*Author to whom all correspondence and reprint requests should be addressed. E-mail: vaya@migal.org.il Inhibition of Serotonin Re-Uptake by Licorice Constituents Rivka Ofir, 2 Snait Tamir, 1 Soliman Khatib, 1 and Jacob Vaya* ,1 1 Laboratory of Natural Compounds for Medicinal Use, Migal—Galilee Technological Center, Kiryat Shmona 10200, Israel; 1 The Department of Biotechnology, Tel-Hai Academic College, Upper Galilee, Israel; and 2 Hatzeva Research and Development Center, Jacob Blaustein Institute for Desert Research, Ben Gurion University of the Negev, Beer Sheva 84105, Israel Received September 1, 2002; Accepted October 3, 2002 Abstract Ovarian steroid hormones, estrogen and progestin, affect the function of the serotonin neural system by inhibiting serotonin re-uptake through allosteric interaction with the serotonin transporter (SERT) in a nonge- nomic mechanism. Blocking or reducing serotonin re-uptake at the synapse alleviates depression. The aim of this study was to test the effect of compounds of the isoflavan and isoflavene groups, subclasses of the flavonoids family, on serotonin re-uptake and to compare the results with the effect of other known phytoestrogens like genistein and daidzein to relate the activity of these compounds to their structure. The effect of these com- pounds on the re-uptake of radioactive serotonin was assayed in HEK-293 cells stably expressed the recombi- nant human serotonin transporter (hSERT). The results demonstrated that the isoflavans glabridin and 4′-O-methylglabridin (4′-OMeG) and the isoflavene glabrene inhibited serotonin re-uptake by 60, 53 and 47%, respectively, at 50 μM, whereas resorcinol, the isoflavan 2′-O-methylglabridin (2′-OMeG), and the isoflavones genistein and daidzein were inactive. The inhibition of serotonin re-uptake is dose dependant with glabridin and estradiol. These results emphasize the importance of the lipophilic part of the isoflavans, as well as the hydroxyl at position 2′ on ring B. In conclusion, this study showed that several isoflavans are unique phytoe- strogens, which like estradiol, affects the serotonergic system and inhibits serotonin re-uptake and, thus, poten- tially may be beneficial for mild to moderate depression in pre- and postmenopausal women. Index Entries: Depression; serotonin; glabridin; glabrene; phytoestrogens; SAR Introduction There is an increase in the prevalence of depres- sive symptoms in women undergoing menopause— an increase that can be related to fluctuating levels of estrogen (Archer, 1999). The serotonergic system plays a major role in depression, although other neu- rotransmitters are also involved (Fuller, 1994; Barker and Blakely, 1995). The biogenic amine serotonin (5-hydroxytryptamine [5-HT]) is a neurotransmitter in the central and peripheral nervous systems (Foz- zard, 1989). A key regulatory process of chemical neurotransmission is the inactivation of neuro- transmitters after their release, mainly caused by the action of biogenic amine transporters. Following release of the transmitter 5-HT, the neuronal trans- fer and synaptic clearance are controlled by specific re-uptake of the transmitter from the synaptic cleft into the presynaptic nerve terminal by the plasma membrane 5-HT serotonin transporter (SERT) (Barker and Blakely, 1995). SERT blockage elevates extracellular 5-HT and potentiates synaptic 5-HT action (Fuller, 1994). Selective blockage of central nervous system SERTs in humans is the initial step in the pharmacological improvement of a wide vari- ety of disorders, including major depression, and Journal of Molecular Neuroscience Copyright © 2003 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/03/20:135–140/$20.00 Journal of Molecular Neuroscience 135 Volume 20, 2003 ORIGINAL ARTICLE