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Pharmacopsychiatry 2003; 36: 24-31
DOI: 10.1055/s-2003-40459
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Cognitive and Other Behavioral Effects of EGb 761® in Animal Models

W. E. Müller1 , S. S. Chatterjee2
  • 1Department of Pharmacology, Biocenter, University of Frankfurt/M. Germany
  • 2Research Department, Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany
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Publication History

Publication Date:
07 July 2003 (online)

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Extensive pre-clinical and clinical studies conducted over more than three decades have established that EGb 761® (definition see editorial) represents a polyvalent therapeutic principle that is useful in the therapy of mildly to moderately severe dementia and other cognitive disorders. Besides cognition, other emotional and affective aspects of brain function also seem to benefit from EGb 761® treatment. Extensive behavioural studies in experimental animals are generally in line with clinical data since cognition improvement, stress protection, and antidepressive effects have been identified with this extract in proper animal models. While individual effects in all areas have been reported for adult animals and acute dosing, more pronounced effects are usually seen in aged animals and after subchronic treatment. Specifically, for the cognition improving properties pronounced beneficial effects are mainly present in those situations where cognition was impaired by aging or other noxious stimuli. Since all these conditions are associated with mitochondrial dysfunction, the stabilizing or even protecting effect of EGb 761® on mitochondrial function seems to be a major mechanism associated with many of EGb 761®’s behavioural effects. Bilobalide is most important in this respect. Moreover, bilobalide and the ginkgolides have recently been shown to affect chloride conductance by interfering with the function of membrane proteins related to receptor-gated chloride channels. These mechanisms are probably associated with behavioural effects requiring acute changes of neuronal activity, but might indirectly also improve mitochondrial function.

References

  • 1 Attela M J, Hoffman S W, Stasio M J, Stein D J. Ginkgo biloba extract facilitates recovery from penetrating brain injury in adult male rats.  Exp Neurol. 1989;  105 62-71
    CrossrefPubMedGoogle Scholar
  • 2 Bastianetto S, Zheng W -H, Quirion R. The Ginkgo biloba extract (EGb 761®) protects and rescues hippocampal cells against nitric Oxide-induced toxicity: involvement of its flavonoid constituents and protein kinase c.  J Neurochem. 2000;  74 2268-2277
    CrossrefPubMedGoogle Scholar
  • 3 Bhattacharya S K, Chakrabarti A, Chatterjee S S. Behavioral effects of bilobalide isolated from Ginkgo biloba leaves: Some experimental observations. Naunyn-Schmiedeberg’s Arch. Pharmacol 1998 358 (Suppl. 2), R 489; Abst. P5121
    Google Scholar
  • 4 Blavet N. Effects of Ginkgo biloba extract (EGb 761®) on learning in the aged rat. In: Effects of Ginkgo biloba extract (EGb 761®) on central nervous system. Eds. Y. Christen, J. Costentin and M. Lacour. Elsevier Paris; 1992: 119-127
    Google 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;  33 249-256
    CrossrefPubMedGoogle Scholar
  • 6 Chandrasekaran K, Mehrabin Z, Spinnewyn B, Drieu K, Fiskum G. Neuroprotective effect of bilobalide, a component of the Ginkgo biloba extract (EGb 761®), in gerbil global ischemia.  Brain Res. 2001;  922 282-292
    CrossrefPubMedGoogle Scholar
  • 7 Chatterjee 1984 S S, Gabard B. Effect of an extract of Ginkgo biloba on experimental neurotoxicity.  Naunyn-Schmiedeberg’s Arch Pharmacol. 1984;  325 (Suppl.) Abs. 327
    PubMedGoogle Scholar
  • 8 Chatterjee S S, Gabard B L, Jaggy H EW. Pharmaceutical composition containing bilobalide for the treatment of neuropathies. US patent no. 4,571,407. 1986
    Google Scholar
  • 9 Chatterjee S S, Klessing K, Jaggy H, Saederup E, Squires R F. Bilobalide and its structural analogs as novel chloride channel ligands without convulsant activity.  Naunyn-Schmiedeberg’s Arch Pharmacol. 2002a;  (Suppl. 1) R79 Abst. 304
    PubMedGoogle Scholar
  • 10 Chatterjee S S, Nöldner M. Behavioral observations demonstrating influences of the extract of Ginkgo biloba (EGb 761®) on some specific central cholinergic systems.  Naunyn-Schmiedeberg’s Arch Pharmacol. 1989;  339 (Suppl.) Abs. 425
    PubMedGoogle Scholar
  • 11 Chatterjee S S. Species specific behavioral activity profile of bilobalide in mice.  Pharmacologist. 2002c;  44 (Suppl. 1) A 129 Abst. 77.6
    PubMedGoogle Scholar
  • 12 Chen Q, Olney J W, Lukasiewicz P D, Almli T, Romano C. Ca+ 2-independent excitotoxic neurodegeneration in isolated retina, an intact neural net: a role for Cl- and inhibitory transmitters.  Mol Pharmacol. 1998;  53 564-572
    PubMedGoogle Scholar
  • 13 Chermat R, Brochet D, DeFeudis F V, Drieu K. Interactions of Ginkgo biloba extract (EGb 761®), diazepam and ethyl β-carboline-3-carboxylate on social behaviour of the rat.  Pharmacol Biochem Behav. 1997;  56 333-339
    CrossrefPubMedGoogle Scholar
  • 14 Chopin P, Briley M. Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats.  Psychopharmacol. 1992;  106 26-30
    PubMedGoogle Scholar
  • 15 Christen Y, Maixent J M. Molecular and cellular studies of Ginkgo biloba extract EGb 761® - From mechanism of action to therapy.  Cell Mol Biol. 2002b;  48 (6) 591- 731
    PubMedGoogle Scholar
  • 16 Christen 2002a Y, Maixent J M. What is Ginkgo biloba extract EGb 761®? An overview - From molecular biology to clinical medicine.  Cell Mol Biol. 2002a ;  48 (6) 601-611
    PubMedGoogle Scholar
  • 17 Clostre F, Millerin M, Betin C, Bazan N, Braquet P. Effects of two platelet-activating factor antagonists, BN 52 063 and alprazolam on forced swimming-induced behavioral despair in mice. In: Ginkgolides: Chemistry, biology, pharmacology and clinical perspective, Vol. 1 Ed. P. Braquet J.R. Prous science publishers Barcelona; 1988: 649-664
    Google Scholar
  • 18 Cohen-Salmon C h., Venault P, Martin B, Raffalli-Sébille M J, Barkats M, Clostre F, Pardon M C, Christen Y, Chapouthier G. Effects of Ginkgo biloba extract (EGb 761®) on learning and possible actions on aging.  J Physiol. 1997;  91 291-300
    PubMedGoogle Scholar
  • 19 Continella G, Drago F. Behavioral effects of Ginkgo-biloba extract. In: Effects of Ginkgo biloba extract on organic cerebral impairment. Eds. A. Angoli, J. R. Rapain, V. Scapagnini and W. V. Weitbrecht John Libbey London - Paris; 1985: 35-42
    Google Scholar
  • 20 DeFeudis F V, Drieu K. Ginkgo biloba extract (EGb 761®) and CNS functions: Basic studies and clinical applications.  Curr Drug Targets. 2000;  1 25-58
    CrossrefPubMedGoogle Scholar
  • 21 Galeffi F, Sinnar S, Schwartz-Bloom R D. Diazepam promotes ATP recovery and prevents cytochrome c release in hippocampal slices after in vitro ischemia.  J Neurochem. 2000;  75 1242-1249
    CrossrefPubMedGoogle Scholar
  • 22 Hoyer S, Lannert H, Nöldner M, Chatterjee S S. Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761).  J Neural Transm. 1999;  106 1171-1188
    CrossrefPubMedGoogle Scholar
  • 23 Inglefield J R, Schwartz-Bloom R D. Activation of excitatory amino acid receptors in rat hippocampal slice increases intracellular Cl- and cell volume.  J Neurochem. 1998b;  71 1396-1404
    PubMedGoogle Scholar
  • 24 Inglefield J R, Schwartz-Bloom R D. Optical imaging of hippocampal neurones with a chloride sensitive dye: Early effects of in vitro ischemia.  J Neurochem. 1998a ;  70 2500-2509
    PubMedGoogle Scholar
  • 25 Janssens D, Michiels C, Delaive E, Eliaers F, Drieu K, Remacle J. Protection of hypoxia-induced ATP decrease in endothelial cells by Ginkgo biloba extract and bilobalide.  Biochem Pharmacol. 1995;  50 991-999
    CrossrefPubMedGoogle Scholar
  • 26 Janssens D, Remacle J, Drieu K, Michiels C. Protection of mitochondrial respiration activity by bilobalide.  Biochem Pharmacol. 1999;  58 109-119
    CrossrefPubMedGoogle Scholar
  • 27 Klusa V, Germane S, Nöldner M, Chatterjee S S. Effects of bilobalide in two rodent learning models. Naunyn-Schmiedeberg’s Arch Pharmacol 1998 358 (Suppl. 2); R 494: Abst. P5143
    Google Scholar
  • 28 Krieglstein J, Ausmeier F, El-Abhar H, Lippert K, Welsch M, Rupalla K, Henrich-Noack P. Neuroprotective effects of Ginkgo biloba constituents.  Eur J Phar Sci. 1995;  3 39-48
    PubMedGoogle Scholar
  • 29 Lambert N, Grover L. The mechanism of biphasic GABA responses.  Science. 1995;  269 928-929
    PubMedGoogle Scholar
  • 30 Lamproglou I, Boisserie G, Vranckx R, Baillet F, Bok B, Drieu K. Cognitive dysfunction induced by cranial irradiation: effect of Ginkgo biloba extract (EGb 761®) in 4-month-old male rats.  Adv Ginkgo biloba Extract Res. 1997;  6 73-87
    PubMedGoogle Scholar
  • 31 Maclennan K M, Darlington C L, Smith P F. The CNS effects of Ginkgo biloba extracts and ginkgolide.  B Progr Neurobiol. 2002;  67 235-257
    PubMedGoogle Scholar
  • 32 Nöldner M, Chatterjee S S. Anxiolytic-like activity of bilobalide. Naunyn-Schmiedeberg’s Arch Pharmacol 1994 349 (Suppl.): Abst. 388
    Google Scholar
  • 33 Nöldner M, Chatterjee S S. Pharmaceutical preparations containing bilobalide for the treatment of nervous tension and anxiety. International Patent A61K31/365,35/78, WO 93/12 784. 1993
    Google Scholar
  • 34 Otani M, Chatterjee S S, Gabard B, Kreutzberg G W. Effect of an extract of Ginkgo biloba on triethyltin-induced cerebral edema. Acta Neuropathol 1886: 54-65
    Google Scholar
  • 35 Pardon M C, Hanoun N, Perez-Diaz F, Launay J M. Christen Y, Hamon M, Cohen-Salmon C. Age-related changes in the effects of a chronic ultramild stress procedure on decision-making, open-field behaviour and some indices of serotoninergic neurotransmission in B6D2F1 mice. Influence of a long-term treatment with EGb 761® (Tanakan®).  In: Advances in Ginkgo biloba extract research, Vol. 8. Ginkgo biloba extract (EGb 761®) as a neuroprotective agent: from basic studies to clinical trials. Ed. Y. Christen Solal éditeur, Marseille; 2001: 187-204
    Google Scholar
  • 36 Porsolt R D, Martin P, Lenégre A, Fromge S, Drieu K. Effects of an extract of Ginkgo biloba (EGb 761®) on ”learned helplessness” and other models of stress in rodents.  Pharmacol Biochem Behav. 1990;  36 963-971
    CrossrefPubMedGoogle Scholar
  • 37 Raffali-Sébille M J, Chapouthier G, Clostre F, Christen Y. Learning improvement in adult and aged mice induced by Ginkgo biloba extract.  In: Effects of Ginkgo biloba extract (EGb 761) on central nervous system. Eds. Y. Christen, J. Costentin and M. Lacour Elsevier, Paris; 1992: 129-134
    Google Scholar
  • 38 Rapin J R, Lamproglou I, Drieu K, DeFeudis F V. Demonstration of the ”anti-stress” activity of an extract of Ginkgo biloba (EGb 761®) using a discrimination learning task.  Gen Pharmacol. 1994;  25 1009-1016
    PubMedGoogle Scholar
  • 39 Rapin J R, Lamproglou I, Drieu K. Anti-stress activity of Ginkgo biloba extract (EGb 761®) on a learning test and neuroendocrine responses.  In: Advances in Ginkgo biloba extract research, Vol. 4. Effects of Ginkgo biloba extract (EGb 761®) on aging and age related disorders. Eds. Y. Christen, Y. Courtois and MT Droy-Lefaix Elsevier, Paris; 1995: 99-106
    Google Scholar
  • 40 Ravel N, Chabaud P, Mannino M, Vigouroux M, Gervais R, Droy-Lefaix M T. Ginkgo biloba extract and short-term olfactory memory.  In: Advances in Ginkgo biloba extract research, Vol. 5. Effects of Ginkgo biloba extract (EGb 761®) on neuronal plasticity. Eds. Y. Christen, M: T: Droy-Lefaix and J. F. Macais-Nunez Elsevier, Paris; 1996: 35-44
    Google Scholar
  • 41 Rickard N S, Kowadlo N, Gibbs M E. Effects of the Ginkgo biloba extract, EGb 761®; on memory formation in day-old chicks.  Pharmacol Biochem Behav. 2001;  69 351-358
    CrossrefPubMedGoogle Scholar
  • 42 Sancesario G, Kreutzberg G W. Stimulation of astrocytes effects cytotoxic brain edema.  Acta Neuropathol. 1986;  72 3-14
    PubMedGoogle Scholar
  • 43 Scheuer K, Stoll S, Paschke U, Weigel R, Müller W E. NMDA receptor density and membrane fluidity as possible determinants of the decline of passive avoidance learning in aging.  Pharmacol Biochem Behav. 1995;  50 65-70
    CrossrefPubMedGoogle Scholar
  • 44 Scheuer K, Rostock A, Bartsch R, Müller W E. Piracetam improves cognitive performance by restoring neurochemical deficits of the aged rat brain.  Pharmacopsychiatry. 1999;  32 10-16
    PubMedGoogle Scholar
  • 45 Schwartz-Bloom R D, Miller K A, Evenson D A, Crain B J, Nadler J V. Benzodiazepines protect hippocampal neurons from degeneration after transient cerebral ischemia: an ultrastructural study.  Neurosci. 2000;  98 471-484
    CrossrefPubMedGoogle Scholar
  • 46 Schwartz-Bloom R D, Sah R. γ-Aminobutyric acidA neurotransmission and cerebral ischemia.  J Neurochem. 2001;  77 353-371
    CrossrefPubMedGoogle Scholar
  • 47 Stoll S, Scheuer K, Pohl O, Müller W E. Ginkgo biloba extract (EGb 761®) independently improves changes in passive avoidance learning and brain membrane fluidity in aging mouse.  Pharmacopsychiat. 1996;  29 144-149
    PubMedGoogle Scholar
  • 48 Tatton W G, Chalmers-Redman R M. Mitochondria in neurodegenerative apoptosis: an opportunity for therapy?.  Ann Neurol. 1998;  44 (Suppl 1) 134-141
    CrossrefPubMedGoogle Scholar
  • 49 Teather L A, Magnusson J E, Wurtman R J. Platelet-activating factor antagonists decrease the inflammatory nociceptive response in rats.  Psychopharmacol. 2002;  163 430-433
    PubMedGoogle Scholar
  • 50 Tendi E A, Bosetti F, DasGupta S F, Stella A MG, Drieu K, Rapoport S I. Ginkgo biloba Extracts EGb 761® and Bilobalide Increase NADH Dehydrogenase mRNA Level and Mitochondrial Respiratory Control Ratio in PC12 Cells . 2002 27: 319-323
    Google Scholar
  • 51 Venkatachalam M A, Weinberg J M, Patel Y, Seikumar P, Dong Z. Cytoprotection of kidney epithelial cells by compounds that target amino acid gated chloride channels.  Kidney Int. 1996;  49 449-460
    PubMedGoogle Scholar
  • 52 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-Schmiedeberg¿s Arch Pharmacol. 1999;  360 609-615
    CrossrefPubMedGoogle Scholar
  • 53 Winter J C, Timineri D. The discriminative stimulus properties of EGb 761®, an extract of Ginkgo biloba.  Pharmacol Biochem Behav. 1999;  62 543-547
    CrossrefPubMedGoogle Scholar
  • 54 Winter J C. Effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat.  Physiol Behav. 1998;  63 425-433
    CrossrefPubMedGoogle Scholar
  • 55 Winter E. Effects of an extract of Ginkgo biloba on learning and memory in mice.  Pharmacol. Biochem. Behav.. 1991;  38 109-114
    CrossrefPubMedGoogle Scholar
  • 56 Wirth S, Stemmelin J, Will B, Christen Y, Scala G D. Facilitative effects of EGb 761® on olfactory recognition in young and aged rats.  Pharmacol Biochem Behav. 2000;  65 321-326
    CrossrefPubMedGoogle Scholar
  • 57 Zhou LJ and Zhu X Z. Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide.  J Pharmacol Exp Ther. 2000;  293 982-988
    PubMedGoogle Scholar
  • 58 Zimmermann M, Colciaghi F, Cattabeni F, DiLuca M. Ginkgo biloba extract: From molecular mechanisms to the treatment of Alzheimer's disease.  Cell Mol Biol. 2002;  48(6) 613-623
    PubMedGoogle Scholar

Prof. Dr. Walter E. Müller

Department of Pharmacology

Biocenter

Goethe University

Marie-Curie-Straße 9

D-60439 Frankfurt/Main

Germany

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