Effects of Hypericum perforatum on Levels of 5-Hydroxytryptamine, Noradrenaline and Dopamine in the Cortex, Diencephalon and Brainstem of the Rat

Abstract

The plant Hypericum perforatum is used in folk medicine to treat several diseases and research attention has been recently focused on its antidepressant action. Hypericin and flavonoids are the most important constituents of the plant, but the exact role of these compounds in the effects of hypericum on mood disorders is not well known. We have investigated the contribution of these compounds to the antidepressant effects of hypericum. The effects of acute administration of hypericum extracts on levels of 5-hydroxytryptamine (5-HT), tryptophan, 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline and dopamine in the cortex, diencephalon and brainstem was evaluated. The levels of these neurotransmitters were measured 1 h and 24 h after administration of two different extracts, one containing 0.3% hypericin and 6% flavonoids (Li 160; 25-500 mgkg(-1)), the other containing 0.3% hypericin and 50% flavonoids (Ph-50; 25-500 mgkg(-1)). Results from experiments performed on 5-HT turnover were compared with the effects of fluoxetine (10-80 mgkg(-1)). Li 160, Ph-50 and fluoxetine induced a significant increase in the 5-HT content of the cortex. In the diencephalon Ph-50, but not Li 160 or fluoxetine, elicited an increase in 5-HT and 5-HIAA levels. In the brainstem Ph-50 and fluoxetine caused an increase in 5-HT content; Li 160 did not change neurotransmitter content. Both Li 160 and Ph-50 caused increases of noradrenaline and dopamine in the diencephalon. In the brainstem only Ph-50 induced an increase in noradrenaline content. Our data confirm that acute administration of hypericum extracts modifies the levels of neurotransmitters involved in the pathophysiology of mood disorders. When the extracts contain a higher concentration of flavonoids the effects are more widespread and involve brain regions such as diencephalon and brainstem that are implicated in depression.

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 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).…”

Effects of Standardized Extracts of St. John's Wort on the Single-Unit Activity of Serotonergic Dorsal Raphe Neurons in Awake Cats Comparisons with Fluoxetine and Sertraline

“…have been shown to exert antidepressant-like effects in several animal models of depression, such as behavioral despair and learned helplessness in rodents (Butterweck et al 1997;Bhattacharya et al 1998;Chatterjee et al 1998;Gobbi et al 1999;Kumar et al 1999). Similar doses have also been reported to increase brain 5-hydroxyindole levels (Calapai et al 1999;Yu 2000), potentiate 5-hydroxytryptophan-induced head-twitches , antagonize reserpine-induced behavioral syndrome Kumar et al 1999), and produce a down-regulation of ␤-adrenergic receptors in the rat frontal cortex after subchronic administration ), a biological marker of antide- pressant efficacy. Similarly, Hyperforat® (0.5-4 ml, i.v.)…”

“…Furthermore, unlike classical serotonin reuptake inhibitors, hypericum extracts do not inhibit the turnover or metabolism of serotonin in the brain after systemic application (Calapai et al 1999;Gobbi et al 1999;Yu 2000), nor do they increase the concentration of extracellular serotonin, as measured by intracerebral microdialysis (Di Matteo et al 2000). In fact, neurochemical studies have shown that St. John's wort can actually increase serotonin turnover and brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (Calapai et al 1999;Yu 2000). This latter finding would also argue against any significant MAO-inhibiting properties of St. John's wort in vivo, since such inhibition prevents the formation of 5-HIAA.…”

“…Such nonselective effects might explain why hypericum extracts (and hyperforin) appear to block the synaptosomal uptake of multiple neurotransmitters, including serotonin, norepinephrine, dopamine, ␥-aminobutyric acid and L-glutamate Singer et al 1999;Wonnemann et al 2000). Furthermore, unlike classical serotonin reuptake inhibitors, hypericum extracts do not inhibit the turnover or metabolism of serotonin in the brain after systemic application (Calapai et al 1999;Gobbi et al 1999;Yu 2000), nor do they increase the concentration of extracellular serotonin, as measured by intracerebral microdialysis (Di Matteo et al 2000). In fact, neurochemical studies have shown that St. John's wort can actually increase serotonin turnover and brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (Calapai et al 1999;Yu 2000).…”

“…Other evidence suggest that hypericum extracts may enhance the release of serotonin from presynaptic stores (Gobbi et al 1999). Neurochemical studies have shown that St. John's wort increases serotonin metabolism and/or turnover in various brain regions (Calapai et al 1999;Yu 2000). Finally, it has been hypothesized that the clinical efficacy of St. John's wort may result from a combination of several mechanisms, with each one unable to account for the therapeutic effect alone (see Bennett et al 1998).…”