Hyperforin in St. John’s Wort’s Central Effects: What is the Mechanism of Action?

The constituent(s) accounting for the antidepressant/anxiolytic, nootropic and anti-Alzheimer’s properties of St John’s wort (SJW) extracts is uncertain but the phloroglucinol hyperforin has been described as the main cause. Although its activities in humans have not yet been thoroughly investigated, it has antidepressant-like and anxiolytic-like effects in animal models, while in vitro studies suggest an interaction with the neurotransmitter systems thought to be involved in depression. Some of its actions on the neurotransmitter systems have also been proposed to explain the nootropic effects of SJW extracts, for which another possible explanation followed the in vitro observation that hyperforin activates transient receptor potential canonical 6 channels, which are vital for the formation of dendritic spines, plasticity and memory. In vitro hyperforin also has direct effects on amyloid(A ) fibrils, providing a potential mechanism for the antagonism of A -induced neurotoxic effects and cognitive impairments. However, considering the low hyperforin brain uptake and concentrations reached in animals after pharmacologically effective doses of SJW extracts or authentic compound and its derivatives, its in vivo actions are unlikely to be due to direct interaction with acknowledged neurotransmitter transporters and receptors. Although it might interact with some central targets not yet evaluated in vitro, or even primarily act peripherally, thereby influencing central transmission, the central action may be due to one or more metabolites. Further neurochemical studies should therefore be extended to potential metabolite(s) which may have characteristic pharmacodynamic properties. Additional information is also needed on the brain uptake of hyperforin compared to its active metabolite(s). These data should enable us to identify the active principle (parent compound or its metabolite) and its target in the site of action, and undoubtedly help in extrapolating pharmacological findings across species. _____________________________________________________________________________________________________________