Ginkgo biloba Extracts and Alzheimer's Disease by zhangyun

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									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
     • toxic, allergenic                                 Origin?
Ginkgolides and Bilobalide in
          EGb716
            Flavonols in EGb761
                               OH                                  OH


HO          O                       HO              O
                               OH


                     OH                                    OH

     OH     O                             OH        O
          Quercetin                            Kaempferol

                                               OH


                HO             O
                                               OMe


                                     OH                 Isorhamnetin
                          OH   O
• 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 dose-
    dependent 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!
•
                                    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 -amyloid-
    derived 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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