Affiliations: [a] Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA | [b] Department of Neurobiology and Physiology, Northwestern University, Evanston, IL, USA | [c] Center for Integrative Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA | [d] Institue of Materia Medica, Chinese Academy of Medical Sciences, Beijing, China | [e] Blanchette Rockefeller Neurosciences Institute, Rockville, MD, USA
Correspondence:
[*]
Address for correspondence: Yuan Luo, PhD, 20 N Pine St. PH501, Baltimore, MD 21201, USA. Tel.: +1 410 706 7739; Fax: +1 410 706 0346; E-mail: yluo@rx.umaryland.edu.
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-β 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.
