ABC  Vol.4 No.2 , April 2014
GABAA Receptor Modulation by Compounds Isolated from Salvia triloba L.
Abstract: Salvia triloba, traditionally known as Greek sage, has been used to enhance memory, as a sedative and to treat headaches. Pharmacological evaluation of purified extracts and isolated compounds of S. triloba were carried out on functional assays using two-electrode voltage clamp methods on recombinant GABA receptors expressed in Xenopus laevis oocytes. Bio-assay guided fractionation led to seven compounds being isolated from S. triloba: ursolic acid, carnosol, oleanolic acid, salvigenin, rosmanol, cirsimaritin and hispidulin. The purified extracts of S. triloba inhibited 54% of the current produced by 300 μM GABA at α1β2γ2L GABAA receptors. Ursolic acid, carnosol, oleanolic acid and rosmanol also acted as negative allosteric modulators. The flavonoids salvigenin, cirsimaritin and hispidulin acted as positive modulators when applied in the presence of low concentrations of GABA but in the presence of high concentrations of GABA acted as negative modulators, demonstrating a biphasic action. These results are consistent with the concept that Salvia triloba may have cognition enhancing properties. In most cases these activities are likely to be occurring via different modulatory sites on GABAA receptor complexes. It may be that the combination of these activities permits cognition enhancement whilst offering protection from convulsant activity.

Cite this paper: Abdelhalim, A. , Chebib, M. , Aburjai, T. , Johnston, G. and Hanrahan, J. (2014) GABAA Receptor Modulation by Compounds Isolated from Salvia triloba L.. Advances in Biological Chemistry, 4, 148-159. doi: 10.4236/abc.2014.42019.

[1]   Tildesley, N.T., Kennedy, D.O., Perry, E.K., Ballard, C.G., Savelev, S., Wesnes, K.A. and Scholey, A.B. (2003) Salvia lavandulaefolia (Spanish Sage) Enhances Memory in Healthy Young Volunteers. Pharmacology Biochemistry and Behavior, 75, 669-674.

[2]   Al-Qura’n, S. (2009) Ethnopharmacological Survey of Wild Medicinal Plants in Showbak, Jordan. Journal of Ethnopharmacology, 123, 45-50.

[3]   Jia, W., Gao, W.Y., Cui, N.Q. and Xiao, P.G. (2003) Anti-Inflammatory Effects of an Herbal Medicine (Xuan-Ju Agent) on Carrageenan- and Adjuvant-Induced Paw Edema in Rats. Journal of Ethnopharmacology, 89, 139-141.

[4]   Johnston, G.A., Hanrahan, J.R., Chebib, M., Duke, R.K. and Mewett, K.N. (2006) Modulation of Ionotropic GABA Receptors by Natural Products of Plant Origin. Advances in Pharmacology, 54, 285-316.

[5]   Salah, S.M. and Jager, A.K. (2005) Screening of Traditionally Used Lebanese Herbs for Neurological Activities. Journal of Ethnopharmacology, 97, 145-149.

[6]   Hosseinzadeh, H. and Lary, P. (2000) Effect of Salvia leriifolia Leaf Extract on Morphine Dependence in Mice. Phytotherapy Research, 14, 384-387.<384::AID-PTR641>3.0.CO;2-F

[7]   Imanshahidi, M. and Hosseinzadeh, H. (2006) The Pharmacological Effects of Salvia Species on the Central Nervous System. Phytotherapy Research, 20, 427-437.

[8]   Chebib, M. and Johnston, G.A. (2000) GABA-Activated Ligand Gated Ion Channels: Medicinal Chemistry and Molecular Biology. Journal of Medicinal Chemistry, 43, 1427-1447.

[9]   Johnston, G.A.R. (2013) Advantages of an Antagonist: Bicuculline and Other GABA Antagonists. British Journal of Pharmacology, 169, 328-336.

[10]   Hanrahan, J.R., Chebib, M. and Johnston, G.A. (2011) Flavonoid Modulation of GABA(A) Receptors. British Journal of Pharmacology, 163, 234-245.

[11]   McKernan, R.M. and Whiting, P.J. (1996) Which GABAA-Receptor Subtypes Really Occur in the Brain? Trends in Neuroscience, 19, 139-143.

[12]   Karim, N., Wellendorph, P., Absalom, N., Johnston, G.A., Hanrahan, J.R. and Chebib, M. (2013) Potency of GABA at Human Recombinant GABA(A) Receptors Expressed in Xenopus Oocytes: A Mini Review. Amino Acids, 44, 1139-1149.

[13]   Singletary, K., MacDonald, C. and Wallig, M. (1996) Inhibition by Rosemary and Carnosol of 7,12-Dimethylbenz[a]-Anthracene (DMBA)-Induced Rat Mammary Tumorigenesis and in Vivo DMBA-DNA Adduct Formation. Cancer Letters, 104, 43-48.

[14]   Awad, R., Muhammad, A., Durst, T., Trudeau, V.L. and Arnason, J.T. (2009) Bioassay-Guided Fractionation of Lemon Balm (Melissa officinalis L.) Using an in Vitro Measure of GABA Transaminase Activity. Phytotherapy Research, 23, 1075-1081.

[15]   Taviano, M.F., Miceli, N., Monforte, M.T., Tzakou, O. and Galati, E.M. (2007) Ursolic Acid Plays a Role in Nepeta Sibthorpii Bentham CNS Depressing Effects. Phytotherapy Research, 21, 382-385.

[16]   Brieskorn, C.H., Fuchs, A., Bredenberg, J.B.-S., McChesney, J.D. and Wenkert, E. (1964) The Structure of Carnosol. The Journal of Organic Chemistry, 29, 2293-2298.

[17]   Huang, M.T., Ho, C.T., Wang, Z.Y., Ferraro, T., Lou, Y.R., Stauber, K., Ma, W., Georgiadis, C., Laskin, J.D. and Conney, A.H. (1994) Inhibition of Skin Tumorigenesis by Rosemary and Its Constituents Carnosol and Ursolic Acid. Cancer Research, 54, 701-708.

[18]   Kim, S.J., Kim, J.S., Cho, H.S., Lee, H.J., Kim, S.Y., Kim, S., Lee, S.Y. and Chun, H.S. (2006) Carnosol, a Component of Rosemary (Rosmarinus officinalis L.) Protects Nigral Dopaminergic Neuronal Cells. Neuroreport, 17, 1729-1733.

[19]   Rutherford, D.M., Nielsen, M.P.C., Hansen, S.K., Witt, M.-R., Bergendorff, O. and Sterner, O. (1992) Isolation and Identification from Salvia officinalis of Two Diterpenes Which Inhibit t-Butylbicyclophosphoro[35S]Thionate Binding to Chloride Channel of Rat Cerebrocortical Membranes in Vitro. Neuroscience Letters, 135, 224-226.

[20]   Ha, J.H., Lee, K.Y., Choi, H.C., Cho, J., Kang, B.S., Lim, J.C. and Lee, D.U. (2002) Modulation of Radioligand Binding to the GABA(A)-Benzodiazepine Receptor Complex by a New Component from Cyperus Rotundus. Biological and Pharmaceutical Bulletin, 25, 128-130.

[21]   Dorman, H.J.D., Peltoketo, A., Hiltunen, R. and Tikkanen, M.J. (2003) Characterisation of the Antioxidant Properties of De-Odourised Aqueous Extracts from Selected Lamiaceae Herbs. Food Chemistry, 83, 255-262.

[22]   Matsingou, T.C., Petrakis, N., Kapsokefalou, M. and Salifoglou, A. (2003) Antioxidant Activity of Organic Extracts from Aqueous Infusions of Sage. Journal of Agriculture and Food Chemistry, 51, 6696-6701.

[23]   Kavvadias, D., Monschein, V., Sand, P., Riederer, P. and Schreier, P. (2003) Constituents of Sage (Salvia officinalis) with in Vitro Affinity to Human Brain Benzodiazepine Receptor. Planta Medica, 69, 113-117.

[24]   Shen, X.L., Nielsen, M., Witt, M.R., Sterner, O., Bergendorff, O. and Khayyal, M. (1994) Inhibition of [Methyl-3H]-Diazepam Binding to Rat Brain Membranes in Vitro by Dinatin and Skrofulein. Acta Pharmacologica Sinica, 15, 385-388.

[25]   Ai, J., Dekermendjian, K., Wang, X., Nielsen, M. and Witt, M.-R. (1997) 6-Methylflavone, a Benzodiazepine Receptor Ligand with Antagonistic Properties on Rat Brain and Human Recombinant GABAA Receptors in Vitro. Drug Development Research, 41, 99-106.<99::AID-DDR7>3.0.CO;2-M

[26]   Hall, B.J., Chebib, M., Hanrahan, J.R. and Johnston, G.A. (2004) Flumazenil-Independent Positive Modulation of Gamma-Aminobutyric Acid Action by 6-Methylflavone at Human Recombinant α1β2γ2L and α1β2 GABAA Receptors. European Journal of Pharmacology, 491, 1-8.

[27]   Butterweck, V., Nahrstedt, A., Evans, J., Hufeisen, S., Rauser, L., Savage, J., Popadak, B., Ernsberger, P. and Roth, B.L. (2002) In Vitro Receptor Screening of Pure Constituents of St. John’s Wort Reveals Novel Interactions with a Number of GPCRs. Psychopharmacology (Berl), 162, 193-202.

[28]   Hanrahan, J.R., Chebib, M., Davucheron, N.L., Hall, B.J. and Johnston, G.A. (2003) Semisynthetic Preparation of Amentoflavone: A Negative Modulator at GABA(A) Receptors. Bioorganic and Medicinal Chemistry Letters, 13, 2281-2284.

[29]   Hansen, R.S., Paulsen, I. and Davies, M. (2005) Determinants of Amentoflavone Interaction at the GABAA Receptor. European Journal of Pharmacology, 519, 199-207.

[30]   Salah, S.M. and Jager, A.K. (2005) Two Flavonoids from Artemisia herbaalba Asso with in Vitro GABAA-Benzodiazepine Receptor Activity. Journal of Ethnopharmacology, 99, 145-146.

[31]   Kavvadias, D., Sand, P., Youdim, K.A., Qaiser, M.Z., Rice-Evans, C., Baur, R., Sigel, E., Rausch, W.D., Riederer, P. and Schreier, P. (2004) The Flavone Hispidulin, a Benzodiazepine Receptor Ligand with Positive Allosteric Properties, Traverses the Blood-Brain Barrier and Exhibits Anticonvulsive Effects. British Journal of Pharmacology, 142, 811-820.