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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 3 of 3. This is the beginning of the thread.
Posted by Larry Hoover on September 5, 2003, at 13:19:29
CNS Drugs. 2003;17(8):539-62.
Mechanism of action of St John's wort in depression : what is known?
Butterweck V.
Institute of Pharmacology and Toxicology, Universitatsklinikum Munster, Munster, Germany. butterv@uni-muenster.de
Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature.
Life Sci. 2003 Jun 20;73(5):627-39.
Step by step removal of hyperforin and hypericin: activity profile of different Hypericum preparations in behavioral models.Butterweck V, Christoffel V, Nahrstedt A, Petereit F, Spengler B, Winterhoff H.
Institute of Pharmacology and Toxicology, Universitatsklinikum Muenster, Domagkstrasse 12, 48149 Muenster, Germany. butterv@uni-muenster.de
Herbal extracts of Hypericum perforatum L. (St. John's wort, SJW) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the antidepressive active compounds. In the present study we used the following strategy to evaluate the relative pharmacological importance of various extract components: 1. preparation of an hydroalcoholic SJW extract containing both hyperforin (3.2%) and hypericin (0.15%) (extract A); 2. step by step removal of hyperforin and hypericin led to the following extracts: Extract B, devoid of hyperforin but still containing hypericin (0.14%) and Extract C, free of hypericin and hyperforin but enriched in flavonoids ( approximately 12%). We characterized the in vivo activity profile of all three preparations using the tail suspension test (TST) in mice and the forced swimming test (FST) in rats as screening models. We further investigated the activity of pure hyperforin. Extract B and C (500 mg/kg each) as well as pure hyperforin (8 mg/kg) significantly shortened immobility time in the TST after acute pre-treatment whereas extract A was inactive. In the FST all three extracts decreased immobility time in a dosage of 500 mg/kg after acute as well as after repeated treatment. The present results clearly show that an SJW extract free of hyperforin and hypericin exerts antidepressant activity in behavioral models, supporting our working hypothesis that flavonoids are part of the constituents responsible for the therapeutic efficacy of SJW extracts. We also could show that hyperforin contributes to the beneficial properties of SJW extract, confirming the hypothesis that the crude SJW extract contains several constituents with antidepressant activity.
Psychopharmacology (Berl). 2002 Jul;162(2):193-202. Epub 2002 May 09.
In vitro receptor screening of pure constituents of St. John's wort reveals novel interactions with a number of GPCRs.Butterweck V, Nahrstedt A, Evans J, Hufeisen S, Rauser L, Savage J, Popadak B, Ernsberger P, Roth BL.
Institute of Pharmacology and Toxicology, Westfalische Wilhelms-Universitat Muenster, Domagkstrasse 12, 48149 Muenster, Germany. butterv@uni-muenster.de
RATIONALE: Hypericum perforatum L. (St. John's wort; SJW) is one of the leading psychotherapeutic phytomedicines and great effort has been devoted to clarifying its mechanism of action. OBJECTIVE: We have undertaken a comprehensive analysis of several pure compounds isolated from the crude extract to gain further insight into the molecular actions of various substituents of SJW. METHODS: We characterized the in vitro pharmacology of the naphthodianthrones hypericin and pseudohypericin, the phloroglucinol derivative hyperforin, and several flavonoids at 42 biogenic amine receptors and transporters using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. RESULTS: The biflavonoid amentoflavone significantly inhibited binding at serotonin (5-HT(1D), 5-HT(2C)), D(3)-dopamine, delta-opiate, and benzodiazepine receptors. The naphthodianthrone hypericin had significant activity at D(3)- and D(4)-dopamine receptors and beta-adrenergic receptors. With the exception of the D(1)-dopamine receptor, the phloroglucinol derivative hyperforin was less active than other SJW constituents tested on all screened receptors. CONCLUSION: Our present in vitro data clearly show that several pure substances in SJW are potential CNS psychoactive agents and may contribute to the antidepressant efficacy of the plant in a complex manner. Our data also reveal novel and heretofore unexpected interactions of pure compounds in SJW at a number of GPCRs, transporters, and ion channels. We hypothesize that additive or synergistic actions of different single compounds may be responsible for the antidepressant efficacy of SJW. These results and this general approach may impact our understanding of phytomedicines in general and H. perforatum specifically.
Eur J Pharmacol. 2003 Jan 5;458(3):251-6.
Antagonist effect of pseudohypericin at CRF1 receptors.Simmen U, Bobirnac I, Ullmer C, Lubbert H, Berger Buter K, Schaffner W, Schoeffter P.
Institute of Pharmaceutical Biology, University of Basel, Witterswil, Switzerland. usimmen@datacomm.ch
St. John's wort (Hypericum perforatum L.) is widely used for the treatment of mild to moderately severe depression. However, the nature of its active principles and the exact mode of antidepressant action are still unknown. It has been suggested repeatedly in preclinical and clinical studies that the content of the acylphloroglucinol hyperforin decisively contributes to the antidepressant efficacy of St. John's wort extracts. Experimental studies in vivo also indicate that the naphthodianthrone hypericin may reduce the activity of the hypothalamic-pituitary-adrenal axis. Exacerbated hypothalamic-pituitary-adrenal activity has often been associated with depressive states in patients. Corticotropin-releasing factor (CRF) seems to be a major determinant in the regulation of the hypothalamic-pituitary-adrenal activity via activation of CRF(1) receptors. In the present study, we investigated the CRF(1) receptor antagonist activity of three main constituents of St. John's wort (hypericin, pseudohypericin and hyperforin) by measuring their effect on CRF-stimulated cAMP formation in recombinant Chinese hamster ovary (CHO) cells. As a selectivity test, the compounds were also tested against calcitonin in the same cells. Of the three compounds tested, only pseudohypericin selectively antagonised CRF (K(B) 0.76 microM). Hypericin and hyperforin affected both CRF and calcitonin with similar potencies and the same type of behaviour (competitive antagonism for hypericin, noncompetitive for hyperforin). It is concluded that pseudohypericin is the only real CRF(1) receptor antagonist of the three constituents tested. In addition, evidence is provided that beside hyperforin, both pseudohypericin and hypericin are implicated in the antidepressant efficacy of St. John's wort.
Pharmacopsychiatry. 2001 Jul;34 Suppl 1:S26-8.Inhibition of substance P-induced cytokine synthesis by St. John's wort extracts.
Fiebich BL, Hollig A, Lieb K.
Department of Psychiatry, University of Freiburg Medical School, Germany. bernd_fiebich@psyallg.ukl.uni-freiburg.de
We tested the hypothesis that extracts from St. John's wort interfere with protein synthesis induced by substance P (SP), a neuropeptide which has been implicated in the etiopathology of depression and anxiety. Using human astrocytoma cells, which express functional neurokinin (NK)-1-receptors, we investigated whether extracts from St. John's wort are able to inhibit SP-induced synthesis of the cytokine interleukin-6 (IL-6). We found a potent and dose-dependent inhibition of SP-induced IL-6 synthesis by various extracts from St. John's wort. These results do not only give further evidence of the anti-inflammatory effects of St. John's wort, but also lend support to the hypothesis that the antidepressant effect of St. John's wort is, at least in part, a result of its inhibitory effects on SP-induced protein synthesis.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Feb;367(2):126-33. Epub 2003 Jan 23.
Autoradiographic quantification of neurochemical markers of serotonin, dopamine and opioid systems in rat brain mesolimbic regions following chronic St John's wort treatment.Chen F, Rezvani AH, Lawrence AJ.
Department of Pharmacology, Faculty of Medicine, Monash University, Wellington Road, PO Box 13E, 3800, Clayton, Victoria, Australia. Feng.Chen@med.monash.edu.au
Effects of chronic treatment with St John's wort (SJW, Hypericum perforatum) on neurochemical markers of serotonin, dopamine and opioid systems in mesolimbic regions of the fawn-hooded rat were investigated by quantitative autoradiography. After 10 days' treatment, SJW significantly increased [(3)H]citalopram binding to 5-HT transporters in multiple mesolimbic regions. In contrast, SJW resulted in a region-specific alteration of [(3)H]mazindol binding to dopamine transporters, such as increased binding of [(3)H]mazindol in the olfactory tubercle and decreased binding in the ventral tegmental area. In addition, SJW also resulted in differential modulation of the binding properties of 5-HT(1A)-, 5-HT(2A)- and mu-opioid receptors in a region-specific manner. The ability of SJW to affect 5-HT, dopamine and opioid systems in mesolimbic regions in the CNS, either by a direct or by indirect (adaptation) mechanism, may help to explain the efficacy of SJW in the treatment of depression clinically and in some of the behavioural effects observed in experimental rodents.
Indian J Exp Biol. 2001 Apr;39(4):339-43.Anti-inflammatory and analgesic activity of Indian Hypericum perforatum L.
Kumar V, Singh PN, Bhattacharya SK.
Department of Pharmaceutics, Banaras Hindu University, Varanasi, India.
A standardised 50% aqueous ethanolic extract of the Indian variety of Hypericum perforatum (IHp) was examined for its putative anti-inflammatory and analgesic activity at the doses of 100 and 200 mg/kg, po. The experimental paradigms used were carrageenan induced pedal edema and cotton pellet induced granuloma for anti-inflammatory activity, whereas the tail flick, hot plate and acetic acid induced writhing methods were used to asses analgesic activity. Indomethacin (20 mg/kg, ip) was used as the standard anti-inflammatory drug. Pentazocine (10 mg/kg, ip) and aspirin (25 mg/kg, ip), both clinically used analgesics, were used as standard analgesics for comparison. IHp extract showed significant anti-inflammatory and analgesic activity at both dose levels, in all the paradigms used. Additionally, IHp potentiated the anti-inflammatory activity of indomethacin and analgesic activities of pentazocine and aspirin.
J Recept Signal Transduct Res. 1999 Jan-Jul;19(1-4):59-74.Extracts and constituents of Hypericum perforatum inhibit the binding of various ligands to recombinant receptors expressed with the Semliki Forest virus system.
Simmen U, Burkard W, Berger K, Schaffner W, Lundstrom K.
Dept. of Pharmaceutical Biology, University of Basel, Switzerland.
Extracts, fractions and constituents of Hypericum perforatum were studied for in vitro receptor binding with various ligands to recombinant CNS receptors expressed with the Semliki Forest virus expression system. For this purpose we have prepared membranes of CHO cells with high density of several opioid, serotonin, estrogen, histamine, GABAA, neurokinin and metabotropic glutamate receptors, respectively. A lipophilic Hypericum fraction revealed relatively potent inhibition to the binding of the mu-, delta- and kappa-opioid and the 5-HT6 and 5-HT7 receptors. Moreover, Hypericum constituents such as the naphthodianthrones, hypericin and pseudohypericin, and the phloroglucinole hyperforin inhibited both binding to the opioid and serotonin receptors in the lower micromolar range. Estrogen binding was 50% inhibited by the biflavonoid I3,II8-biapigenin at micromolar concentration. The lipophilic Hypericum fraction provided a less potent inhibition of the neurokinin-1 receptor binding compared to the opioid and serotonin receptors. A total ethanolic Hypericum extract potently inhibited GABAA binding at approximately 3 micrograms/ml. This inhibition is however not specific to Hypericum, since extracts of plants like Valeriana officinalis and Passiflora incarnata showed similar inhibitions. Binding to neither histamine nor metabotropic glutamate receptors was affected by Hypericum extracts. These results support the hypothesis that several active constituents of Hypericum might in a synergistic way contribute to its antidepressant effect in the central nervous system.
Posted by McPac on September 6, 2003, at 12:41:37
In reply to SJW abstracts: mechanism of action, posted by Larry Hoover on September 5, 2003, at 13:19:29
Lar, IF I start taking just 5 mg of Lexapro a day (an ssri, of course) does that mean that I have to stop taking SJW? (I also take Remeron 30 mg/day) Thanks!
Posted by Larry Hoover on September 21, 2003, at 5:47:09
In reply to Lar, Re: SJW abstracts: mechanism of action, posted by McPac on September 6, 2003, at 12:41:37
> Lar, IF I start taking just 5 mg of Lexapro a day (an ssri, of course) does that mean that I have to stop taking SJW? (I also take Remeron 30 mg/day) Thanks!
No. Just pay attention for adverse effects associated with excess serotonin, e.g. nausea, drowsiness, insomnia, loose stools, tremor, nervousness, sweating, fatigue, dizziness. More severe symptoms are constant diaphoresis (sweating), teeth chattering, shivering, chills, over confidence / aggressiveness and impaired concentration and thinking.
These symptoms would be constant, rather than something that comes and goes. If you're normally nervous, then that's not a good symptom to focus on, ya know?
Lar
This is the end of the thread.
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