Stimulation of Neurogenesis and Synaptogenesis by Bilobalide and Quercetin via Common Final Pathway in Hippocampal Neurons

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.

C1q-induced LRP1B and GPR6 Proteins Expressed Early in Alzheimer Disease Mouse Models, Are Essential for the C1q-mediated Protection against Amyloid-β Neurotoxicity

“…Here, the addition of C1q to fA␤-injured neurons resulted in increased phosphorylation and nuclear translocation of CREB, similar to what was observed in nutrient-stressed neurons (10) and in monocytes (46). CREB is a transcription factor vital for long term memory and synaptic plasticity (34), neurogenesis (47)(48)(49), and induction of neurotrophic factors in the CNS (35). In addition, pCREB is a central transcription factor in brain-derived neurotrophic factor signaling (50) and also induces brain-derived neurotrophic factor upon activation (51).…”

Effects of Ginkgo biloba Extract on Promotion of Neurogenesis in the Hippocampal Dentate Gyrus in C57BL/6 Mice

“…The increase of Ki67-immunoreactive cells in the DG in this present study is supported by an previous in vitro study, in which bilobalide treatment could induce a significant increase of 5-bromo-2-deoxyguanosine (BrdU) incorporation with a dose-dependent manner in the hippocampal progenitor cells derived from embryonic day 18 in rats [34]. It was reported that 100 mg/kg Gb treatment for 1 month sig- nificantly enhanced cell proliferation in the DG of both adult (6 months) and aged (22 months) Alzheimer mice compared with their untreated counterparts [30].…”

“…Repeated treatments with Gb to aged rats elicit robust hippocampal long-term potentiation [36,38]. In addition, bilobalide treatment shows dendritic arborations and welldeveloped dendritic branches in the hippocampal progenitor cells derived from embryonic day 18 in rats [34]. In conclusion, repeated administration of Gb increases cell proliferation and neuroblast differentiation in the hippocampal DG and consumption of Gb may be helpful to increase endogenous neurogenesis in adults.…”

Effect of quercetin on the brain-derived neurotrophic factor gene expression in the rat brain

“…In vitro and in vivo studies have shown that neuroprotective effects of quercetin are exerted by different molecular mechanisms (19). Our study, in converge with these works, suggested a new possible mechanism for neuroprotection by quercetin.…”