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
-
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
-
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
-
4
Breitinger H G, Becker C M.
The inhibitory glycine receptor: prospects for a therapeutic orphan?.
Curr Pharm Des.
1998;
4 (4)
315-334
-
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
-
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
-
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)
-
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
-
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
-
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
-
11 Davies J A, Jahns L, Jones F A. Effects of bilobalide on cerebral amino acid neurotransmission. Pharmacopsychiatry 2003 this issue
-
12 DeFeudis F V. Ginkgo biloba extract (EGb761): from chemistry to the clinic. Ullstein Medical ed. Wiesbaden 1998
-
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
-
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
-
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
-
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
-
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
-
18 Klaassen C D. Nonmetallic environmental toxicants. In Goodman and Gilman’s. The Pharmacological Basis of Therapeutics 2002: 1689-1690
-
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
-
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
-
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
-
22
Koch E, Chatterjee S S.
Experimentelle Grundlage für die therapeutische Anwendung von Ginkgo biloba extrakt EGb 761®.
Haemostaseologie.
1993;
13
11-27
-
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
-
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
-
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
-
26
Lambert N, Grover L.
The mechanism of biphasic GABA responses.
Science.
1995;
269 (5226)
928-929
-
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
-
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
-
29 Möhler M. (Editor): Pharmacology of GABA and glycine neurotransmission. Handb Exp Pharmacol. Springer-Verlag Berlin, Heidelberg; 2001: 150
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
38
Sun M K, Alkon D L.
Carbonic anhydrase gating of attention: Memory therapy and enhancement.
TIPS.
2002;
23
83-89
-
39 Von Beek T A. Ginkgo biloba. Harwood academic publishers 2000
-
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
-
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
Dr. S. S. Chatterjee
Dr. Willmar Schwabe Arzneimittel GmbH & Co. KG
Research and Development
Postfach 41 09 29
76209 Karlsruhe
