Two Lignan Glycosides from Albizia julibrissin Durazz. Noncompetitively Inhibit Serotonin Transporter.

Bishan Huang,Yuan-Wei Zhang,Hanhe Liu,Qingfa Tang,Chan Li,Yingyao Wu

doi:10.3390/ph15030344

Abstract

Albizia julibrissin Durazz. is one of the most common herbs used for depression and anxiety treatment, but its molecular basis and mechanism of action as an antidepressant or anxiolytic drug are not understood. In this study, we separated and identified two lignan glycosides that inhibit serotonin transporter (SERT) noncompetitively by decreasing Vmax with little change in Km for its fluorescence substrate. In addition, treatment with lignan glycosides did not alter total and cell surface expression levels of the transporter protein. The two compounds decreased the accessibility of a cysteine residue placed in the extracellular substrate permeation pathway by inducing a conformational shift toward an outward-closed state of SERT. These results are consistent with molecular docking for the association of the lignan glycosides to the allosteric site in SERT. The present work supports the proposal that these compounds act on SERT by a novel underlying mechanism of action different from that of conventional antidepressant drugs.

Highlights

Albizia julibrissin Durazz., a leguminous deciduous shrub, is one of the most common herbs used for depression and anxiety treatment in East Asia
APP+ has emerged as a powerful tool to fluorometrically examine Serotonin transporter (SERT) transport in various aspects [40–43]
We examined the inhibitory effects of all fractions in the separation of Albizia julibrissin Durazz. on hSERT activity, and performed further separation on the fractions with strong potency antagonizing APP+ uptake according to their Ki values

Summary

Introduction

Albizia julibrissin Durazz., a leguminous deciduous shrub, is one of the most common herbs used for depression and anxiety treatment in East Asia. Its dried flowers or bark are generally processed for medicinal purposes. Include triterpenoids, lignans, flavonoids, saponins, and sterols [1]. Preclinical studies showed that these ingredients exhibit a broad array of pharmacological activities ranging from antidepressant and anxiolytic [2–5], anti-inflammatory [6,7], antioxidant [8], and antitumor [9,10], to the enhancement of immunological function [11]. Their molecular mechanisms of action, are not understood. Serotonin transporter (SERT) is a presynaptic plasma membrane protein responsible for

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Conclusion