Download PDF
Pharmacopsychiatry 2003; 36: 68-77
DOI: 10.1055/s-2003-40455
Original Paper

© Georg Thieme Verlag Stuttgart · New York

Structure-activity Studies with Ginkgo biloba Extract Constituents as Receptor-gated Chloride Channel Blockers and Modulators

S. S. Chatterjee1 , E. L. Kondratskaya2 , O. A. Krishtal2
  • 1Dr. Willmar Schwabe GmbH & Co. KG, Dept. of Pharmacology, Germany
  • 2Department of Cellular Membranology, A. A. Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev, Ukraine
Further Information

Publication History

Publication Date:
07 July 2003 (online)

Also available at
    Permissions and Reprints

The constituents of Ginkgo biloba leaf extract, ginkgolides A, B, C and J are known as effective antagonists of platelet-activating factor (PAF). Here, we will demonstrate that these substances are also effective blockers of glycine-activated chloride channels in the hippocampal neurons of rat. As examined in several other voltage- and ligand-operated channels, this ginkgolide action is selective. The blocking action of all tested ginkgolides is use-dependent - they block open glycine-activated channels. The IC50 values for saturating blocking action of ginkgolides B and C are 0.273 μM and 0.267 μM, respectively, while ginkgolides A and J are less effective - IC50 values are 1.97 μM and 2.0 μM. Corresponding dose-response relationships are close to single-site binding isotherms. Another constituent of EGb 761®, bilobalide, is a weak inhibitor of NMDA receptor-activated current. Its synthetic analogue, NV-31, demonstrates a weak facilitatory action on Gly-activated conductance. Novel findings have indicated the possibility that the unique modulating activity profiles of the EGb 761® (definition see editorial) constituents examined are due to their effects on the anion homeostasis of central neurons.

References

  • 1 Ahlemeyer B, Junker V, Huhne R, Krieglstein J. Neuroprotective effects of NV-31, a bilobalide-derived compound: evidence for an antioxidative mechanism.  Brain Res. 2001;  890 (2) 38-342
    CrossrefPubMedGoogle Scholar
  • 2 Bhattacharya S K, Chakrabarti A, Chatterjee S S. Behavioural effects of bilobalide isolated from Ginkgo biloba leaves: Some experimental observations.  Naunyn-Schmiedeberg’s Arch Pharmacol. 2002;  358 (Suppl. 2) R 489:P 5121
    PubMedGoogle Scholar
  • 3 Braquet P. The ginkgolides: Potent platelet-activating factor antagonists isolated from Ginkgo biloba L: Chemistry pharmacology and clinical applications.  Drugs of the Future. 1987;  12 43
    PubMedGoogle Scholar
  • 4 Breitinger H G, Becker C M. The inhibitory glycine receptor: prospects for a therapeutic orphan?.  Curr Pharm Des. 1998;  4 (4) 315-334
    PubMedGoogle Scholar
  • 5 Brochet D, Chermat R, DeFeudis F V, Drieu K. Effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761) and its terpene trilactone constituents on barbital-induced narcosis in the mouse.  Gen Pharmacol. 1999;  33 (3) 249-256
    CrossrefPubMedGoogle Scholar
  • 6 Chatterjee S S. Species specific behavioral activity profile of bilobalide in mice. Presented at the 14th World Congress of Pharmacology (IUPHAR) 2002: abstr.77.6
    Google Scholar
  • 7 Chatterjee S S, Klessing K, Jaggy H, Seederup E, Squires R F. Bilobalide and its structural analogs as novel chloride channel ligands without convulsant activity.  Naunyn-Schmiedeberg’s Arch Pharmacol. 2002;  365 (Suppl. 1; R 79)
    PubMedGoogle Scholar
  • 8 Chatterton J E, Awobuluyi M, Premkumar L S, Takahashi H, Talantova M, Shin Y. et al . Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.  Nature. 2002;  415 (6873) 793-798
    PubMedGoogle Scholar
  • 9 Chen Q, Olney J W, Lukasiewicz P D, Almli T, Romano C. Ca2+-independent excitotoxic neurodegeneration in isolated retina, an intact neural net: a role for Cl- and inhibitory transmitters.  Mol Pharmacol. 1998;  53 (3) 564-572
    PubMedGoogle Scholar
  • 10 Continella G, Drago F. Behavioral effects of Ginkgo biloba extract. In effects of Ginkgo biloba extract on organic cerebral impairment. W V John Libbey Eurotext Ltd 1985: 35-42
    Google Scholar
  • 11 Davies J A, Jahns L, Jones F A. Effects of bilobalide on cerebral amino acid neurotransmission. Pharmacopsychiatry 2003 this issue
    Google Scholar
  • 12 DeFeudis F V. Ginkgo biloba extract (EGb761): from chemistry to the clinic. Ullstein Medical ed. Wiesbaden 1998
    Google Scholar
  • 13 Du X Y, Li X Y. Effect of ginkgolides on interleukin 1, tumor necrosis factor-alpha and nitric oxide production by rat microglia stimulated with lipopolysaccharides in vitro.  Arzneimittelforsch. 1998;  48 1126-1130
    PubMedGoogle Scholar
  • 14 Hu L, Chen Z, Cheng X, Xie Y. Chemistry of ginkgolides: structure-activity relationship as PAF antagonists.  Pure Appl Chem. 1999;  71 (6) 1153-1156
    PubMedGoogle Scholar
  • 15 Inglefield J R, Schwartz-Bloom R D. Activation of excitatory amino acid receptors in the rat hippocampal slice increases intracellular Cl- and cell volume.  J Neurochem. 1998;  71 (4) 1396-1404
    PubMedGoogle Scholar
  • 16 Janssens D, Delaive E, Remacle J, Michiels C. Protection by bilobalide of the ischaemia-induced alterations of the mitochondrial respiratory activity.  Fundam Clin Pharmacol. 2000;  14 (3) 193-201
    PubMedGoogle Scholar
  • 17 Jones F A, Chatterjee S S, Davies J A. Effects of bilobalide an amino acid release and electrophysiology of cortical slices.  Aminoacids. 2002;  22 369-379
    PubMedGoogle Scholar
  • 18 Klaassen C D. Nonmetallic environmental toxicants. In Goodman and Gilman’s. The Pharmacological Basis of Therapeutics 2002: 1689-1690
    Google Scholar
  • 19 Klein J, Chatterjee S S, Löffelholz K. Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba.  Brain Res. 1997;  755 (2) 347-350
    CrossrefPubMedGoogle Scholar
  • 20 Klein J, Weichel O, Hilgert M, Johanna R, Chatterjee S S, Nawrath H. Excitotoxic hippocampal membrane breakdown and its inhibition by bilobalide: Role of chloride fluxes. Pharmacopsychiatry 2003 this issue
    Google Scholar
  • 21 Klusa V, Germane S, Noeldner M, Chatterjee S S. Effects of bilobalide in two rodent learning models.  Naunyn-Schmiedeberg’s Arch Pharmacol. 2002;  358 ((Suppl. 2) R 494-5143
    PubMedGoogle Scholar
  • 22 Koch E, Chatterjee S S. Experimentelle Grundlage für die therapeutische Anwendung von Ginkgo biloba extrakt EGb 761®.  Haemostaseologie. 1993;  13 11-27
    PubMedGoogle Scholar
  • 23 Kondratskaya E L, Lishko P V, Chatterjee S S, Krishtal O A. BN52021, a platelet activating factor antagonist, is a selective blocker of glycine-gated chloride channel.  Neurochem Int. 2002;  40 (7) 647-653
    CrossrefPubMedGoogle Scholar
  • 24 Krishtal O, Lozovaya N, Fisunov A, Tsintsadze T, Pankratov Y, Kopanitsa M. et al . Modulation of ion channels in rat neurons by the constituents of Hypericum perforatum.  Pharmacopsychiatry. 2001;  34 Suppl 1 S74-S82
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Krishtal O A, Marchenko S M, Pidoplichko V I. Receptor for ATP in the membrane of mammalian sensory neurons.  Neurosci Lett. 1983;  35 (1) 41-45
    CrossrefPubMedGoogle Scholar
  • 26 Lambert N, Grover L. The mechanism of biphasic GABA responses.  Science. 1995;  269 (5226) 928-929
    PubMedGoogle Scholar
  • 27 Lenoir M, Pedruzzi E, Rais S, Drieu K, Perianin A. Sensitization of human neutrophil defense activities through activation of platelet-activating factor receptors by ginkgolide B, a bioactive component of the Ginkgo biloba extract EGB 761.  Biochem Pharmacol. 2002;  63 (7) 1241-1249
    CrossrefPubMedGoogle Scholar
  • 28 Miller L G, Bazan N G, Roy R B, Clostre F, Gaver A, Braquet P. Platelet activating factor antagonists interact with GABAa receptors.  Res Commun Chem Pathol Pharmacol. 1991;  74 (2) 253-256
    PubMedGoogle Scholar
  • 29 Möhler M. (Editor): Pharmacology of GABA and glycine neurotransmission.  Handb Exp Pharmacol. Springer-Verlag Berlin, Heidelberg; 2001: 150
    Google Scholar
  • 30 Pietri S, Maurelli E, Drieu K, Culcasi M. Cardioprotective and anti-oxidant effects of the terpenoid constituents of Ginkgo biloba extract (EGb 761).  J Mol Cell Cardiol. 1997;  29 (2) 733-742
    CrossrefPubMedGoogle Scholar
  • 31 Rundstrom N, Schmieden V, Betz H, Bormann J, Langosch D. Cyanotriphenylborate: subtype-specific blocker of glycine receptor chloride channels.  Proc Natl Acad Sci U S A. 1994;  91 (19) 8950-8954
    PubMedGoogle Scholar
  • 32 Sasaki K, Oota I, Wada K, Inomata K, Ohshika H, Haga M. Effects of bilobalide, a sesquiterpene in Ginkgo biloba leaves, on population spikes in rat hippocampal slices.  Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1999;  124 (3) 315-321
    PubMedGoogle Scholar
  • 33 Sasaki K, Hatta S, Wada K, Ohshika H, Haga M. Anticonvulsant activity of bilobalide, a sesquiterpene in Ginkgo biloba leaves, against chemical-induced and electroshock induced convulsions in mice.  Res Commun Biol Psychiatry. 1995;  20 145-156
    PubMedGoogle Scholar
  • 34 Song W, Guan H J, Zhu X Z, Chen Z L, Yin M L, Cheng X F. Protective effect of bilobalide against nitric oxide-induced neurotoxicity in PC12 cells.  Acta Pharmacol.Sin.. 2000;  21 415-420
    PubMedGoogle Scholar
  • 35 Staley K J, Soldo B L, Proctor W R. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors.  Science. 1995;  269 (5226) 977-981
    CrossrefPubMedGoogle Scholar
  • 36 Sun D, Murali S G. Stimulation of Na+-K+-2Cl- cotransporter in neuronal cells by excitatory neurotransmitter glutamate.  Am J Physiol. 1998;  275 (3 Pt 1) C772-779
    PubMedGoogle Scholar
  • 37 Sun M K, Alkon D L. Pharmacological enhancement of synaptic efficacy, spatial learning, and memory through carbonic anhydrase activation in rats.  J Pharmacol Exp Ther. 2001;  297 (3) 961-967
    PubMedGoogle Scholar
  • 38 Sun M K, Alkon D L. Carbonic anhydrase gating of attention: Memory therapy and enhancement.  TIPS. 2002;  23 83-89
    PubMedGoogle Scholar
  • 39 Von Beek T A. Ginkgo biloba. Harwood academic publishers 2000
    Google Scholar
  • 40 Weichel O, Hilgert M, Chatterjee S S, Lehr M, Klein J. Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus.  Naunyn Schmiedebergs Arch Pharmacol. 1999;  360 (6) 609-615
    CrossrefPubMedGoogle Scholar
  • 41 Wettstein A. Cholinesterase inhibitors and Gingko biloba extracts - are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months’ duration.  Phytomedicine. 2000;  6 (6) 393-401
    PubMedGoogle Scholar

Dr. S. S. Chatterjee

Dr. Willmar Schwabe Arzneimittel GmbH & Co. KG

Research and Development

Postfach 41 09 29

76209 Karlsruhe