Stimulation of glutamate, aspartate and gamma-aminobutyric acid release from synaptosomes by hyperforin.
Hyperforin is one pharmacologically active constituent of the medicinal herb Hypericum perforatum. The mechanism of its antidepressant-like activity is currently considered to be the inhibition of synaptic reuptake of neurotransmitters. Here, we will demonstrate that it also stimulates the release of glutamate from rat cortical synaptosomes, and that this effect is preceded by an increase in their free calcium [Ca2+]i levels. These hyperforin-related effects were also observed in the absence of Ca2+ in the medium. Although we noted enhanced glutamate, aspartate and GABA release under the influence of hyperforin, the release of various other amino acids was not enhanced. In contrast, reserpine did not influence the release of any of the amino acids studied. Adding hyperforin to synaptosomal suspension decreased their pHi, which returned to basal levels under certain incubation conditions. It also prevented the generation of ATP-induced pH gradients of isolated synaptic vesicles, and preformed pH-gradients were reversed by it. We will discuss the implications of our studies in understanding the mechanisms of hyperforin activity in relation to current findings on its pharmacological activity profile. Our observations suggest that neurotransmitter release stimulation from synaptosomes and the previously reported reuptake inhibitory properties of hyperforin are consequences of its effects on synaptosomal ionic homeostasis, and that it is not a reserpine-like agent.
Chatterjee
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SS
Research Department, Dr. Willmar Schwabe GmbH & Co., Karlsruhe, Germany.
Biber
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A
Weibezahn
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D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001224:Aspartic Acid / Q000378:metabolism; D001643:Bridged Bicyclo Compounds; D002118:Calcium / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010696:Phloroglucinol / Q000031:analogs & derivatives; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D014150:Antipsychotic Agents; D001643:Bridged Bicyclo Compounds; D002614:Chelating Agents; D018377:Neurotransmitter Agents; D013729:Terpenes; D001224:Aspartic Acid; D018698:Glutamic Acid; D004533:Egtazic Acid; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D014701:Veratridine; D012110:Reserpine; D000255:Adenosine Triphosphate; D010696:Phloroglucinol; C001654:hyperforin; D002118:Calcium