Stimulation of neurogenesis and synaptogenesis by bilobalide and quercetin via common final pathway in hippocampal neurons.

Loss of synapses has been correlated with dementia in Alzheimer's disease (AD) as an early event during the disease progression. Hence, synaptogenesis and neurogenesis in adulthood could serve as a therapeutic target for the prevention and treatment of AD. Recently, we have demonstrated enhanced hippocampal neurogenesis by oral administration of Ginkgo biloba extract (EGb 761) to a mouse model of AD. This study aims to identify the constituents that contribute to EGb 761-induced neurogenesis. Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and, brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-beta oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation.

[1]  Yen-Chou Chen,et al.  Quercetin inhibition of ROS-dependent and -independent apoptosis in rat glioma C6 cells. , 2006, Toxicology.

[2]  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.

[3]  J. Davies,et al.  Effects of bilobalide on amino acid release and electrophysiology of cortical slices , 2002, Amino Acids.

[4]  R. Brinton,et al.  Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent. , 2006, Current Alzheimer research.

[5]  D. Kupfer,et al.  Serotonin in Aging, Late-Life Depression, and Alzheimer's Disease: The Emerging Role of Functional Imaging , 1998, Neuropsychopharmacology.

[6]  R. Brinton,et al.  The Neurosteroid Allopregnanolone Promotes Proliferation of Rodent and Human Neural Progenitor Cells and Regulates Cell-Cycle Gene and Protein Expression , 2005, The Journal of Neuroscience.

[7]  O. Vitolo,et al.  Protection against β-amyloid induced abnormal synaptic function and cell death by Ginkgolide J , 2009, Neurobiology of Aging.

[8]  Y. Nakaya,et al.  Antidepressant effect of extracts from Ginkgo biloba leaves in behavioral models. , 2006, Biological & pharmaceutical bulletin.

[9]  C. Rice-Evans,et al.  Modulation of Pro-survival Akt/Protein Kinase B and ERK1/2 Signaling Cascades by Quercetin and Its in Vivo Metabolites Underlie Their Action on Neuronal Viability* , 2003, Journal of Biological Chemistry.

[10]  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.

[11]  Fred H. Gage,et al.  An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus , 2007, Proceedings of the National Academy of Sciences.

[12]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[13]  Brett Chromy,et al.  Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus , 2002, Brain Research.

[14]  S. Davis,et al.  Regulated transcription of the immediate‐early gene Zif268: Mechanisms and gene dosage‐dependent function in synaptic plasticity and memory formation , 2002, Hippocampus.

[15]  J. V. Smith,et al.  Studies on molecular mechanisms of Ginkgo biloba extract , 2004, Applied Microbiology and Biotechnology.

[16]  Y. Christen,et al.  Restoration of impaired phosphorylation of cyclic AMP response element‐binding protein (CREB) by EGb 761 and its constituents in Aβ‐expressing neuroblastoma cells , 2007, The European journal of neuroscience.

[17]  J. Hartmann,et al.  Role of GABAergic antagonism in the neuroprotective effects of bilobalide , 2007, Brain Research.

[18]  Chunmei Zhao,et al.  Functional Convergence of Neurons Generated in the Developing and Adult Hippocampus , 2006, PLoS biology.

[19]  O. Krishtal,et al.  Structure-activity studies with Ginkgo biloba extract constituents as receptor-gated chloride channel blockers and modulators. , 2003, Pharmacopsychiatry.

[20]  F. Gage,et al.  Experience-Specific Functional Modification of the Dentate Gyrus through Adult Neurogenesis: A Critical Period during an Immature Stage , 2007, The Journal of Neuroscience.

[21]  O. Krishtal,et al.  Inhibition of hippocampal LTP by ginkgolide B is mediated by its blocking action on PAF rather than glycine receptors , 2004, Neurochemistry International.

[22]  R. Terry.  Cell death or synaptic loss in Alzheimer disease. , 2000, Journal of neuropathology and experimental neurology.

[23]  Karl Deisseroth,et al.  Excitation-Neurogenesis Coupling in Adult Neural Stem/Progenitor Cells , 2004, Neuron.

[24]  S. DeKosky,et al.  Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity , 1990, Annals of neurology.

[25]  E. Bigio,et al.  Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers , 2008, Neurobiology of Aging.

[26]  F. Schmitt,et al.  Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment , 2007, Neurology.

[27]  P. Schultz,et al.  Age-related effects of Ginkgo biloba extract on synaptic plasticity and excitability , 2004, Neurobiology of Aging.

[28]  Y. Christen,et al.  EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  Koji Nakanishi,et al.  Terpene trilactones from Gingko biloba: from ancient times to the 21st century. , 2005, Bioorganic & medicinal chemistry.

[30]  M. Esiri,et al.  Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease , 2005, Psychopharmacology.

[31]  Lewis H Kuller,et al.  Ginkgo biloba for prevention of dementia: a randomized controlled trial. , 2008, JAMA.

[32]  Fred H. Gage,et al.  Neurogenesis in the Adult Brain , 2002, The Journal of Neuroscience.

[33]  Y. Song,et al.  Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten , 2003, Brain Research.

[34]  G. Bartosz,et al.  Antioxidative and prooxidative effects of quercetin on A549 cells , 2007, Cell biology international.

[35]  M. Greenberg,et al.  Serine 133-Phosphorylated CREB Induces Transcription via a Cooperative Mechanism That May Confer Specificity to Neurotrophin Signals , 1995, Molecular and Cellular Neuroscience.

[36]  G. Fiskum,et al.  Neuroprotective Effects of Bilobalide, a Component of Ginkgo biloba Extract (EGb 761®) in Global Brain Ischemia and in Excitotoxicity-induced Neuronal Death , 2003 .

[37]  L. Goya,et al.  Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). , 2006, The Journal of nutrition.

[38]  C. Finch,et al.  Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers , 2004, The Journal of Neuroscience.

[39]  F. Gage,et al.  Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis , 2003, The European journal of neuroscience.

[40]  F. V. Defeudis,et al.  Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. , 2000, Current drug targets.

[41]  R. Mason,et al.  The production of reactive oxygen species by dietary flavonols. , 1990, Free radical biology & medicine.

[42]  J. Goutman,et al.  Flavonoid modulation of ionic currents mediated by GABA(A) and GABA(C) receptors. , 2003, European journal of pharmacology.

[43]  Eric J. Nestler,et al.  Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus , 2000, The Journal of Neuroscience.

[44]  Mikko Sairanen,et al.  Brain-Derived Neurotrophic Factor and Antidepressant Drugs Have Different But Coordinated Effects on Neuronal Turnover, Proliferation, and Survival in the Adult Dentate Gyrus , 2005, The Journal of Neuroscience.

[45]  W. Klein,et al.  Amyloid beta oligomers induce impairment of neuronal insulin receptors , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[46]  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.

[47]  Y. Christen,et al.  Amyloid-β-Induced Pathological Behaviors Are Suppressed by Ginkgo biloba Extract EGb 761 and Ginkgolides in Transgenic Caenorhabditis elegans , 2006, The Journal of Neuroscience.

[48]  Bernardo L Sabatini,et al.  Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway , 2007, The Journal of Neuroscience.

[49]  T. Gianfagna,et al.  Antidepressant and antistress activity of GC‐MS characterized lipophilic extracts of Ginkgo biloba leaves , 2007, Phytotherapy research : PTR.

[50]  R. Malinow,et al.  AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss , 2006, Neuron.

[51]  C. Pittenger,et al.  Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms , 2008, Neuropsychopharmacology.

[52]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[53]  David R Kaplan,et al.  Signaling mechanisms underlying dendrite formation , 2003, Current Opinion in Neurobiology.

[54]  R. Stackman,et al.  Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment , 2003, Experimental Neurology.

[55]  M. Buhot,et al.  Role of serotonin in memory impairment , 2000, Annals of medicine.

[56]  W. Klein,et al.  Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease , 2007, The Journal of Neuroscience.

[57]  E. Nestler,et al.  Regulation of Neurogenesis in Adult Mouse Hippocampus by cAMP and the cAMP Response Element-Binding Protein , 2002, The Journal of Neuroscience.

[58]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[59]  D. Ginty,et al.  Function and Regulation of CREB Family Transcription Factors in the Nervous System , 2002, Neuron.

[60]  D. Selkoe,et al.  Soluble Aβ Inhibits Specific Signal Transduction Cascades Common to the Insulin Receptor Pathway* , 2007, Journal of Biological Chemistry.

[61]  M. Segal,et al.  Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[62]  R. Bourtchouladze,et al.  Targeting the CREB pathway for memory enhancers , 2003, Nature Reviews Drug Discovery.

[63]  M. Héry,et al.  Serotonin-Induced Increases in Adult Cell Proliferation and Neurogenesis are Mediated Through Different and Common 5-HT Receptor Subtypes in the Dentate Gyrus and the Subventricular Zone , 2004, Neuropsychopharmacology.