting/refuting the use of Hypericum perforatum in the treatment of depression. CNS Neurol Disord Drug Targets. 2013;12(4):474–86.

    Article  CAS  PubMed  Google Scholar 

  28. Kraus B, Wolff H, Elstner EF, Heilmann J. Hyperforin is a modulator of inducible nitric oxide synthase and phagocytosis in microglia and macrophages. Naunyn Schmiedebergs Arch Pharmacol. 2010;381(6):541–53.

    Article  CAS  PubMed  Google Scholar 

  29. Bukhari IA, Dar A. Behavioral profile of Hypericum perforatum (St. John’s wort) extract. A comparison with standard antidepressants in animal models of depression. Eur Rev Med Pharmacol Sci. 2013;17(8):1082–9.

    CAS  PubMed  Google Scholar 

  30. Liu JX, Fang YQ, Wei ZX, Yang XQ, Zeng LH. Synergic antidepressive effect of quercetin and Hypericum perforatum extract in mice. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2013;42(6):615–9. (Journal of Zhejiang University Medical Sciences).

    CAS  PubMed  Google Scholar 

  31. Uzbay IT, Coskun I, Kayir H, Ozturk N, Ozturk Y. Extract of Hypericum perforatum blocks caffeine-induced locomotor activity in mice: a possible role of nitric oxide. Phytother Res. 2007;21(5):415–9.

    Article  PubMed  Google Scholar 

  32. Grundmann O, Kelber O, Butterweck V. Effects of St. John’s wort extract and single constituents on stress-induced hyperthermia in mice. Planta Med. 2006;72(15):1366–71.

    Article  CAS  PubMed  Google Scholar 

  33. Crupi R, Mazzon E, Marino A, Spada GL, Bramanti P, Battaglia F, et al. Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice. BMC Complement Altern Med. 2011;11:7.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Vissiennon C, Nieber K, Kelber O, Butterweck V. Route of administration determines the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin—are they prodrugs? J Nutr Biochem. 2012;23(7):733–40.

    Article  CAS  PubMed  Google Scholar 

  35. Schulz HU, Schurer M, Bassler D, Weiser D. Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteers. Arzneimittelforschung. 2005;55(10):561–8.

    CAS  PubMed  Google Scholar 

  36. Schulz HU, Schurer M, Bassler D, Weiser D. Investigation of the bioavailability of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin following single and multiple oral dosing of a hypericum extract containing tablet. Arzneimittelforschung. 2005;55(1):15–22.

    CAS  PubMed  Google Scholar 

  37. Trofimiuk E, Holownia A, Braszko JJ. St. John’s wort may relieve negative effects of stress on spatial working memory by changing synaptic plasticity. Naunyn Schmiedebergs Arch Pharmacol. 2011;383(4):415–22.

    Article  CAS  PubMed  Google Scholar 

  38. Trofimiuk E, Braszko JJ. Alleviation by Hypericum perforatum of the stress-induced impairment of spatial working memory in rats. Naunyn Schmiedebergs Arch Pharmacol. 2008;376(6):463–71.

    Article  CAS  PubMed  Google Scholar 

  39. Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci. 2011;7:121–47.

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Herbresearch Germany, Wartbergweg 15, 86874, Tussenhausen, Germany

    Mathias Schmidt PhD

  2. Institut für Pharmazeutische Technologie, Hochschule für Biowissenschaften, Fachhochschule Nordwestschweiz, Gründenstr. 40, 4132, Muttenz, Switzerland

    Veronika Butterweck

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Correspondence to Mathias Schmidt PhD.

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Schmidt, M., Butterweck, V. The mechanisms of action of St. John’s wort: an update. Wien Med Wochenschr 165, 229–235 (2015). https://doi.org/10.1007/s10354-015-0372-7

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  • DOI: https://doi.org/10.1007/s10354-015-0372-7

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