Hyperforin - Antidepressant Activity by a Novel Mechanism of Action

Abstract

Hyperforin represents a major antidepressive constituent of St. John's wort (SJW) extract. It not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine like many other antidepressants, but also inhibits GABA and L-glutamate uptake. This broad-spectrum effect is obtained by an elevation of the intracellular Na+ concentration, probably due to activation of sodium conductive pathways not yet finally identified but most likely ionic channels. This makes hyperforin the first member of a new class of compounds with a preclinical antidepressant profile due to a completely novel mechanism of action.

Hyperforin-Containing Extracts of St John's Wort Fail to Alter Gene Transcription in Brain Areas Involved in HPA Axis Control in a Long-Term Treatment Regimen in Rats

“…The phloroglucinol derivative hyperforin has recently become a molecule of increasing interest. Studies have demonstrated significant effects of hyperforin on various serotonergic, noradrenergic, dopaminergic, cholinergic, and opioid system activities in vitro (Chatterjee et al, 1998a;Holcomb et al, 1982;Müller et al, 1998Müller et al, , 2001Neary et al, 2001;Simmen et al, 1999;Singer et al, 1999;Wonnemann et al, 2001). As the in vitro data have been used to argue that hyperforin is the major active principle of SJW extract, we determined in the present study whether it is active in vivo in a model of therapeutic efficacy.…”

“…The pharmacological activity of SJW extracts has recently been reviewed (Butterweck, 2003;Greeson et al, 2001;Nathan, 1999). Reports about the antidepressant activity of SJW extracts and their constituents both in vivo and in vitro have been published (Baureithel et al, 1997;Butterweck et al, 1997Butterweck et al, , 1998Butterweck et al, , 2000Butterweck et al, , 2001aButterweck et al, , b, 2002Calapai et al, 1999;Chatterjee et al, 1996Chatterjee et al, , 1998aDi Matteo et al, 2000;Franklin and Cowen, 2001;Gobbi et al, 1999Gobbi et al, , 2001Müller et al, 1997Müller et al, , 1998Müller et al, , 2001Simmen et al, 1999Simmen et al, , 2001Singer et al, 1999;Wonnemann et al, 2001).…”

The pharmaceutical industry and natural products: historical status and new trends

“…The metabolism of these drugs increases, resulting in a decrease in the concentration and thus has negatively impacted clinical effects. In this case, the principal constituents thought to be responsible is hyperforin (21) which is the bioactive NP partly responsible for the pharmacological in vitro effects that have explained the antidepressant activity of the NP extract (Muller et al 2001). In the in vitro pharmacological assays, the extract was found to be more active than hyperforin (21) alone, and some companies have marketed Saint John's Wort extracts with low amount of hyperforin (21) to reduce such interactions whilst still claiming good clinical efficacy (Woelk 2000).…”

Dual Modulation of Striatal Acetylcholine Release by Hyperforin, a Constituent of St. John's Wort

“…Accordingly, hyperforin was shown to increase extracellular levels of catecholamines, serotonin, and glutamate in rat brain in vivo (Kaehler et al, 1999). Because the relative efficacies of St. John's wort extracts in various animal models correlated with its hyperforin content, hyperforin was suggested to be responsible for some or all of the antidepressive effects of St. John's wort extracts Mü ller et al, 2001).…”

“…Experimental studies searched for mechanisms of action known from classical synthetic antidepressants. Indeed, treatment of rodents with extracts of St. John's wort caused changes of brain adrenergic and serotonergic receptors, and behavioral effects that were reminiscent of the effects of tricyclic antidepressants; and in vitro experiments demonstrated inhibition of amine uptake systems by these extracts Mü ller et al, 2001). Hyperforin, a lipophilic acylphloroglucinol derivative, was identified as an active constituent of St. John's wort.…”