Elsevier

Life Sciences

Volume 79, Issue 2, 6 June 2006, Pages 105-111
Life Sciences

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Hyperforin: More than an antidepressant bioactive compound?

https://doi.org/10.1016/j.lfs.2005.12.027Get rights and content

Abstract

Hyperforin is a lipophilic compound that is present in great amounts in St. John's wort and that has been described as the main responsible for the antidepressant effects of this medicinal plant. In the last few years, evidence has accumulated pointing to other different effects of hyperforin with potential pharmacological interest. They include other neurological effects, effects on inflammation, as well as antibacterial, antitumoral and antiangiogenic effects.

Introduction

St. John's wort (Hypericum perforatum L.) is an herbaceous plant that has been used as a medicinal plant for centuries to fight against infections and for the treatment of respiratory and inflammatory diseases, pectic ulcers and skin wounds (Di Carlo et al., 2001). In 1525 the Swiss physician Paracelsus established its use for the treatment of psychiatric disorders; since then, it has been used in the traditional European medicine to treat neuralgia, anxiety, neurosis and depression (Bilia et al., 2002). In 1984, the German Commission E for psychovegetative disturbances, depressive moods, anxiety and nervous unrest approved the use of St. John's wort against these psychiatric disorders. Two relatively recent meta-analyses have concluded that St. John's wort is more effective than placebo for the treatment of mild-to-moderate depression and less likely to cause side effects than commonly prescribed antidepressants (Linde et al., 1996, Kasper, 2001). In the last years, several standardized extracts have been approved and, in fact, their total sales figures in Germany surpass those of fluoxetine, one of the most popular antidepressants. In the last few years, two reviews devoted to the use of St. John's wort against depression and its antidepressant mechanisms have been published in Life Sciences (Bilia et al., 2002, Mennini and Gobbi, 2004).

St. John's wort contains at least ten different kinds of biochemical compounds: naphtodianthrone derivatives, flavonoids, phloroglucinol derivatives, procyanidines, tannins, essential oils, amino acids, phenylpropanes, xantones and other hydrosoluble compounds (organic acids, peptides and polysaccharides) (Greeson et al., 2001). The first three groups are the most abundant ones and the main responsible agents for the described traditional uses of this herbaceous plant. The naphtodianthrone hypericin is the most potent natural photosensitizer so far described, with potential application for antitumoral photodynamic therapy (Agostinis et al., 2002). Quercitin and other flavonoids contribute to the antinflammatory effects of the plant (Tedeschi et al., 2003). In the last few years, the phloroglucinol derivative hyperforin has attracted remarked attention as the main active component with antidepressant effects (Laakmann et al., 1998). However, this interest in hyperforin has contributed to identify and characterize other bioactivities of this compound with potential pharmacological, biomedical interest. This review is aimed to describe the recent progress in the knowledge of hyperforin bioactivities.

Section snippets

Hyperforin chemistry and sources

Hyperforin (Fig. 1) is a prenylated phloroglucinol derivative that consists of a phloroglucinol skeleton with lipophilic isoprene chains. It is one of the most abundant bioactive compounds contained in the leaves and flowers of St. John's wort, where it is a major lipophilic constituent amounting up to 4% of their dried weight. Hyperforin is an easily degradable compound, which makes more difficult its study. In fact, hyperforin is prone to air oxidation and unstable in most organic solvents.

Antidepressant effect

Hyperforin has been identified as one of the main components of Hypericum extracts responsible for their antidepressant effects (Laakmann et al., 1998, Briskin, 2000, Di Carlo et al., 2001, Muller, 2003). Many antidepressant drugs behave as more or less selective inhibitors for the reuptake of one or more neurotransmitters (mainly, serotonin), acting as competitive inhibitors at the transmitter binding sites of the transporter proteins involved in this reuptake. Hyperforin is exceptional,

Other neurological effects

The influence of hyperforin on β-amyloid precursor protein could be especially relevant (Froestl et al., 2003). It seems well established that massive accumulation and aggregation of extracellular β-amyloid into amyloid plaques of Alzheimer's disease patients is, at least in part, a consequence of altered proteolytic processing by secretases. Sequential cleavages of amyloid precursor protein by β-secretase and γ-secretase produce β-amyloid peptides that vary in length between 39 and 43 amino

Antiinflammatory and proinflammatory effects

In contrast to the high number of studies devoted to the antidepressive effects of St. John's wort, little is known about the molecular basis of its antiinflammatory action. Lipophilic extracts of the wort have been recommended for the topical treatment of superficial wounds, scars, burns and dermatitis (Maisenbacher and Kovar, 1992). Although the antiinflammatory effects of St. John's wort have been mainly attributed to the inhibitory effects of quercetin on pro-inflammatory signal

Antibacterial effects

The traditional use of St. John's wort against infections is supported by the early reported antibacterial properties of its extracts (Gaind and Ganjoo, 1959). In the early seventies, a Russian scientific group postulated that there should be an antibiotic contained in St. John's wort extracts. They named this postulated antibiotic as hyperforin (Gurevich et al., 1971). The same group elucidated the chemical structure of hyperforin in 1975 (Bystrov et al., 1975). It has been confirmed that

Antitumoral effects

A number or recent relevant investigations has shown the antineoplastic potential of hyperforin, based on the sum of its anticarcinogenic, antiproliferant, proapoptotic, antiinvasive and antimetastasic effects.

Antiangiogenic effect

In the previously commented article describing the antiinvasive and antimetastatic effects of hyperforin, some microscopic images of experimental lung metastases show that those from hyperforin-treated mice have reduced irrigation as compared to control metastases from non-treated mice, suggesting a reduced neovascularization (Dona et al., 2004). Angiogenesis, the formation of new blood vessels from the existing vascular bed, has been described as one of the hallmarks of cancer, playing an

Concluding remarks

In the last few years, evidence has accumulated pointing to multiple potential pharmacological uses of the liphophylic acyl-phloroglucinol derivative hyperforin. It seems not only the main cause of the antidepressant effect of St. John's wort, but it also exhibits other neurological effects, inflammation modulatory effects, as well as antibacterial, antitumoral and antiangiogenic effects. Table 1 summarizes the so far described hyperforin effects, with mention of the molecular mechanisms and

Acknowledgements

Our experimental work is supported by grants SAF2002-02586, SAF2005-01812 and PTR95-0904 (Spanish Ministry of Education and Science) and funds from group CVI-267.

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