Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes

doi:10.1016/S0006-8993(98)01126-3

Brain Research

Volume 816, Issue 2, 23 January 1999, Pages 358-363

https://doi.org/10.1016/S0006-8993(98)01126-3 Get rights and content

Abstract

Extracts of Hypericum perforatum, commonly known as St. John's wort, are frequently used in Germany and other European countries to treat mild to moderately severe depression, but the mechanism of antidepressant activity of Hypericum is not understood. Because known mechanisms of antidepressant activity include inhibition of serotonin and/or norepinephrine uptake, we investigated the effects of standardized extracts of Hypericum LI 160 on the transport of these monoamine neurotransmitters into astrocytes, cells which surround synaptic terminals and regulate neurotransmission by means of their uptake systems. We found that LI 160 inhibited both serotonin and norepinephrine uptake in a dose-dependent manner. The two monoamine transport systems were affected differently by LI 160: for serotonin, the main effect was a 50% decrease in the rate of maximal transport, whereas for norepinephrine, the main effect was a 4.5 fold reduction in the apparent affinity of norepinephrine for its uptake sites. Upon removal of LI 160, uptake was restored, thereby indicating that the inhibition was not due to a toxic effect of Hypericum on the cells. These findings suggest that the ability of LI 160 to inhibit serotonin and norepinephrine uptake may underlie the antidepressant activity of this Hypericum extract.

Introduction

To treat depressive, anxiety, and sleep disorders, extracts of Hypericum perforatum (St. John's wort) are frequently prescribed in Germany and other European countries. The antidepressant activity of Hypericum has been indicated from a number of controlled studies (reviewed in Ref. [7]). A recent meta-analysis of 23 randomized clinical trials indicated that Hypericum extracts were significantly better than placebo and as effective as some antidepressants in cases of mild or moderately severe depressive disorders [12]. The reported incidence of side-effects was very low compared to the tricyclic antidepressants and serotonin re-uptake inhibitors. In contrast, very little information is available about the molecular mechanism(s) underlying the antidepressant activity of Hypericum.

Serotonin and norepinephrine are believed to play key roles in depression. Drugs that inhibit re-uptake of serotonin and norepinephrine are effective in the treatment of major depression. For example, tricyclic antidepressant drugs such as imipramine, amitriptyline, and venlafaxine inhibit both norepinephrine and serotonin uptake, while desipramine and nortriptyline preferentially inhibit norepinephrine uptake. Drugs such as fluoxetine (Prozac) and paroxetine preferentially inhibit serotonin transport and have been termed selective serotonin re-uptake inhibitors (SSRIs). Uptake is the main mechanism for terminating the actions of synaptically-released serotonin and norepinephrine 1, 11, 19, 20, 21, and uptake of these monoamine neurotransmitters is mediated by distinct transporters which are inhibited by the tricylic antidepressants and SSRIs 5, 6, 8, 18. Serotonin and norepinephrine transporters are present on both neurons and astrocytes. Astrocytes engulf synaptic terminals and serve to regulate neurotransmission by means of their uptake systems [15]. Monoamine transporters on cultured astrocytes are sensitive to antidepressants [10], and recent in vivo studies indicate an important role for glia in serotonin uptake in rat brain [2]. To determine whether a standardized Hypericum extract (LI 160) acts in a manner similar to synthetic antidepressant drugs, we investigated the effect of LI 160 on serotonin and norepinephrine transport in rat astrocyte cultures.

Section snippets

Cell culture and treatment

Astrocyte cultures were prepared from neonatal rat cerebral cortices as described [16]. In brief, cerebral cortices from 1–2 day old rat pups were dissected free of meninges, minced, dissociated by trituration, and seeded at a density of 300,000 cells/35 mm plate or 2.25×10⁶ cells/T-flask. Cultures were incubated at 37°C in a humidified chamber provided with 5% CO₂ and 95% air in Dulbecco's modified Eagle media containing 15% fetal calf serum (FCS), fungizone, penicillin and streptamycin. Media

Effect of Hypericum LI 160 on serotonin uptake

Rat astrocyte cultures were incubated for various times and with various concentrations of Hypericum LI 160 prior to measurement of serotonin uptake. The characteristics of the LI 160 extracts used in these studies are listed in Table 1. In preincubation studies with 50 μg ml⁻¹ LI 160, we found significant inhibition after a 5 min preincubation period with little additional inhibition at 30 and 60 min preincubation. In dose-response studies, we found that Hypericum inhibited serotonin uptake in

Discussion

Although extracts of the plant H. perforatum exhibit antidepressant activity, little is known about the molecular actions of Hypericum. An early study reported that Hypericum inhibited the neurotransmitter-metabolizing enzymes, monoamine oxidase A and B, but this was not confirmed by later studies 3, 22. More recently, Hypericum has been reported to inhibit uptake of monoamine neurotransmitters in synaptosomal preparations [14], but the work presented here is the first report of the effects of

Note added in proof

This work has been presented in preliminary form elsewhere: J.T. Neary, Y. Bu, Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes, Soc. Neurosci. Abstr. 24 (1998) 1492.

Acknowledgements

This work was supported by Lichtwer Pharma and the Department of Veterans Affairs.

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Research reportHypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes

Abstract

Introduction

Section snippets

Cell culture and treatment

Effect of Hypericum LI 160 on serotonin uptake

Discussion

Note added in proof

Acknowledgements

Brain Res.

J. Biol. Chem.

Neuroscience

Brain Res.

Neurotransmitter transporters: recent progress

Annu. Rev. Neurosci.

Antidepressant drugs inhibit a glial 5-hydroxytryptamine transporter in rat brain

Eur. J. Neurosci.

Inhibition of MAO by fractions and constituents of hypericum extract

J. Geriatr. Psychiatr. Neurol.

Astrocytes as mediators of methylmercury neurotoxicity: effects on d-aspartate and serotonin uptake

Dev. Neurosci.

Serotonin uptake and serotonin uptake inhibition

Ann. New York Acad. Sci.

Inhibition of uptake of tritiated-noradrenaline in the intact rat brain by imipramine and structurally related compounds

Nature

Clinical investigation of the antidepressant effectiveness of hypericum

J. Geriatr. Psychiatr. Neurol.

Research report
Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes