Ginkgo biloba Extracts and
Alzheimer’s Disease
Adapted from presentation
by Erik Domingues, M.D.
Alzheimer’s Disease (AD)
• Progressive brain disorder
• Accompanied by behavioral changes
• Develops mostly in people 65 and over
• Genetic predisposition
• Certain health conditions may contribute to AD
development
• Incurable
Biological Characteristics of AD
• Neuronal cell atrophy
• Amyloid- (A) precursor protein (APP) is
cleaved by - and γ-secretase to A
• Deposition of A plaques and neurofibrillary
tangles in hippocampus and cortex
• A induces apoptosis (programmed cell death)
in normal neurons
• Higher levels of oxidative damage
• Deficiency in neurotransmitters such as
acetylcholine
Ginkgo biloba
• Ginkgoaceae family
• Also known as maidenhair tree
• World’s oldest tree species
• Thought to improve cerebral circulation
• Dosage of 40-200 mg/day recommended
• Cognitive enhancer
• May be beneficial in reducing AD onset
• Some side effects (GI, headache)
Animal Trials ofGinkgo
• Several trials used a standardized extract of
Ginkgo biloba, EGb761
• EGb761 composition:
– 5-7% terpene lactones (TTLs)
• Ginkgolides A, B, C, J, and M and bilobalide (BB)
– 22-24 % flavonols
• Quercetin, kaempferol, isorhamnetin
– max 5 ppm ginkgolic acid
Origin?
• toxic, allergenic
Ginkgolides and Bilobalide in
EGb716
Flavonols in EGb761
OH
OH
HO
HO
O
O
OH
OH
OH
OH
OH
O
O
Kaempferol
Quercetin
OH
HO
O
OMe
OH
OH
O
Isorhamnetin
• Effects of Ginkgo extract from animal studies
– Spatial memory deficits
– A buildup (plaque formation)
– Apoptosis of neuronal cells and activation of
caspases
– Cholesterol-lowering effect
• Epidemiological study
EPIDOS - France
• Study used a Tg2576 mouse model and Ginkgo
extract EGb761
– This mouse overexpresses APP, gets A plaque deposits and
exhibits oxidative stress in its brain
• Mice were treated for 6 months with EGb761 at 70
mg/kg/day
A Morris water maze was
used to test the effects of
the extract on the mice
Spatial memory impairment
was reduced in the Ginkgo
treated mice
Blueberries have also been
shown to improve
performance in similar tests
by Joseph, et al 
• Studied effects of EGb761 on A buildup, caspase-3
•
•
activity (enzyme controlling apoptotic cascade), and
induction of apoptosis in neuroblastoma cells
A proliferation was prevented
Apoptosis rates and associated caspase-3 activity
decreased with treatment
• Effect of EGb761 on A-induced neurotoxicity in PC12
•
•
•
•
•
nerve cells was tested
Exposure to A for 12 or 24 hours increased ROS
levels
Treatment decreased ROS production in a dosedependent manner
Simultaneous treatment with EGb761 and A
decreased cell death compared to exposure to A
alone
Anti-apoptotic effects were only seen when the cells
were treated simultaneously with EGb761 and A
Treatment with a different extract was not
neuroprotective
• Free cholesterol may be involved in APP and A production
• Study analyzed effects of EGb761 on free cholesterol levels and
•
•
amyloidogenesis
An increase in A and APP production is observed in presence
of cholesterol
As Brown Norway rats age, A levels increased
– EGb761 decreased the plaques significantly
– APP levels in cerebral cortex and hippocampus were decreased
• EGb761 treatment
– reduced free cholesterol by 16%
– reduced amount of free cholesterol binding to low density proteins
– decreased influx of cholesterol and increased efflux from neuronal cells
• Study used a different Ginkgo extract, GbE
– 26 % flavone glycosides and 6 % diterpene lactones
•
•
•
•
Effects of GbE on caspase-3 and APP
Rats were treated for 14 days with 100 mg/kg of GbE
APP level higher in treated rats (less cleavage to A)
Caspase-3 levels were higher in treated rats
– Caspase-3 had been shown to convert APP to A
• A case study involving 414 women in France
• Women diagnosed with AD were older, had a lower
financial status, and a lower educational level, and
were less knowledgeable about their health
– The only difference between these women and the undiagnosed was the
lack of vasotherapeutic treatment
• Women in the group without dementia were three
•
times more likely to be regularly taking treatments like
Ginkgo than women in the group with dementia
About 50 % of these women reported taking EGb761
In summary, Ginkgo extract
• Decreased A proliferation
• Decreased apoptotic activity
• Increased neuronal cell viability
• Decreased free cholesterol levels, linked to less
amyloid formation
• Improved cognitive performance in rats
• Was linked to decreased incidence of AD in
French women
• Keeps brain cells healthier!
•
•
•
•
•
•
•
•
•
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References
[1] Alzheimer’s Disease. www.encarta.com, 2006.
[2] Alzheimer’s Disease. www.wikipedia.org, 2006.
[3] Stackman, Robert W.; Eckenstein, Felix; Frei, Balz; Kulhanek, Doris; Nowlin, Jessica; Quinn, Joseph F.
Prevention of Age-related Spatial Memory Deficits in a Transgenic Mouse Model of Alzheimer’s Disease by
Chronic Ginkgo Biloba Treatment. Experimental Neurology. 2003, 184, 510-520.
[4] Luo, Yuan; Smith, Julie V.; Paramasivam, Vijaykumar; Burdick, Adam; Curry, Kenneth J.; Buford, Justin
P.; Khan, Ikhlas; Netzer, William J.; Xu, Huaxi; Butko, Peter. Inhibition of amyloid- aggregation and
caspase-3 activation by the Ginkgo biloba extract EGb761. PNAS. 2002, 99, 12197-12202.
[5] Ginkgo. www.wikipedia.org, 2006.
[6] Nakanishi, Koji. Terpene trilactones from Ginkgo biloba: From ancient times to the 21st century.
Bioorganic and Medicinal Chemistry. 2005, 13, 4987-5000.
[7] Ginkgo Biloba. www.umm.edu/altmed/consherbs/print/ginkgobilobach.html, 2006.
[8] Andrieu, Sandrine; Gillete, Sophie; Amouyal, Karine; Nourhashemi, Fati; Reynish, Emma; Ousset, Pierre
Jean; Albarede, Jean Louis; Vellas, Bruno; Grandjean, Helene. Association of Alzheimer’s Disease Onset with
Ginkgo Biloba and Other Symptomatic Cognitive Treatments in a Population of Women Aged 75 Years and
Older From the EPIDOS Study. Journal of Gerontology. 2003, 58A, 372-377.
[9] Can, LUO; Qin, WU; Xie-Nan, HUANG; An-Sheng, SUN; Jing-Shan, SHI. Ginkgo biloba Leaf Extract
Enhances Levels of Caspase-3 and Amyloid Precursor Protein in Normal Rat Hippocampus. Acta. Pharmacol.
Sin. 2003, 2, 152-156.
[10] Yao, Zhi-Xing; Han, Zeqiu; Drieu, Katy; Papadopoulos, Vassilios. The Ginkgo biloba extract EGb761
rescues the PC12 neuronal cells from -amyloid-induced cell death by inhibiting the formation of -amyloidderived diffusible neurotoxic ligands. Brain Research. 2001, 889, 181-190.
[11] Yao, Zhi-Xing; Han, Zeqiu; Drieu, Katy; Papadopoulos, Vassilios. Ginkgo biloba Extract (EGb761)
Inhibits -amyloid (A) Production by Lowering Free Cholesterol Levels. Journal of Nutritional Biochemistry.
2004, 15, 749-756.
[12] Colciaghi, Francesca; Borroni, Barbara; Zimmermann, Martina; Bellone, Camilla; Longhi, Annalisa;
Padovani, Alessandro; Cattabeni, Flaminio; Christen, Yves; Di Luca, Monica. Amyloid Precursor Protein
Metabolism is Regulated Toward Alpha-secretase Pathway by Ginkgo biloba Extracts. Neurobiology of
Disease. 2004, 16, 454-460.
[13] Bastianetto, Stephane; Zheng, Wen-Hua; Quirion, Remi. The Ginkgo biloba Extract (EGb 761) Protects
and Rescues Hippocampal Cells Against Nitric Oxide-Induced Toxicity: Involvement of Its Flavonoid
Constituents and Protein Kinase C. J. Neurochem. 2000, 74, 2268-2277.
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Ginkgo biloba Extracts and Alzheimer’s Disease