Hyperforin inhibitors serotonin

The hypericin fraction was initially reported to have MAO-A and -B inhibitor properties. Later studies found that the concentration required for this inhibition was higher than that achieved with recommended dosages. In vitro studies using the commercially formulated hydroalcoholic extract have shown inhibition of nerve terminal reuptake of serotonin, norepinephrine, and dopamine. While the hypericin constituent did not show reuptake inhibition for any of these systems, the hyperforin constituent did. Chronic administration of the commercial extract has also been reported to significantly down-regulate the expression of cortical 13 adrenoceptors and up-regulate the expression of serotonin receptors (5-HT2) in a rodent model. 

Assays with extracts devoid of hypericin but with a high content of hyperforin as well as assays with pure hyperforin demonstrated that this metabolite can modulate the function of various neurotransmitters involved in depression, being a potent inhibitor of serotonin, dopamine, noradrenaline and GABA uptake with almost equal potency. Moreover, results from clinical studies evidenced that the antidepressant efficacy of Hypericum preparations correlates with their content of hyperforin [6,87],... 

In a specific work, it has been shown that chemical modification of hyperforin by acylation, oxidation and alkylation produce detrimental effects on the molecule activity as inhibitor of serotonin uptake [89], and the presence of the enolized cyclohexanedione moiety in its structure has been related to its efficacy on the re-uptake of neurotransmitters. 

A commoniy reported drug-dietary suppiement interaction is between St. John s Wort and FiiV protease inhibitors, ieading to drug resistance and treatment faiiure. St. John s wort is a popuiar dietary suppiement often used for depression. Of the two substances found in St. John s wort, hypericin and hyperforin, hyperforin appears to be the main constituent, with in vitro seieotive serotonin reuptake inhibitor (SSRi) activity (see Chapter 21). Hyperforin aiso appears to be the more potent inducer of CYP3A enzymes based on in vitro and in vivo studies. 

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