Download PDF
Pharmacopsychiatry 2001; 34(Suppl1): 8-10
DOI: 10.1055/s-2001-15507
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Interleukin-6 Involvement in Antidepressant Action of Hypericum Perforatum

G. Calapai1 , A. Crupi2 , F. Firenzuoli3 , G. Inferrera1 , G. Ciliberto4 , A. Parisi1 , G. De Sarro4 , A. P. Caputi1
  • 1Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica Policlinico Universitario, Italy
  • 2Pharmalife-Italia, Airuno (LC) Italy
  • 3Service of Phytotherapy, S. Giuseppe Hospital, ASL n. Empoli, Italy
  • 4Department of Clinical and Experimental Medicine, University of Reggio Calabria, Italy
Further Information

Publication History

Publication Date:
31 December 2001 (online)

Also available at
    Permissions and Reprints

Hypericum, a plant widely used as antidepressant has been shown to interact with the immune system. We studied the effects of the administration of the Hypericum perforatum extract Ph-50, a Hypericum extract, standardized to flavonoids (50 %) and containing 0.3 % of hypericin and 4.5 % of hyperforin in a forced swimming test and tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) diencephalic content using a high performance liquid chromatography method in male interleukin-6 (IL-6) knock-out (IL-6-/-) and wild type (IL-6+/+) mice. Hypericum extract (Ph-50; 500 mg/kg) oral acute administration reduced the immobility time of wild type, but not of knockout mice. Tryptophan content was not modified by Hypericum in all the animal groups. Serotonin and 5-HIAA diencephalic content was increased by Hypericum in both wild type and knockout mice. However, the increase observed in the wild type was greater than in knockout mice. These data indicate that IL-6 could be necessary to the antidepressant action of Hypericum, and that this cytokine (probably) mediates the effects of Hypericum through activation of the serotonin system.

References

  • 1 Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine.  Adv Immunol. 1993;  54 1-78
    PubMedGoogle Scholar
  • 2 Barkhudaryan N, Dunn A J. Molecular mechanisms of actions of interleukin-6 on the brain, with special reference to serotonin and the hypothalamo-pituitary-adrenocortical axis.  Neurochem Res. 1999;  24 1169-1180
    CrossrefPubMedGoogle Scholar
  • 3 Barton B E. The biological effects of interleukin-6.  Med Res Rev. 1996;  16 87-109
    CrossrefPubMedGoogle Scholar
  • 4 Baumann H, Gauldi J. The acute phase response.  Immunol Today. 1994;  15 74-80
    CrossrefPubMedGoogle Scholar
  • 5 Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of Hypericum extract.  J Geriatric Psychiatr Neurol. 1994;  7 S57-S59
    PubMedGoogle Scholar
  • 6 Bennett D A, Phun L, Polk J F, Voglino S A, Zlotnik V, Raffa R B. Neuropharmacology of St. John's Wort (Hypericum).  Ann Pharmacother. 1998;  32 1201-1208
    PubMedGoogle Scholar
  • 7 Calapai G, Crupi A, Firenzuoli F, Inferrera G, Campo G M, Caputi A P. Effects of Hypericum perforatum on levels of 5-Hydroxytryptamine, Noradrenaline and Dopamine in the cortex, diencephalon and brainstem of the rat.  J Pharm Pharmacol. 1999a;  51 723-728
    CrossrefPubMedGoogle Scholar
  • 8 Calapai G, Corica F, Corsonello A, Sautebin L, Di Rosa M, Campo G M, Buemi M, Nicita Mauro V, Caputi A P. Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis.  J Clin Invest. 1999b;  104 975-982
    PubMedGoogle Scholar
  • 9 Kluger M J, Kozak W, Leon L R, Conn C A. The use of knockout mice to understand the role of cytokines in fever.  Clin Exp Pharmacol Physiol. 1998;  25 141-144
    PubMedGoogle Scholar
  • 10 Linde K, Ramirez G, Mulrow C D, Pauls A, Weidenhammer W, Melchart D. St John's wort for depression - an overview and meta-analysis of randomised clinical trials.  Brit Med J. 1996;  313 253-258
    PubMedGoogle Scholar
  • 11 Lucki I. The forced swimming test as a model for core and component behavioral effects of antidepressant drugs.  Behav Pharmacol. 1997;  8 523-532
    CrossrefPubMedGoogle Scholar
  • 12 Lutgendorf S K, Garand L, Buckwalter K C, Reimer T T, Hong S Y, Lubaroff D M. Life stress, mood disturbance, and elevated interleukin-6 in healthy older women.  J Gerontol A Biol Sci Med Sci. 1999;  54 M434-M439
    CrossrefPubMedGoogle Scholar
  • 13 Meyers C A. Mood and cognitive disorders in cancer patients receiving cytokine therapy.   Adv Exp Med Biol. 1999;  461 75-81
    PubMedGoogle Scholar
  • 14 Müller W E, Rossol R. Effects of Hypericum extract on the expression of serotonin receptors.  J Geriatr Psychiatry Neurol. 1994;  7 (Suppl. 1) S63-S64
    PubMedGoogle Scholar
  • 15 Müller W E, Singer A, Wonnemann M, Hafner U, Rolli M, Schafer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hypericum extract.  Pharmacopsychiat.. 1998;  31 (Suppl. 1) 16-2 1
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Nahrstedt A, Butterweck V. Biologically active and other chemical constituents of the herb of Hypericurn perforatum L.  Pharmacopsychiat.. 1997;  30 (Suppl. 2) 29-34
    PubMedGoogle Scholar
  • 17 Nathan P. The experimental and clinical pharmacology of St. John's Wort (Hypericum perforatum L).  Mol. Psichiatry. 1999;  4 333-338
    CrossrefPubMedGoogle Scholar
  • 18 Porsolt R D, Anton G, Blavet N, Jafre M. Behavioral despair in rats: A new model sensitive to antidepressant.  Eur J Pharmacol. 1978;  47 379-391
    CrossrefPubMedGoogle Scholar
  • 19 Schobitz B, de Kloet E R, Holsboer F. Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain.  Prog Neurobiol. 1994;  44 397-432
    CrossrefPubMedGoogle Scholar
  • 20 Schobitz B, de Kloet E R, Sutanto W, Holsboer F. Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain.  Eur J Neurosci. 1993;  5 1426-1435
    PubMedGoogle Scholar
  • 21 Schobitz B, Pezeshki G, Pohl T, Hemman U, Heinrich P C, Holsboer F, Reul J MHM. Soluble interleukin-6 (IL-6) receptor augments central effects of IL-6 in vivo.  FASEB J. 1995;  9 659-664
    PubMedGoogle Scholar
  • 22 Sébire G, Emilie D, Wallon C, Wry C, Devergne O, Delfraissy J F, Galanaud P, Tardieu M. In vitro production of IL-6, IL-1b, and tumor necrosis factor-a by human embryonic microglial and neural cells.  J Immunol. 1993;  150 1517-1523
    PubMedGoogle Scholar
  • 23 Seidel A, Rothermundt M, Rink L. Cytokine production in depressed patients.  Adv Exp Med Biol. 1999;  461 47-57
    PubMedGoogle Scholar
  • 24 Song C, Merali Z, Anisman H. Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment.  Neuroscience. 1999;  88 823-836
    CrossrefPubMedGoogle Scholar
  • 25 Suzuki O, Katsumata Y, Oya M, Bladt S, Wagner H. Inhibition of monoamine oxidase by hypericin.  Planta Med.. 1984;  50 272-274
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Thiele B, Brink I, Ploch, M. Modulation of cytokine expression by hypericum extract.  J Geriatr Psychiatry Neurol. 1994;  7 (Suppl. 1) S60-S62
    PubMedGoogle Scholar
  • 27 Yu P H. Effect of Hypericum perforatum extract on serotonin turnover in the mouse brain.  Pharmacopsychiat.. 2000;  33 60-65
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Wang J, Dunn A J. Mouse interleukin-6 stimulates the HPA axis and increases brain tryptophan and serotonin metabolism.  Neurochem Int. 1998;  33 143-154
    CrossrefPubMedGoogle Scholar

MD Dr. Gioacchino Calapai

Institute of Pharmacology
School of Medicine
University of Messina

Via Consolare Valeria 49

Policlinico Universitario - Torre Biologica 5° Piano

98124 - Messina

Italy

Phone: 090/2213646

Fax: 090/2213300

Email: gcalapai@unime.it

      >