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

J Alzheimers Dis. 2009;18(4):787-98. doi: 10.3233/JAD-2009-1189.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology*
  • Animals
  • Blotting, Western
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclopentanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Furans / pharmacology*
  • Ginkgolides / pharmacology*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Mice
  • Neurogenesis / drug effects*
  • Phosphorylation
  • Plant Extracts / pharmacology*
  • Quercetin / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / drug effects

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Cyclopentanes
  • Furans
  • Ginkgolides
  • Plant Extracts
  • Ginkgo biloba extract
  • Quercetin
  • bilobalide