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Vol. 290, Issue 3, 1363-1368, September 1999
Department of Pharmacology, Biocenter, University of Frankfurt,
Frankfurt, Germany
Extracts of Hypericum perforatum (St. John's Wort) are
widely used for the treatment of depressive disorders and are
unspecific inhibitors of the neuronal uptake of several
neurotransmitters. Previous studies have shown that hyperforin
represents the reuptake inhibiting constituent. To characterize the
mechanism of serotonin reuptake inhibition, kinetic analyses in
synaptosomes of mouse brain were performed. Michaelis-Menten kinetics
revealed that hyperforin (2 µM) induces a decrease in
Vmax by more than 50% while only slightly
decreasing Km, indicating mainly
noncompetitive inhibition. By contrast, citalopram (1 nM) leads to an
elevation of Km without changing
Vmax. Monensin, a
Na+/H+ exchanger, showed similar properties as
hyperforin (decrease of Vmax without
changing Km). Compared with classical
antidepressants, such as selective serotonin reuptake inhibitors and
tricyclic antidepressants, hyperforin is only a weak inhibitor of
[3H]paroxetine binding relative to its effects on
serotonin uptake. As monensin decreases serotonin uptake by increasing
Na+/H+ exchange, we compared the effects of
hyperforin and monensin on the free intracellular sodium
concentration ([Na+]i) in platelets by
measuring 1,3-benzenedicarboxylic acid,
4,4'-[1,4,10-trioxa-7,13-diazacyclopentadecan-7,13-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetraammonium salt (SBFI/AM) fluorescence. Both drugs elevated [Na+]i over basal levels, with a maximal
[Na+]i of 69 ± 16.1 mM (50 µM
hyperforin) and 140 ± 9.1 mM (10 µM monensin). Citalopram at
concentrations relevant for [3H]serotonin uptake
inhibition had no effect on [Na+]i. Although
the mode of action of hyperforin seems to be associated with elevated
[Na+]i similar to those levels found with
monensin, the molecular mechanism might be different, as even at
high concentrations, hyperforin does not elevate free intracellular
sodium concentration ([Na+]i) up to the
extracellular level, as monensin does. Hyperforin represents the first
substance with a known preclinical antidepressant profile that inhibits
serotonin uptake by elevating [Na+]i.
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