Chemistry and Biological Activities of Ginkgo Biloba

ABSTRACT: Ginkgo biloba L. is the solo member of the Ginkgoaceae family, and its leaf extract (EGb) has been clinically used for the treatment of cerebral insufficiency. Several experimental studies have demonstrated that EGb has neuroprotective properties against various age-related physiological changes and cerebral injuries induced by ischemia, edema and apoptosis. The major bioactive principles of EGb are recognized to be flavonoids and terpenoids, ginkgolides and bilobalide. Pharmacological actions of EGb and its constituents indude platelet-activating factor antagonism, anti-oxidant and free radical scavenging properties, as well as modulation of neurotransmission, cerebral glucose and lipid metabolism and cerebral membrane fluidity. These effects are involved in the mechanism related to the protective effect of the extract in the central nervous system.

[1]  Kunio Kato,et al.  Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation , 1994, Nature.

[2]  M. Haag-Berrurier,et al.  Seasonal Variations of the Flavonoid Content from Ginkgo biloba Leaves. , 1991, Planta medica.

[3]  L. Packer,et al.  [46] Antioxidant action of Ginkgo biloba extract EGb 761 , 1994 .

[4]  R. Cuppini,et al.  Regeneration of motor nerves in bilobalide-treated rats. , 1993, Planta medica.

[5]  K. Weinges,et al.  Chemie der Ginkgolide, VI. Herstellung von 1,10‐Dihydroxy‐ und 1,7,10‐Trihydroxyginkgolid aus 1,3,7,10‐Tetrahydroxyginkgolid , 1993 .

[6]  R. Anton,et al.  High-performance liquid chromatography of biflavones from Gingko biloba L. , 1982 .

[7]  T. A. Beek,et al.  Production of ginkgolide and bilobalide in transformed and gametophyte derived cell cultures of Ginkgo biloba , 1997 .

[8]  R. Sapolsky,et al.  Glucocorticoids, stress, and their adverse neurological effects: relevance to aging , 1999, Experimental Gerontology.

[9]  V. Petkov,et al.  Age-related changes of the effects of a group of nootropic drugs on the content of rat brain biogenic monoamines. , 1991, General pharmacology.

[10]  Y. Siow,et al.  Inhibitory effect of Ginkgo biloba extract on the expression of inducible nitric oxide synthase in endothelial cells. , 1999, Biochemical pharmacology.

[11]  K. Wada,et al.  An antivitamin B6, 4'-methoxypyridoxine, from the seed of Ginkgo biloba L. , 1985, Chemical & pharmaceutical bulletin.

[12]  M. Vanhaelen,et al.  Countercurrent chromatography for isolation of flavonol glycosides from Ginkgo biloba leaves , 1988 .

[13]  G. Némoz,et al.  Decreased adenosine cyclic 3',5'-monophosphate phosphodiesterase activity in rat brain following triethyltin intoxication. , 1984, Biochemical pharmacology.

[14]  V. Papadopoulos,et al.  Free radicals and lipid peroxidation do not mediate β-amyloid-induced neuronal cell death , 1999, Brain Research.

[15]  P. Mauri,et al.  Reversed-phase high-performance liquid chromatographic method for the analysis of biflavones in Ginkgo biloba L. extracts , 1988 .

[16]  Patrick Martin,et al.  Effects of an extract of Ginkgo Biloba (EGB 761) on “learned helplessness” and other models of stress in rodents , 1990, Pharmacology Biochemistry and Behavior.

[17]  C. Zorumski,et al.  Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor , 1992, Neuron.

[18]  M. Nöldner,et al.  Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761) , 1999, Journal of Neural Transmission.

[19]  K. Drieu,et al.  Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) and bilobalide on glucose uptake and glycogen synthesis in rat erythrocytes: An ex vivo study , 1994 .

[20]  D. Hosford,et al.  Recent progress in ginkgolide research , 1991, Medicinal research reviews.

[21]  K. Köse,et al.  Lipoperoxidation Induced by Hydrogen Peroxide in Human Erythrocyte Membranes , 1995, The Journal of international medical research.

[22]  T. A. Beek,et al.  Distribution of ginkgolides and terpenoid biosynthetic activity in Ginkgo biloba , 1998 .

[23]  P. Fuchs,et al.  Myricetin and quercetin, the flavonoid constituents ofGinkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca2+-loaded brain neurons , 1994, Brain Research.

[24]  Y. Siow,et al.  Inhibition by ginkgolides and bilobalide of the production of nitric oxide in macrophages (THP-1) but not in endothelial cells (HUVEC). , 2001, Biochemical pharmacology.

[25]  F. Silverstein,et al.  The Platelet-Activating Factor Antagonist BN 52021 Attenuates Hypoxic-Ischemic Brain Injury in the Immature Rat , 1996, Pediatric Research.

[26]  R. T. Coutts,et al.  Identification of Kaempferol as a Monoamine Oxidase Inhibitor and Potential Neuroprotectant in Extracts of Ginkgo Biloba Leaves , 2000, The Journal of pharmacy and pharmacology.

[27]  M. Lindenmaier,et al.  High-performance liquid chromatography-electrospray ionization-mass spectrometry study of ginkgolic acid in the leaves and fruits of the ginkgo tree (Ginkgo biloba). , 2000, Journal of chromatographic science.

[28]  V. Petkov,et al.  Age-related changes in brain biogenic monoamines and monoamine oxidase. , 1987, General pharmacology.

[29]  Identification of flavonoid metabolites after oral administration to rats of a Ginkgo biloba extract. , 1995, Journal of chromatography. B, Biomedical applications.

[30]  D. Mash,et al.  Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation. , 1985, Science.

[31]  H. Lipp,et al.  Swimming navigation and structural variations of the infrapyramidal mossy fibers in the hippocampus of the mouse , 1991, Hippocampus.

[32]  P. Mauri,et al.  Identification of flavonoids from Ginkgo biloba L., Anthemis nobilis L. and Equisetum arvense L. by high-performance liquid chromatography with diode-array UV detection , 1991 .

[33]  P. Mauri,et al.  Liquid chromatography/electrospray mass spectrometry of bioactive terpenoids in Ginkgo biloba L. , 1999, Journal of mass spectrometry : JMS.

[34]  R. Anton,et al.  La 5′-méthoxybilobétine, une biflavone extraite du Ginkgo biloba , 1980 .

[35]  Y. Christen,et al.  Prevention by Ginkgo biloba extract (EGb 761) and trolox C of the decrease in synaptosomal dopamine or serotonin uptake following incubation. , 1992, Biochemical pharmacology.

[36]  N. Bazan,et al.  EGb 761 inhibits stress-induced polydipsia in rats , 1993, Physiology and Behavior.

[37]  B. Cooper,et al.  Extracts of Ginkgo biloba leaves inhibit monoamine oxidase. , 1996, Life sciences.

[38]  K. Robinson,et al.  280. The structures of the naturally occurring biflavonyls , 1963 .

[39]  F. Huguet,et al.  α2‐Adrenoceptor Changes During Cerebral Ageing. The Effect of Ginkgo biloba Extract , 1992, The Journal of pharmacy and pharmacology.

[40]  O Sticher,et al.  Quality of Ginkgo Preparations1 , 1993, Planta medica.

[41]  Y. Christen,et al.  The Ginkgo biloba extract, EGb761, increases synaptosomal uptake of 5‐hydroxytryptamine: in‐vitro and ex‐vivo studies , 1992, The Journal of pharmacy and pharmacology.

[42]  Turan M. Itil,et al.  A Placebo-Controlled, Double-blind, Randomized Trial of an Extract of Ginkgo Biloba for Dementia , 1997 .

[43]  R. Quirion,et al.  The Ginkgo biloba Extract (EGb 761) Protects and Rescues Hippocampal Cells Against Nitric Oxide‐Induced Toxicity , 2000, Journal of neurochemistry.

[44]  K. Sasaki,et al.  Isolation of bilobalide and ginkgolide A from Ginkgo biloba L. shorten the sleeping time induced in mice by anesthetics. , 1993, Biological & pharmaceutical bulletin.

[45]  B. Ahlemeyer,et al.  Inhibition of serum deprivation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents. , 1999, European journal of pharmacology.

[46]  D. Hosford,et al.  Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents. , 1991, Journal of ethnopharmacology.

[47]  M. Poelman,et al.  In‐vivo and In‐vitro Assessment of the Free‐radical‐scavenger Activity of Ginkgo Flavone Glycosides at High Concentration , 1999, The Journal of pharmacy and pharmacology.

[48]  Relative importance of growth and light level on terpene content of Ginkgo biloba , 1992 .

[49]  G. Sancesario,et al.  Stimulation of astrocytes affects cytotoxic brain edema , 2004, Acta Neuropathologica.

[50]  P. Mcgeer,et al.  Chemistry of mood and emotion. , 1980, Annual review of psychology.

[51]  P. Braquet,et al.  Effects of an extract of Ginkgo biloba on noradrenergic systems of rat cerebral cortex. , 1985, Pharmacological research communications.

[52]  L. Packer,et al.  Antioxidant action of Ginkgo biloba extract EGb 761. , 1994, Methods in enzymology.

[53]  N. Bazan,et al.  Decreased Electroconvulsive Shock‐Induced Diacylglycerols and Free Fatty Acid Accumulation in the Rat Brain by Ginkgo biloba Extract (EGb 761): Selective Effect in Hippocampus as Compared with Cerebral Cortex , 1993, Journal of neurochemistry.

[54]  Y. Ito,et al.  Multidimensional counter-current chromatographic system and its application. , 1998, Journal of chromatography. A.

[55]  J. Shih,et al.  Ginkgo biloba abolishes aggression in mice lacking MAO A. , 2000, Antioxidants & redox signaling.

[56]  Y. Christen,et al.  Facilitative Effects of EGb 761 on Olfactory Recognition in Young and Aged Rats , 2000, Pharmacology Biochemistry and Behavior.

[57]  Y. Oyama,et al.  Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide , 1996, Brain Research.

[58]  T. Rantio,et al.  Determination of ginkgolides and bilobalide in Ginkgo biloba leaves and phytopharmaceuticals , 1991 .

[59]  T. Wei,et al.  Hydrogen peroxide-induced oxidative damage and apoptosis in cerebellar granule cells: protection by Ginkgo biloba extract. , 2000, Pharmacological research.

[60]  Gas chromatographic-mass spectrometric analysis of ginkgolides produced by Ginkgo biloba cell culture , 1991 .

[61]  P. Chopin,et al.  Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats , 2005, Psychopharmacology.

[62]  T. Takigawa,et al.  Long-chain betulaprenol-type polyprenols from the leaves of Ginkgo biloba. , 1983, The Biochemical journal.

[63]  V. E. Pettorossi,et al.  Role of Platelet activating factor in the long term potentiation of the rat medial vestibular nuclei. , 1998 .

[64]  K. Drieu,et al.  In vitro and in vivo effects of an extract of Ginkgo biloba (EGb 761), ginkgolide B, and bilobalide on apoptosis in primary cultures of rat hippocampal neurons , 1998 .

[65]  V. Petkov,et al.  Age-related changes in rat brain muscarinic receptors and β-adrenoreceptors , 1989 .

[66]  M. Reivich,et al.  THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1 , 1977, Journal of neurochemistry.

[67]  Y. Oyama,et al.  Flow cytometric estimation of the effect of Ginkgo biloba extract on the content of hydrogen peroxide in dissociated mammalian brain neurons. , 1992, Japanese journal of pharmacology.

[68]  C. Nasr,et al.  Kaempferol coumaroyl glucorhamnoside from Ginkgo biloba , 1986 .

[69]  H. Ohshika,et al.  Effects of bilobalide on gamma-aminobutyric acid levels and glutamic acid decarboxylase in mouse brain. , 1999, European journal of pharmacology.

[70]  C. Drewke,et al.  Occurrence of Neurotoxic 4′-O-Methylpyridoxine in Ginkgo biloba Leaves, Ginkgo Medications and Japanese Ginkgo Food , 1996, Planta medica.

[71]  Y. Christen,et al.  In vivo regulation of cerebral monoamine oxidase activity in senescent controls and chronically stressed mice by long-term treatment with Ginkgo biloba extrac3t (EGb 761) , 2000, Mechanisms of Ageing and Development.

[72]  L. Stinus,et al.  Behavioral sensitization to amphetamine is dependent on corticosteroid receptor activation , 1989, Brain Research.

[73]  J. Remacle,et al.  Protection of mitochondrial respiration activity by bilobalide. , 1999, Biochemical pharmacology.

[74]  K. Köse,et al.  Lipoperoxidation Induced by Hydrogen Peroxide in Human Erythrocyte Membranes. 1. Protective Effect of Ginkgo Biloba Extract (EGb 761) , 1995, The Journal of international medical research.

[75]  C. Nasr,et al.  Quercetin coumaroyl glucorhamnoside from Ginkgo biloba , 1987 .

[76]  N. Boyadjieva,et al.  Effects of standardized extracts GK501, from Ginkgo biloba L., G115 from Panax ginseng C. A. Meyer, and their combination, gincosan® (PHL‐00701), on the brain levels of biogenic monoamines and on the serum content of prolactin, growth hormone and ACTH , 1993 .

[77]  Y. Christen,et al.  Prevention by a Ginkgo biloba Extract (GBE 761) of the Dopaminergic Neurotoxicity of MPTP , 1990, The Journal of pharmacy and pharmacology.

[78]  K. Drieu,et al.  Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) and bilobalide on liver and muscle glycogen contents in the non‐insulin‐dependent diabetic rat , 1997 .

[79]  V. Papadopoulos,et al.  The Ginkgo biloba extract EGb 761 rescues the PC12 neuronal cells from β-amyloid-induced cell death by inhibiting the formation of β-amyloid-derived diffusible neurotoxic ligands , 2001, Brain Research.

[80]  J. Krieglstein,et al.  Effects of Ginkgo biloba constituents related to protection against brain damage caused by hypoxia. , 1988, Pharmacological research communications.

[81]  Y. Christen,et al.  Effect of long-term treatment with EGb 761 on age-dependent structural changes in the hippocampi of three inbred mouse strains. , 1994, Life sciences.

[82]  Y. Kimura,et al.  Purification and some chemical properties of 30 kDa Ginkgo biloba glycoprotein, which reacts with antiserum against beta 1-->2 xylose-containing N-glycans. , 1999, Bioscience, biotechnology, and biochemistry.

[83]  J. Sastre,et al.  Mitochondria, oxidative stress and aging , 2000, Free radical research.

[84]  Y. Christen,et al.  Ginkgo biloba extract EGb 761 or trolox C prevent the ascorbic acid/Fe2+ induced decrease in synaptosomal membrane fluidity. , 1993, Free radical research communications.

[85]  A S KESTON,et al.  THE FLUOROMETRIC ANALYSIS OF ULTRAMICRO QUANTITIES OF HYDROGEN PEROXIDE. , 1965, Analytical biochemistry.

[86]  J. Krieglstein,et al.  Effect of an extract of Ginkgo biloba on rat brain energy metabolism in hypoxia , 1984, Naunyn-Schmiedeberg's Archives of Pharmacology.

[87]  C. Gardana,et al.  Identification of Gingko biloba flavonol metabolites after oral administration to humans. , 1997, Journal of chromatography. B, Biomedical sciences and applications.

[88]  Effects of Ginkgo biloba extract (EGb 761) on the guinea pig vestibular system , 1992, Pharmacology Biochemistry and Behavior.

[89]  S. Chatterjee,et al.  Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba , 1997, Brain Research.

[90]  K. Weinges,et al.  Kondensierte Ringsysteme, II1) Bilobalid A, ein neues Sesquiterpen mit tert.‐Butyl‐Gruppe aus den Blättern von Ginkgo biloba L , 1969 .

[91]  P. Henrich-Noack,et al.  Neuroprotective effects of Ginkgo biloba constituents , 1995 .

[92]  Y. Oyama,et al.  Ca(2+)-induced increase in oxidative metabolism of dissociated mammalian brain neurons: effect of extract of ginkgo biloba leaves. , 1993, Japanese journal of pharmacology.

[93]  R. Anton,et al.  Analysis of terpenes from ginkgo biloba L. by high-performance liquid chromatography , 1983 .

[94]  R. Williamson,et al.  Biosynthesis of 4‘-O-Methylpyridoxine (Ginkgotoxin) from Primary Precursors† , 2000 .

[95]  C. Thompson,et al.  Apoptosis in the pathogenesis and treatment of disease , 1995, Science.

[96]  R. Ridge,et al.  Ginkgo Biloba A Global Treasure , 1997, Springer Japan.

[97]  F. V. Defeudis,et al.  Demonstration of the "anti-stress" activity of an extract of Ginkgo biloba (EGb 761) using a discrimination learning task. , 1994, General pharmacology.

[98]  K. Nakazawa,et al.  Syntheses of Ring-substituted Flavonoids and Allied Compounds. X. Synthesis of Ginkgetin. , 1963 .

[99]  J. C. Winter,et al.  The Effects of an Extract of Ginkgo biloba, EGb 761, on Cognitive Behavior and Longevity in the Rat , 1998, Physiology & Behavior.

[100]  D. Murphy,et al.  Monoamine oxidase-inhibiting antidepressants. A clinical update. , 1984, The Psychiatric clinics of North America.

[101]  W. Damerau,et al.  Antioxidative activity of ginkgolides against superoxide in an aprotic environment. , 1997, Chemico-biological interactions.

[102]  U. Spampinato,et al.  Aging associated changes in serotoninergic and dopaminergic pre- and postsynaptic neurochemical markers in the rat brain , 1990, Neurobiology of Aging.

[103]  J. Langston,et al.  MPTP: insights into the etiology of Parkinson's disease. , 1987, European neurology.

[104]  J. Pincemail,et al.  Superoxide anion scavenging effect and superoxide dismutase activity ofGinkgo biloba extract , 1989, Experientia.

[105]  J. Tassin,et al.  Ginkgo biloba extract EGb761 reduces the development of amphetamine-induced behavioral sensitization: effects on hippocampal type II corticosteroid receptors , 1999, Brain Research.

[106]  K. Tan-No,et al.  Effects of ginkgo biloba extract on impairment of learning induced by cerebral ischemia in mice. , 1998, The American Journal of Chinese Medicine.

[107]  J. Gardette,et al.  Effects of ginkgo biloba extract on glucose transport and glycogen synthesis of cultured smooth muscle cells from pig aorta aorta , 1989 .

[108]  K. Nakanishi,et al.  The ginkgolides. I. Isolation and characterization of the various groups , 1967 .

[109]  L. Packer,et al.  Peroxyl radical scavenging activity of Ginkgo biloba extract EGb 761. , 1995, Biochemical pharmacology.

[110]  M. Lacour,et al.  Plasticity mechanisms in vestibular compensation in the cat are improved by an extract of ginkgo biloba (EGb 761) , 1991, Pharmacology Biochemistry and Behavior.

[111]  I. Izquierdo,et al.  Memory enhancement by intrahippocampal, intraamygdala, or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance task. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[112]  Takeshi Hayashi,et al.  Protective effect of Ginkgo extract on rat brain with transient middle cerebral artery occlusion , 2000, Neurological research.

[113]  V. Papadopoulos,et al.  Drug-induced inhibition of the peripheral-type benzodiazepine receptor expression and cell proliferation in human breast cancer cells. , 2000, Anticancer research.

[114]  J. Remacle,et al.  Protection of hypoxia-induced ATP decrease in endothelial cells by ginkgo biloba extract and bilobalide. , 1995, Biochemical pharmacology.

[115]  M. Carini,et al.  Thermospray liquid chromatography-mass spectrometry of flavonol glycosides from medicinal plants , 1994 .

[116]  V. Petkov,et al.  Memory Effects of Standardized Extracts of Panax ginseng (G115), Ginkgo biloba (GK 501) and their Combination Gincosan® (PHL-00701) , 1993, Planta medica.

[117]  Y. Hirashima,et al.  Involvement of platelet-activating factor (PAF) in glutamate neurotoxicity in rat neuronal cultures , 1997, Brain Research.

[118]  P. Mauri,et al.  Application of micellar electrokinetic capillary chromatography to the determination of flavonoid drugs , 1991 .

[119]  F. Squadrito,et al.  Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis. , 2000, Life sciences.

[120]  V. Petkov,et al.  Age-related changes in brain neurotransmission. , 1988, Gerontology.

[121]  C. Michiels,et al.  Protection by bilobalide of the ischaemia‐induced alterations of the mitochondrial respiratory activity , 2000, Fundamental & clinical pharmacology.

[122]  J. Krieglstein,et al.  Influence of an extract of Ginkgo biloba on cerebral blood flow and metabolism. , 1986, Life sciences.

[123]  M. Akısü,et al.  Platelet-Activating Factor Is an Important Mediator in Hypoxic Ischemic Brain Injury in the Newborn Rat , 1998, Neonatology.

[124]  Beat Meier,et al.  Identification and determination of the flavonoids from Ginkgo biloba by high-performance liquid chromatography , 1992 .

[125]  C. N. Gillis,et al.  Superoxide scavenging effect of Ginkgo biloba extract on serotonin-induced mitogenesis. , 1998, Biochemical pharmacology.

[126]  P. Curtis‐Prior,et al.  Therapeutic Value of Ginkgo biloba in Reducing Symptoms of Decline in Mental Function , 1998, The Journal of pharmacy and pharmacology.

[127]  F. V. Defeudis,et al.  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. , 1999, General pharmacology.

[128]  K. Wada,et al.  Bilobalide prevents reduction of gamma-aminobutyric acid levels and glutamic acid decarboxylase activity induced by 4-O-methylpyridoxine in mouse hippocampus. , 2000, Life sciences.

[129]  H. Morita,et al.  A quantitative structure-activity relationship for antitumor activity of long-chain phenols from Ginkgo biloba L. , 1989, Chemical & pharmaceutical bulletin.

[130]  W. Müller,et al.  Ginkgo Biloba Extract (EGb 761) Independently Improves Changes in Passive Avoidance Learning and Brain Membrane Fluidity in the Aging Mouse , 1996, Pharmacopsychiatry.

[131]  Michael J. Stasio,et al.  Ginkgo biloba extract facilitates recovery from penetrating brain injury in adult male rats , 1989, Experimental Neurology.

[132]  S. Rapoport,et al.  Effects of EGb 761 on fatty acid reincorporation during reperfusion following ischemia in the brain of the awake gerbil. , 1998, Molecular and chemical neuropathology.

[133]  Analysis of Ginkolides and Biobalides by Capillary Electrophoresis , 1995 .

[134]  R. Anton,et al.  Comparative Antilipoperoxidant, Antinecrotic and Scavanging Properties of Terpenes and Biflavones from Ginkgo and some Flavonoids , 1995, Planta medica.

[135]  J. Hou,et al.  Preventive effect of Ginkgo biloba extract on apoptosis in rat cerebellar neuronal cells induced by hydroxyl radicals , 1996, Neuroscience Letters.

[136]  A. Wettstein.  Cholinesterase inhibitors and Ginkgo extracts — are they comparable in the treatment of dementia? , 2000 .

[137]  K. Drieu,et al.  Decreased cerebral 5‐HT1A receptors during ageing: reversal by Ginkgo biloba extract (EGb 761) , 1994, The Journal of pharmacy and pharmacology.

[138]  J. Pincemail,et al.  Ginkgo biloba extract inhibits oxygen species production generated by phorbol myristate acetate stimulated human leukocytes , 1987, Experientia.

[139]  N. Kawano,et al.  Studies on Bisflavones in the Leaves of Podocarpus macrophylla and P. nagi , 1969 .

[140]  F. V. Defeudis,et al.  Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761), bilobalide and ginkgolide B on the electrical activity of pancreatic beta cells of normal or alloxan-diabetic mice: an ex vivo study with intracellular microelectrodes. , 1994, General pharmacology.

[141]  Supercritical fluid chromatographic analysis of polyprenols in Ginkgo biloba L , 1992 .

[142]  S. Akiba,et al.  Inhibitory effect of the leaf extract of Ginkgo biloba L. on oxidative stress‐induced platelet aggregation , 1998, Biochemistry and molecular biology international.

[143]  A. El-Fattah,et al.  Lipid peroxide, phospholipids, glutathione levels and superoxide dismutase activity in rat brain after ischaemia: effect of ginkgo biloba extract. , 1995, Pharmacological research.

[144]  J. Kraus.  Water-soluble polysaccharides from Ginkgo biloba leaves. , 1991, Phytochemistry.

[145]  L. Packer,et al.  Different effects of the constituents of EGb761 on apoptosis in rat cerebellar granule cells induced by hydroxyl radicals , 1999, Biochemistry and molecular biology international.

[146]  R. Dom,et al.  Treatment of Alzheimer's disease: an evaluation of the cholinergic approach. , 1999, Acta neurologica Belgica.

[147]  M. De Vivo,et al.  Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. , 1986, The Journal of pharmacology and experimental therapeutics.

[148]  C. Oliver,et al.  Effect of chronic administration of Ginkgo biloba extract or Ginkgolide on the hypothalamic-pituitary-adrenal axis in the rat. , 1998, Life sciences.

[149]  P. Braquet,et al.  BN 52021 and related compounds: A new series of highly specific PAF-acether receptor antagonists isolated from Ginkgo biloba L. , 1985 .

[150]  Arun K. Ghosh,et al.  INTRAMOLECULAR AND INTERMOLECULAR HYDROXYL REACTIVITY DIFFERENCES IN GINKGOLIDES A, B AND C AND THEIR CHEMICAL APPLICATIONS. , 1992, Tetrahedron letters.

[151]  B. Meier,et al.  Complex flavonol glycosides from the leaves of Ginkgo biloba. , 1992, Phytochemistry.

[152]  S. Snyder,et al.  Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[153]  J. Kleijnen,et al.  Ginkgo biloba for cerebral insufficiency. , 1992, British journal of clinical pharmacology.

[154]  R. Clavier,et al.  Partial protection from the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by four different antioxidants in the mouse , 1985, Neuroscience Letters.

[155]  J. Sastre,et al.  A Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress. , 1998, Free radical biology & medicine.

[156]  Y. Asakawa,et al.  Antitumor principles from Ginkgo biloba L. , 1987, Chemical & pharmaceutical bulletin.

[157]  S. Rapoport,et al.  Effects of Ginkgolide B and Ginkgo biloba extract on local cerebral glucose utilization in the awake adult rat , 1991 .

[158]  P. Braquet,et al.  Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in Mongolian gerbils. , 1987, Prostaglandins.

[159]  G. Fillion,et al.  Stress‐induced 5‐HT1A receptor desensitization: protective effects of Ginkgo biloba extract (EGb 761) , 1995, Fundamental & clinical pharmacology.

[160]  Y. Christen,et al.  Ginkgo biloba extract (EGb 761): inhibitory effect on nitric oxide production in the macrophage cell line RAW 264.7. , 1997, Biochemical pharmacology.

[161]  M. Hilgert,et al.  Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus , 1999, Naunyn-Schmiedeberg's Archives of Pharmacology.

[162]  K. Nakanishi,et al.  Structure of bilobalide, a rare tert-butyl containing sesquiterpenoid related to the C20-ginkgolides , 1971 .

[163]  Z. Krištofíková,et al.  In vitro effect of Ginkgo biloba extract (EGb 761) on the activity of presynaptic cholinergic nerve terminals in rat hippocampus. , 1997, Dementia and geriatric cognitive disorders.

[164]  E. Winter.  Effects of an extract of Ginkgo biloba on learning and memory in mice , 1991, Pharmacology Biochemistry and Behavior.

[165]  S. Pierre,et al.  Ginkgo biloba extract (EGb 761) protects Na,K-ATPase activity during cerebral ischemia in mice. , 1999, Neuroreport.

[166]  B. Ahlemeyer,et al.  Neuroprotective effects of NV-31, a bilobalide-derived compound: evidence for an antioxidative mechanism , 2001, Brain Research.

[167]  L. Zhou,et al.  Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide. , 2000, The Journal of pharmacology and experimental therapeutics.

[168]  G. Kreutzberg,et al.  Effect of an extract of Ginkgo biloba on triethyltin-induced cerebral edema , 2004, Acta Neuropathologica.

[169]  G. Némoz,et al.  Effects of an Extract of Ginkgo biloba on the 3′,5′‐Cyclic AMP Phosphodiesterase Activity of the Brain of Normal and Triethyltin‐Intoxicated Rats , 1987, Journal of neurochemistry.

[170]  K. Nakanishi,et al.  Biosynthesis of ginkgolide B, its diterpenoid nature, and origin of the tert-butyl group , 1971 .

[171]  D. Duverger,et al.  Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) on cerebral glucose utilization in the rat: an autoradiographic study. , 1995, General pharmacology.

[172]  P. Mauri,et al.  Analysis of terpenes fromGinkgo biloba L. extracts by reversed phase high-performance liquid chromatography , 1990 .

[173]  Paul F. Smith,et al.  The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). , 1996, Journal of ethnopharmacology.

[174]  Xing-zu Zhu,et al.  Involvement of monoamine oxidase inhibition in neuroprotective and neurorestorative effects of Ginkgo biloba extract against MPTP-induced nigrostriatal dopaminergic toxicity in C57 mice. , 1999, Life sciences.

[175]  B. Meier,et al.  High-performance liquid chromatographic determination of five widespread flavonoid aglycones. , 1990, Journal of chromatography.

[176]  E. Perry,et al.  Medicinal Plants and Alzheimer's Disease: from Ethnobotany to Phytotherapy ** , 1999, The Journal of pharmacy and pharmacology.