Download PDF
Pharmacopsychiatry 2001; 34(Suppl1): 83-88
DOI: 10.1055/s-2001-15511
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Effects of Hypericum perforatum L. on Evoked Potentials in Guinea Pig Hippocampal Slices

J. M. Langosch1 , X.-Y. Zhou1 , M. Heinen1 , S. S. Chatterjee2 , M. Nöldner2 , J. Walden1
  • 1Department of Psychiatry, University of Freiburg
  • 2Department of Pharmacology, Willmar-Schwabe-GmbH & Co, Karlsruhe, Germany
Further Information

Publication History

Publication Date:
31 December 2001 (online)

Also available at
    Permissions and Reprints

Therapeutic uses of Hypericum extracts have been demonstrated as safe and effective in treating mild to moderate depression in numerous clinical trials. To date, however, no definitive statements on their mode of action can be made, and little information on their electrophysiological effects is available. The present communication summarises the results of our efforts directed towards clarifying the effects of an ethanolic Hypericum extract (HYP) and its hydrosoluble fraction (HYPWS), and two of its constituents hypericin and hyperforin on electrically evoked population spikes in guinea pig hippocampal slices. In higher concentrations (>10 µM), the two extract constituents tested revealed inhibitory effects only, whereas concentration-dependent (between 10-6 to 10-4 g/l) excitatory effects were observed for HYP and HYPWS. The excitatory effects were strongly amplified by the GABAB antagonist phaclofen, whereas the effects of bicucullin, a GABAA antagonist, were marginal. The excitations were completely blocked by the AMPA antagonist CNQX, but not by the NMDA antagonists APV and MK801 or the L-type calcium-channel blocker verapamil. This kind of excitatory effect on the hippocampus is unknown in other antidepressants and; indeed, many of the latter reduce neuronal excitability. We conclude, therefore, that the mechanisms involved in the antidepressant activity of Hypericum extracts are different from those of conventional antidepressants, and that identifying their excitatory components may facilitate their more rational standardisation.

References

  • 1 Andersen P, Sundberg S H, Sveen O, Swann J W, Wigstrom H. Possible mechanisms for long-lasting potentiation of synaptic transmission in hippocampal slices from guinea pigs.  J Physiol. 1980;  302 463-482
    PubMedGoogle Scholar
  • 2 Asnis G M, Wetzler S, Sanderson W C, Kahn R S, van Praag H M. Functional interrelationship of serotonin and norepinephrine: cortisol responses to MCCP and DMI in patients with panic disorder, patients with depression and normal control subjects.  Psychiatry Research. 1992;  43 65-76
    CrossrefPubMedGoogle Scholar
  • 3 Baker G B, Greenshaw A J. Effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system.  Cellular and Molecular Neurobiology. 1989;  9 1-44
    CrossrefPubMedGoogle Scholar
  • 4 Bartolotto Z A, Bashir Z I, Davies C H, Collingridge G L. A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation.  Nature. 1994;  368 740-743
    CrossrefPubMedGoogle Scholar
  • 5 Bijak M. Prolonged treatment with antidepressant drugs increases the excitatory effect of quinpirole in hippocampal slices.  Polish Journal of Pharmacology.. 1993;  45 381-390
    PubMedGoogle Scholar
  • 6 Bingmann D, Speckmann E J. Specific suppression of pentylenetetrazol-induced epileptiform discharges in CA 3 neurons (hippocampal slice, guinea pig) by the organic calcium antagonists flunarizine and verapamil.  Exp Brain Res. 1989;  72 239-48
    PubMedGoogle Scholar
  • 7 Chatterjee S, Filippov V, Lishko P, Maximyuk O, Nöldner M, Krishtal O. Hyperforin attenuates various ionic conductance mechanisms in the isolated hippocampal neurons of rat.  Life Sciences. 1999;  65 2395-2405
    CrossrefPubMedGoogle Scholar
  • 8 Chatterjee S S, Bhattacharya S K, Wonnemann M, Singer A, Müller W E. Hyperforin as a possible antidepressant component of Hypericum extracts.  Life Sciences. 1998;  63 499-510
    CrossrefPubMedGoogle Scholar
  • 9 Choi J J, Huang G J, Shafik E, Wu W H, McArdle J J. Imiprimine’s selective suppression of a L-type calcium channel in neurons of murine dorsal root ganglia involves G proteins.  Journal of Pharmacology and Experimental Therapeutics. 1992;  263 49-53
    PubMedGoogle Scholar
  • 10 Collingridge G L, Kehl S J, McLennan H. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.  Journal of Physiology. 1983;  334 33-46
    PubMedGoogle Scholar
  • 11 Connors B W, Malenka R C, Silva L R. Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat.  J Physiol. 1988;  406 443-468
    PubMedGoogle Scholar
  • 12 Cookson J. Side effects of antidepressants.  British Journal of Psychiatry. 1993;  163 20-24
    PubMedGoogle Scholar
  • 13 Cott J M. In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract.  Pharmacopsychiatry. 1997;  30 ((Suppl 2)) 108-112
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Czekalla J, Gastpar M, Hübner W -H, Jäger D. The effect of Hypericum extract on cardiac conduction as seen in the electrocardiogram compared to that of imipramine.  Pharmacopsychiatry. 1997;  30 ((Suppl 2)) 86-88
    PubMedGoogle Scholar
  • 15 Czyrak A, Mogilnicka E, Maj J. Dihydropyridine calcium channel antagonists as antidepressant drugs in mice and rats.  Neuropharmacology. 1989;  28 229-233
    CrossrefPubMedGoogle Scholar
  • 16 Dubovsky S L, Buzan R D. Novel alternatives and supplements to lithium and anticonvulsants for bipolar affective disorder.  Journal of Clinical Psychiatry. 1997;  58 224-242
    PubMedGoogle Scholar
  • 17 Enna S J, Karbon E W, Duman R S. GABA-B agonist and imipramine-induced modifications in rat brain beta-adrenergic receptor binding and function. In Bartholini G, Lloyd KG, Morselli PL, editors GABA and mood disorders. Experimental and clinical research. New York; Raven press 1986: p 23-49
    Google Scholar
  • 18 Erdelmeier C AJ. Hyperforin, possibly the major non-nitrogenous secondary metabolite of Hypericum perforatum L.  Pharmacopsychiatry. 1998;  31 ((Suppl)) 2-6
    PubMedGoogle Scholar
  • 19 Ernst E. Second thoughts about safety of St John’s wort.  Lancet. 1999;  354 2014-2016
    CrossrefPubMedGoogle Scholar
  • 20 Fröhlich R, Patzelt C, Illes P. Inhibition by ethanol of excitatory amino acid receptors and nicotinic acetylcholine receptors at rat locus coeruleus neurons.  Naunyn-Schmiedeberg’s Archives of Pharmacology. 1994;  350 626-631
    PubMedGoogle Scholar
  • 21 Fugh-Berman A. Herb-drug interactions.  Lancet. 2000;  355 134-138
    CrossrefPubMedGoogle Scholar
  • 22 Laakmann G, Schüle C, Baghai T, Kieser M. St. John’s Wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy.  Pharmacopsychiatry. 1998;  31 ((Suppl)) 54-59
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Langosch J M, Berger M, Walden J. Effects of the atypical antidepressant trimipramine on long term potentiation in guinea pig hippocampal slices.  European Journal of Neuroscience. 1998;  10 ((Suppl 10)) 25
    PubMedGoogle Scholar
  • 24 Langosch J M, Normann C, Schirrmacher K, Berger M, Walden J. The influence of (±)-kavain on population spikes and long-term potentiation in guinea pig hippocampal slices.  Comparative Biochemistry and Physiology. 1998;  120 545-549
    PubMedGoogle Scholar
  • 25 Langosch J M, Repp M, Berger M, Walden J. Effects of the atypical antidepressant trimipramine on field potentials in the low Mg2+-model in guinea pig hippocampal slices.  European Neuropsychopharmacology. 1998;  8 209-212
    CrossrefPubMedGoogle Scholar
  • 26 Langosch J M, Zhou X -Y, Frick A, Berger M, Walden J. The influence of Hypericum perforatum and hyperforin on population spikes in guinea pig hippocampal slices.  European Archives of Psychiatry and Clinical Neuroscience. 1998;  248 93S
    PubMedGoogle Scholar
  • 27 Langosch J M, Zhou X -Y, Heinen M, Kupferschmid S, Chatterjee S S, Nöldner M, Walden J. St John’s wort modulates evoked potentials in guinea pig hippocampal slices via AMPA and GABA receptors. Neuropharmacology (2001) submitted
    Google Scholar
  • 28 Langosch J M, Zhou X -Y, Heinen M, Walden J. Effects of Hypericum extract, hyperforin and hypericin on neuronal excitability, synaptic transmission and LTP in guinea pig hippocampal slices.  Pharmacopsychiatry. 1999;  32 192
    PubMedGoogle Scholar
  • 29 Leonard B E. SSRI differentiation: pharmacology and pharmcokinetics.  Human Psychopharmacology. 1995;  10 149-151S
    PubMedGoogle Scholar
  • 30 Leonard B E. The comparative pharmacology of new antidepressants.  Journal of Clinical Psychiatry. 1993;  54 ((Suppl)) 3-15
    PubMedGoogle Scholar
  • 31 Müller W E, Rolli M, Schäfer C, Hafner U. Effects of Hypericum extract (LI 160) in biochemical models of antidepressant activity.  Pharmacopsychiatry. 1997;  30 ((Suppl 2)) 102-107
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Müller W E, Singer A, Wonnemann M, Hafner U, Rolli M, Schäfer C. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of Hypericum extract.  Pharmacopsychiatry. 1998;  31 ((Suppl)) 16-21
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Nahrstedt A, Butterweck V. Biologically active and other chemical constituents of the herb of Hypericum perforatum L.  Pharmacopsychiatry. 1997;  30 ((Suppl 2)) 129-134
    PubMedGoogle Scholar
  • 34 Nelson D R, Thomas D R, Johnson A M. Pharmacological effects of paroxetine after repeated administration to animals.  Acta Psychiatrica Scandinavica. 1989;  350 ((Suppl)) 21-23
    PubMedGoogle Scholar
  • 35 Nielsen N P, Cesana B, Zizolfi S, Ascalone V, Priore P, Morselli P L. Therapeutic effects of fengabine, a new GABAergic agent, in depressed outpatients: A double-blind study versus clomipramine.  Acta Psychiatr Scand. 1990;  82 366-71
    PubMedGoogle Scholar
  • 36 Rammes G, Parsons C, Müller W, Swandulla D. Modulation of fast excitatory synaptic transmission by cyclothiazide and GYKI 52 466 in the rat hippocampus.  Neurosci Lett. 1994;  175 21-24
    CrossrefPubMedGoogle Scholar
  • 37 Richardson E. Synaptic effects of antidepressants.  Journal of Clinical Psychopharmacology. 1996;  16 1-7S
    CrossrefPubMedGoogle Scholar
  • 38 Stolz J F, Marsden C A, Middlemiss D M. Effect of chronic antidepressant treatment and subsequent withdrawal on 3H-5HT and 3H-spiperone binding in rat frontal cortex and serotonin mediated behaviour.  Psychopharmacology. 1983;  80 150-155
    CrossrefPubMedGoogle Scholar
  • 39 Teufel-Mayer R, Gleitz J. Effects of long-term administration of Hypericum extracts on the affinity and density of the central serotonergic 5-HT1A and 5-HT2A receptors.  Pharmacopsychiatry. 1997;  30 ((Suppl 2)) 13-116
    PubMedGoogle Scholar
  • 40 van Praag H M. Studies in the mechanism of action of serotonin precursors in depression.  Psychopharmacological Bulletin. 1984;  20 599-602
    PubMedGoogle Scholar
  • 41 Volz H -P. Controlled clinical trials of Hypericum extracts in depressed patients - an overview.  Pharmacopsychiatry. 1997;  30 ((Suppl 2)) 72-76
    PubMedGoogle Scholar
  • 42 Vorbach E U, Arnoldt K H, Hübner W -D. Efficacy and tolerability of St. John’s Wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10.  Pharmacopsychiatry. 1997;  30 ((Suppl 2)) 81-85
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Watanabe Y, Saito H, Abe K. Tricyclic antidepressants block NMDA receptor-mediated synaptic responses and induction of long-term potentiation in rat hippocampal slices.  Neuropharmacology. 1993;  32 479-486
    CrossrefPubMedGoogle Scholar
  • 44 Wheatley D. LI 160, an extract of St. John’s Wort, versus amitriptyline in mildly to moderately depressed outpatients - a controlled 6-week clinical trial.  Pharmacopsychiatry. 1997;  30 ((Suppl 2)) 77-80
    PubMedGoogle Scholar

Dr. J. M. Langosch

Department of Psychiatry, University of Freiburg

Hauptstraße 5

79104 Freiburg

Germany

Phone: (+49) 761 2706501

Fax: (+49) 761 2706593

Email: jens_langosch@psyallg.ukl.uni-freiburg.de

      >