title: EGb761 provides a protective effect against Aβ1-42 oligomer-induced cell damage and blood-brain barrier disruption in an in vitro bEnd.3 endothelial model.
abstract: Alzheimer's disease (AD) is the most common form of senile dementia which is characterized by abnormal amyloid beta (Aβ) accumulation and deposition in brain parenchyma and cerebral capillaries, and leads to blood-brain barrier (BBB) disruption. Despite great progress in understanding the etiology of AD, the underlying pathogenic mechanism of BBB damage is still unclear, and no effective treatment has been devised. The standard Ginkgo biloba extract EGb761 has been widely used as a potential cognitive enhancer for the treatment of AD. However, the cellular mechanism underlying the effect remain to be clarified. In this study, we employed an immortalized endothelial cell line (bEnd.3) and incubation of Aβ(1-42) oligomer, to mimic a monolayer BBB model under conditions found in the AD brain. We investigated the effect of EGb761 on BBB and found that Aβ1-42 oligomer-induced cell injury, apoptosis, and generation of intracellular reactive oxygen species (ROS), were attenuated by treatment with EGb761. Moreover, treatment of the cells with EGb761 decreased BBB permeability and increased tight junction scaffold protein levels including ZO-1, Claudin-5 and Occludin. We also found that the Aβ(1-42) oligomer-induced upregulation of the receptor for advanced glycation end-products (RAGE), which mediates Aβ cytotoxicity and plays an essential role in AD progression, was significantly decreased by treatment with EGb761. To our knowledge, we provide the first direct in vitro evidence of an effect of EGb761 on the brain endothelium exposed to Aβ(1-42) oligomer, and on the expression of tight junction (TJ) scaffold proteins and RAGE. Our results provide a new insight into a possible mechanism of action of EGb761. This study provides a rational basis for the therapeutic application of EGb761 in the treatment of AD.
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Wen-bin
authors.initials: WB
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Cao
authors.affiliation: Geriatrics Department of Traditional Chinese Medicine, Huadong Hospital, Fudan University, Shanghai, China.
authors.forename: Lu-mei
authors.initials: LM
authors.lastname: Liu
authors.affiliation: Department of Perinatal Medicine Pregnancy Research Centre and University of Melbourne Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, VIC, Australia.
authors.forename: Bill
authors.initials: B
authors.lastname: Kalionis
authors.affiliation: Shanghai Geriatric Institute of Chinese Medicine, Shanghai, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Acupuncture, Massage and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China.
authors.forename: Xian-tao
authors.initials: XT
authors.lastname: Tai
authors.affiliation: Geriatrics Department of Traditional Chinese Medicine, Huadong Hospital, Fudan University, Shanghai, China.
authors.forename: Ya-ming
authors.initials: YM
authors.lastname: Li
authors.affiliation: Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai, China.
authors.forename: Shi-jin
authors.initials: SJ
authors.lastname: Xia
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects; D002461:Cell Line, Transformed; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D020441:Ginkgo biloba; D006801:Humans; D008954:Models, Biological; D018697:Nootropic Agents / Q000494:pharmacology*; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism; D000096983:Ginkgo Extract
chemical_list: D016229:Amyloid beta-Peptides; D062507:Claudin-5; D018697:Nootropic Agents; D062793:Occludin; D010446:Peptide Fragments; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D062826:Zonula Occludens-1 Protein; C107466:CLDN5 protein, human; C568985:OCLN protein, human; C569042:TJP1 protein, human; C075222:amyloid beta-protein (1-42); C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract