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Inhibition of serotonin re-uptake by licorice constituents

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 nongenomic 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 compounds on the re-uptake of radioactive serotonin was assayed in HEK-293 cells stably expressed the recombinant 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 phytoestrogens, which like estradiol, affects the serotonergic system and inhibits serotonin re-uptake and, thus, potentially may be beneficial for mild to moderate depression in pre- and postmenopausal women.

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References

  • Anstead G. M., Carlson K. E., and Katzenellenbogen J. A. (1997) The estradiol pharmacophore: ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids 62(3), 268–303.

    PubMed  Article  CAS  Google Scholar 

  • Archer J. S. (1999) NAMS/Solvay Resident Essay Award. Relationship between estrogen, serotonin, and depression. Menopause 6(1), 71–78.

    PubMed  Article  CAS  Google Scholar 

  • Barker E. L. and Blakely R. D. (1995) Norepinephrine and serotonin transporter: molecular targets of antide-pressant drugs, in Psychopharmacology: The Fourth Generation of Progress, Bloom F. E. and Kupfer D. J., eds., Raven, New York, pp. 321–333.

    Google Scholar 

  • Belinky P. A., Aviram M., Mahmood S., and Vaya J. (1998) Structural aspects of the inhibitory effect of glabridin on LDL oxidation. Free Radic. Biol. Med. 24(9), 1419–1429.

    PubMed  Article  CAS  Google Scholar 

  • Bethea C. L., Pecins-Thompson M., Schutzer W. E., Gundlah C., and Lu Z. N. (1998) Ovarian steroids and serotonin neural function. Mol. Neurobiol. 18(2), 87–123.

    PubMed  Article  CAS  Google Scholar 

  • Chang A. S. and Chang S. M. (1999) Nongenomic steroidal modulation of high-affinity serotonin transport. Biochim. Biophys. Acta 1417(1), 157–166.

    PubMed  Article  CAS  Google Scholar 

  • Egner U., Heinrich N., Ruff M., Gangloff M., Mueller-Fahrnow A., and Wurtz J. M. (2001) Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists. Med. Res. Rev. 21(6), 523–539.

    PubMed  Article  CAS  Google Scholar 

  • Eshleman A. J., Carmolli M., Cumbay M., Martens C. R., Neve K. A., and Janowsky A. (1999) Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type. J. Pharmacol. Exp. Ther. 289(2), 877–885.

    PubMed  CAS  Google Scholar 

  • Fozzard J. (1989) Peripheral actions of 5-hydroxytryptamine, in Peripheral Actions of 5-Hydroxytryptamine, Fozzard J., ed., Oxford University Press, New York, p. 410.

    Google Scholar 

  • Fuller R. W. (1994) Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sci. 55(3), 163–167.

    PubMed  Article  CAS  Google Scholar 

  • Mackey R. and Eden J. (1998) Phytoestrogens and the menopause. Climacteric 1(4), 302–308.

    PubMed  Article  CAS  Google Scholar 

  • Qian Y., Galli A., Ramamoorthy S., Risso S., DeFelice L. J., and Blakely R. D. (1997) Protein kinase C activation regulates human serotonin transporters in HEK-293 cells via altered cell surface expression. J. Neurosci. 17(1), 45–57.

    PubMed  CAS  Google Scholar 

  • Rubinow D. R., Schmidt P. J., and Roca C. A. (1998) Estrogen-serotonin interactions: implications for affective regulation. Biol. Psychiatry 44(9), 839–850.

    PubMed  Article  CAS  Google Scholar 

  • Tamir S., Eizenberg M., Somjen D., Stern N., Shelach R., Kaye A., and Vaya J. (2000) Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells. Cancer Res. 60(20), 5704–5709.

    PubMed  CAS  Google Scholar 

  • Tamir S., Eizenberg M., Somjen D., Izrael S., and Vaya J. (2001) Estrogen-like activity of glabrene and other constituents isolated from licorice root. J. Steroid Biochem. Mol. Biol. 78(3), 291–298.

    PubMed  Article  CAS  Google Scholar 

  • Tamir S., Izrael S., and Vaya J. (2002) The effect of oxidative stress on ERa and ERb expression. J. Steroid Biochem. Mol. Biol. 81, 327–332.

    PubMed  Article  CAS  Google Scholar 

  • Vaya J., Belinky P. A., and Aviram M. (1997) Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic. Biol. Med. 23(2), 302–313.

    PubMed  Article  CAS  Google Scholar 

  • Wiseman H. (2000) The therapeutic potential of phytoestrogens. Expert Opin. Invest. Drugs 9(8), 1829–1840.

    Article  CAS  Google Scholar 

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Correspondence to Jacob Vaya.

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Ofir, R., Tamir, S., Khatib, S. et al. Inhibition of serotonin re-uptake by licorice constituents. J Mol Neurosci 20, 135–140 (2003). https://doi.org/10.1385/JMN:20:2:135

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  • DOI: https://doi.org/10.1385/JMN:20:2:135

Index Entries

  • Depression
  • serotonin
  • glabridin
  • glabrene
  • phytoestrogens
  • SAR