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Original Article |
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Neuropsychopharmacology (2000) 23 188-197.10.1038/sj.npp.1395510
Inhibition of Synaptosomal Uptake of 3H-L-glutamate and 3H-GABA by Hyperforin, a Major Constituent of St. John's Wort: The Role of Amiloride Sensitive Sodium Conductive Pathways
M Wonnemann MS, A Singer MS and WE Müller Ph.D |
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Department of Pharmacology, Biocenter Niederursel, University of Frankfurt, Frankfurt, Germany
Correspondence: Dr WE Müller, Department of Pharmacology, Biocenter Niederursel, N260, University of Frankfurt, Marie-Curie Strasse 9, D-60439 Frankfurt a.M., Germany. Tel.: ++49-69-79829373/76; Fax: ++49-69-79829374; E-mail: W.E.Mueller@em.uni-frankfurt.de
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ABSTRACT
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Extracts of St. John's Wort are widely used for the treatment of depressive disorders. The active principles have not yet been finally elucidated. We have recently shown that hyperforin, a major active constituent of St. John's Wort, not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine, but also that of L-glutamate and GABA. No other antidepressant compound exhibits a similar broad uptake inhibiting profile. To investigate this unique kind of property, kinetic analyses were performed regarding the uptake of 3H-L-glutamate and 3H-GABA into synaptosomal preparations of mouse brain. Michaelis-Menten kinetics revealed a reduction of Vmax (8.27 to 1.80 pmol/mg/min for 3H-L-glutamate, 2.76 to 0.77 pmol/mg/min for 3H-GABA) while Km was nearly unchanged in both cases, suggesting non-competitive inhibition. The unselective uptake inhibition by hyperforin could be mimicked by the Na+- ionophore monensin and by the Na+-K+-ATPase inhibitor ouabain. However, both mechanisms can be discarded for hyperforin. Several amiloride derivatives known to affect sodium conductance significantly enhance 3H-GABA and 3H-L-glutamate uptake and inhibit the uptake inhibition by hyperforin, while monensin or ouabain inhibition were not influenced. Selective concentrations of benzamil for amiloride sensitive Na+-channels and selective concentrations of 5'-ethylisopropylamiloride (EIPA) for the Na+-H+-exchangers both had an attenuating effect on the hyperforin inhibition of L-glutamate uptake, suggesting a possible role of amiloride sensitive Na+-channels and Na+-H+-exchangers in the mechanism of action of hyperforin.
Keywords: Hyperforin; St. John's Wort; Amiloride sensitive sodium channel; Na+-H+ exchange; Synaptosomal uptake inhibition |
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