biapigenin and hypericin

The example of St. John's wort offers convincing evidence for the concept that modern methods of pharmacological and phytochemical research are effective in advancing the development of traditional herbal remedies. As a consequence of these efforts, it is known today that several compounds from different structural groups and with different mechanisms of action seem to be responsible for the observed antidepressant efficacy of St. John's Wort. Co-effectors in the extract improve the bioavailability of active constituents such as hypericin (1) (pharmacokinetic synergy). Unwanted side effects are preventable without remarkable loss of activity when the responsible constituent(s) are carefully removed during the extraction process, as demonstrated for hyperforin (3), which is responsible for the induction of cytochrome P450 (CYP)-metabolizing enzymes (CYP3A4, in particular). On the basis of our findings, it is likely that positive interactions between single compounds occur more frequently in traditionally used herbal preparations than is known presently.

Topics: Anthracenes; Antidepressive Agents; Bridged Bicyclo Compounds; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Hypericum; Molecular Structure; Perylene; Phloroglucinol; Plant Preparations; Plants, Medicinal; Terpenes

Interactions between neurotransmitter receptors involved in the pathophysiology of depression, anxiety and ethanol consumption and two extracts (hydromethanolic and lipophilic extracts obtained with hypercritical CO2) from Hypericum Perforatum L or St. John's wort (SJW) and three constituents (hyperforin, hypericin and biapigenin) were evaluated by in vitro binding assays. The two extracts, tested at 10 microg/ml, did not inhibit ligand binding at the following receptors: serotonin 5-HT6 and 5-HT7, benzodiazepine, sigma and neuropeptide Y (NPY) Y1 and Y2 receptors. The hydromethanolic extract, but not the lipophilic extract, interacted with GABA(A) receptors (IC50 5.5 microg/ml), while both interacted with the dopamine (DA) transporters, albeit with high IC50 values (24.5 and 12.9 microg/ml, respectively). Biapigenin (1 microg/ml, 2 microM) inhibited ligand binding at benzodiazepine receptors only (IC50: 2 microM). Hyperforin (1 microg/ml, 2 microM) only inhibited [3H]WIN-35,428 binding to DA transporters, although the IC50 (5 microM) was higher than the IC50 found for inhibition of the synaptosomal DA reuptake (0.8 microM). This finding extended the same observation previously described for the 5-HTergic system to the DAergic system, confirming that the inhibition of monoamine reuptake is due to a different mechanism than that of synthetic antidepressants. Hypericin showed micromolar affinities for both NPY-Y1 and Y2 receptors and for sigma receptors (IC50 3-4 microM). These hypericin activities might be of interest because NPY and sigma receptors have been associated with anxiety disorders, depressive illnesses and ethanol consumption. However, they were present at relatively high hypericin concentrations, and were also light-dependent (i.e. the IC50 values increased when binding assays were carried out in the dark). Thus, our in vitro binding results may suggest that either the pharmacological effects of SJW are due to other molecules than hypericin or hyperforin (other constituents or active metabolites), or that the mechanism of action is different from those that have been considered up to now.

Topics: Animals; Anthracenes; Antidepressive Agents; Apigenin; Biflavonoids; Bridged Bicyclo Compounds; Dopamine Plasma Membrane Transport Proteins; Flavonoids; Hypericum; In Vitro Techniques; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Perylene; Phloroglucinol; Plant Extracts; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, Neuropeptide Y; Receptors, Serotonin; Receptors, sigma; Terpenes