Despite almost forty years of widespread use, the mode of action of antidepressant drugs is still largely unknown. There is agreement that these drugs interact with central neurotransmission. Common findings are acute inhibitory actions on reuptake mechanisms for norepinephrine (NE) and for serotonin (5-HT) at presynaptic axons and chronic adaptive effects on neurotransmitter receptors on postsynaptic membranes. In particular, beta-adrenoceptor downregulation has been observed after chronic treatment with most antidepressants in vivo and in cell culture systems. We studied the effectiveness of Ze 117 (St. John's wort) extract (Hypericum perforatum) on NE- and 5-HT-uptake into rat brain slices. Potency and efficacy of the Ze 117 extract were compared with those of tricyclic (TCA) and selective serotonin reuptake inhibitor (SSRI)-type antidepressants. A dose-dependent inhibition was seen on NE and 5-HT uptake into brain slices. The Ze 117 extract was more selective for the uptake of NE than for that of 5-HT. The maximal extent of uptake inhibition by Ze 117 extract was comparable to that of imipramine (IMI), desipramine (DMI) or fluvoxamine for 5-HT, but lower for NE transport, than that of the synthetic antidepressants. Chronic exposure (8 days) of confluent C6-cell cultures to Ze 117 extract resulted in a dose-dependent beta-adrenoceptor downregulation equal to that induced by DMI, a potent TCA. None of these effects could be achieved with either hypericin or hyperforin alone in a relevant dose range. Our results indicate that the St. John's wort extract Ze 117 contains active, but as yet unknown antidepressant principles with effects comparable to those of TCAs.

1 Cationic amphiphilic drugs (CADs) are widely used in chronic pharmacotherapies in spite of frequently observed side effects connected with lysosomal phospholipid (PL) storage. 2 It has recently been shown that cx-tocopherol (a-Toc) inhibits drug-and PL accumulation in cell cultures chronically exposed to the CAD, amiodarone. 3 The mechanisms of a-Toc action on drug kinetics and PL storage were studied in human cultured fibroblasts exposed to single and repetitive doses of desipramine and other CADs. 4 a-Toc did not influence the initial, pH-dependent rapid phase of drug uptake. It inhibited, in a dosedependent manner, the slow and the cumulative phases of drug uptake and coincidently the accumulation of cellular PLs. 5 The inhibitory effects of c-Toc on CAD and PL accumulations depends on the ratio between CAD and a-Toc concentrations in the medium. This points to competition between a-Toc and CADs for PL complex formation. 6 Effectiveness of a-Toc on drug uptake varies among different CADs. It depends on its structural integrity but is independent of stereoisomerism. The inhibitory action is restricted to the piggyback slow drug uptake and therefore related to the proportion of membrane-mediated transport to permeation into lysosomes (rapid uptake). This proportion differs among CADs. 7 a-Toc prevents lysosomal membrane-PL storage, accelerates disintegration of PL-stores and normalizes drug-related increased membrane fluidity. This strongly suggests that a-Toc restores membrane recycling, impaired by CAD exposure.8 It remains to be tested in vivo whether cx-Toc reduces CAD side effects without interfering with drug effectiveness.

The mode of action of antidepressants is still a matter of debate. Acute inhibition of neurotransmitter reuptake in central neuronal synapses, followed by a down-regulation of central postsynaptic beta-adrenoceptor (beta-AR) numbers were consistently observed in vivo, while a reduction in surface beta-AR density was found in cell cultures. Effects of the tricyclic antidepressant desipramine (DMI) were abolished by vitamin E (alpha-TOC) in vitro as well as in vivo. Alpha-TOC interfered with antidepressant-induced changes of cellular plasma membrane properties and with recycling of beta-AR. St. John's wort (SJW) extract reduced beta-AR numbers in cultured cells to a similar extent as DMI or the selective serotonin re-uptake inhibitor fluoxetine. We chronically co-exposed cell cultures to SJW extract and to alpha-TOC. Receptor down-regulation following exposure to the plant extract was inhibited in the presence of alpha-TOC suggesting a mode of action of SJW extract comparable to that of synthetic antidepressants. Inhibition of cell proliferation by the plant extract was also significantly reduced by alpha-TOC.

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