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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
12
Cookson J.
Side effects of antidepressants.
British Journal of Psychiatry.
1993;
163
20-24
-
13
Cott J M.
In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract.
Pharmacopsychiatry.
1997;
30
((Suppl 2))
108-112
-
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
-
15
Czyrak A, Mogilnicka E, Maj J.
Dihydropyridine calcium channel antagonists as antidepressant drugs in mice and rats.
Neuropharmacology.
1989;
28
229-233
-
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
-
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
-
18
Erdelmeier C AJ.
Hyperforin, possibly the major non-nitrogenous secondary metabolite of Hypericum perforatum L.
Pharmacopsychiatry.
1998;
31
((Suppl))
2-6
-
19
Ernst E.
Second thoughts about safety of St John’s wort.
Lancet.
1999;
354
2014-2016
-
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
-
21
Fugh-Berman A.
Herb-drug interactions.
Lancet.
2000;
355
134-138
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
29
Leonard B E.
SSRI differentiation: pharmacology and pharmcokinetics.
Human Psychopharmacology.
1995;
10
149-151S
-
30
Leonard B E.
The comparative pharmacology of new antidepressants.
Journal of Clinical Psychiatry.
1993;
54
((Suppl))
3-15
-
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
-
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
-
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
-
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
-
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
-
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
-
37
Richardson E.
Synaptic effects of antidepressants.
Journal of Clinical Psychopharmacology.
1996;
16
1-7S
-
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
-
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
-
40
van Praag H M.
Studies in the mechanism of action of serotonin precursors in depression.
Psychopharmacological Bulletin.
1984;
20
599-602
-
41
Volz H -P.
Controlled clinical trials of Hypericum extracts in depressed patients - an overview.
Pharmacopsychiatry.
1997;
30
((Suppl 2))
72-76
-
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
-
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
-
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
Dr. J. M. Langosch
Department of Psychiatry, University of Freiburg
Hauptstraße 5
79104 Freiburg
Germany
Telefon: (+49) 761 2706501
Fax: (+49) 761 2706593
eMail: jens_langosch@psyallg.ukl.uni-freiburg.de
