Ginkgo bilobaGinkgo biloba Extracts and Extracts andAlzheimer’s DiseaseAlzheimer’s Disease

Adapted from presentation Adapted from presentation by Erik Domingues, M.D.by Erik Domingues, M.D.

Alzheimer’s Disease (AD)Alzheimer’s Disease (AD)

• Progressive brain disorderProgressive brain disorder

• Accompanied by behavioral changesAccompanied by behavioral changes

• Develops mostly in people 65 and overDevelops mostly in people 65 and over

• Genetic predispositionGenetic predisposition

• Certain health conditions may contribute Certain health conditions may contribute to AD developmentto AD development

• IncurableIncurable

Biological Characteristics of Biological Characteristics of ADAD

• Neuronal cell atrophyNeuronal cell atrophy

• Amyloid-Amyloid- (A (A) precursor protein (APP) is ) precursor protein (APP) is cleaved by cleaved by - and - and γγ-secretase to -secretase to AA

• Deposition of ADeposition of A plaques and neurofibrillary plaques and neurofibrillary tangles in hippocampus and cortex tangles in hippocampus and cortex

• AA induces apoptosis (programmed cell induces apoptosis (programmed cell death) in normal neurons death) in normal neurons

• Higher levels of oxidative damageHigher levels of oxidative damage

• Deficiency in neurotransmitters such as Deficiency in neurotransmitters such as acetylcholineacetylcholine

Ginkgo bilobaGinkgo biloba

• Ginkgoaceae familyGinkgoaceae family

• Also known as maidenhair treeAlso known as maidenhair tree

• World’s oldest tree speciesWorld’s oldest tree species

• Thought to improve cerebral circulationThought to improve cerebral circulation

• Dosage of 40-200 mg/day recommendedDosage of 40-200 mg/day recommended

• Cognitive enhancerCognitive enhancer

• May be beneficial in reducing AD onsetMay be beneficial in reducing AD onset

• Some side effects (GI, headache)Some side effects (GI, headache)

Animal Trials ofAnimal Trials ofGinkgoGinkgo

• Several trials used a standardized extract Several trials used a standardized extract of of Ginkgo biloba, Ginkgo biloba, EGb761EGb761

• EGb761 composition:EGb761 composition:– 5-7% terpene lactones (TTLs)5-7% terpene lactones (TTLs)

•Ginkgolides A, B, C, J, and M and bilobalide (BB)Ginkgolides A, B, C, J, and M and bilobalide (BB)

– 22-24 % flavonols22-24 % flavonols•Quercetin, kaempferol, isorhamnetinQuercetin, kaempferol, isorhamnetin

– max 5 ppm ginkgolic acidmax 5 ppm ginkgolic acid•toxic, allergenictoxic, allergenic

Origin?

Ginkgolides and Bilobalide Ginkgolides and Bilobalide in EGb716in EGb716

Flavonols in EGb761Flavonols in EGb761

OH O

OH O

OH

OH

OHOH O

OH O

OH

OH

Quercetin Kaempferol

OH O

OH O

OH

OH

OMe

Isorhamnetin

• Effects of Effects of GinkgoGinkgo extract from animal extract from animal studiesstudies– Spatial memory deficitsSpatial memory deficits– AA buildup (plaque formation) buildup (plaque formation)– Apoptosis of neuronal cells and activation of Apoptosis of neuronal cells and activation of

caspasescaspases– Cholesterol-lowering effectCholesterol-lowering effect

• Epidemiological studyEpidemiological studyEPIDOS - FranceEPIDOS - France

• Study used a Tg2576 mouse model and Ginkgo Study used a Tg2576 mouse model and Ginkgo extract EGb761extract EGb761– This mouse overexpresses APP, gets AThis mouse overexpresses APP, gets A plaque plaque

deposits and exhibits oxidative stress in its braindeposits and exhibits oxidative stress in its brain

• Mice were treated for 6 months with EGb761 at Mice were treated for 6 months with EGb761 at 70 mg/kg/day70 mg/kg/day

A Morris water maze A Morris water maze was used to test the was used to test the effects of the extract on effects of the extract on the micethe mice

Spatial memory Spatial memory impairment was impairment was reduced in the Ginkgoreduced in the Ginkgotreated micetreated mice

Blueberries have also Blueberries have also been shown to improve been shown to improve performance in similar performance in similar tests by Joseph, et al tests by Joseph, et al

• Studied effects of EGb761 on AStudied effects of EGb761 on A buildup, caspase- buildup, caspase-3 activity (enzyme controlling apoptotic cascade), 3 activity (enzyme controlling apoptotic cascade), and induction of apoptosis in neuroblastoma cellsand induction of apoptosis in neuroblastoma cells

• AA proliferation was prevented proliferation was prevented

• Apoptosis rates and associated caspase-3 activity Apoptosis rates and associated caspase-3 activity decreased with treatmentdecreased with treatment

• Effect of EGb761 on AEffect of EGb761 on A-induced neurotoxicity in -induced neurotoxicity in PC12 nerve cells was testedPC12 nerve cells was tested

• Exposure to AExposure to A for 12 or 24 hours increased ROS for 12 or 24 hours increased ROS levelslevels

• Treatment decreased ROS production in a dose-Treatment decreased ROS production in a dose-dependent mannerdependent manner

• Simultaneous treatment with EGb761 and ASimultaneous treatment with EGb761 and A decreased cell death compared to exposure to Adecreased cell death compared to exposure to A alonealone

• Anti-apoptotic effects were only seen when the cells Anti-apoptotic effects were only seen when the cells were treated simultaneously with EGb761 and Awere treated simultaneously with EGb761 and A

• Treatment with a different extract was not Treatment with a different extract was not neuroprotectiveneuroprotective

• Free cholesterol may be involved in APP and AFree cholesterol may be involved in APP and A productionproduction

• Study analyzed effects of EGb761 on free cholesterol Study analyzed effects of EGb761 on free cholesterol levels and amyloidogenesislevels and amyloidogenesis

• An increase in AAn increase in A and APP production is observed in and APP production is observed in presence of cholesterolpresence of cholesterol

• As Brown Norway rats age, AAs Brown Norway rats age, A levels increased levels increased– EGb761 decreased the plaques significantlyEGb761 decreased the plaques significantly– APP levels in cerebral cortex and hippocampus were decreasedAPP levels in cerebral cortex and hippocampus were decreased

• EGb761 treatment EGb761 treatment – reduced free cholesterol by 16%reduced free cholesterol by 16%– reduced amount of free cholesterol binding to low density reduced amount of free cholesterol binding to low density

proteinsproteins– decreased influx of cholesterol and increased efflux from decreased influx of cholesterol and increased efflux from

neuronal cellsneuronal cells

• Study used a different Study used a different GinkgoGinkgo extract, extract, GbEGbE– 26 % flavone glycosides and 6 % diterpene lactones26 % flavone glycosides and 6 % diterpene lactones

• Effects of Effects of GbEGbE on caspase-3 and APP on caspase-3 and APP

• Rats were treated for 14 days with 100 mg/kg Rats were treated for 14 days with 100 mg/kg of of GbEGbE

• APP level higher in treated rats (less cleavage APP level higher in treated rats (less cleavage to Ato A))

• Caspase-3 levels were higher in treated ratsCaspase-3 levels were higher in treated rats– Caspase-3 had been shown to convert APP to ACaspase-3 had been shown to convert APP to A

• A case study involving 414 women in FranceA case study involving 414 women in France

• Women diagnosed with AD were older, had a lower Women diagnosed with AD were older, had a lower financial status, and a lower educational level, and financial status, and a lower educational level, and were less knowledgeable about their healthwere less knowledgeable about their health– The only difference between these women and the undiagnosed was The only difference between these women and the undiagnosed was

the lack of vasotherapeutic treatmentthe lack of vasotherapeutic treatment

• Women in the group without dementia were three Women in the group without dementia were three times more likely to be regularly taking treatments times more likely to be regularly taking treatments like Ginkgo than women in the group with dementialike Ginkgo than women in the group with dementia

• About 50 % of these women reported taking About 50 % of these women reported taking EGb761EGb761

In summary, Ginkgo In summary, Ginkgo extractextract

• Decreased ADecreased A proliferation proliferation

• Decreased apoptotic activityDecreased apoptotic activity

• Increased neuronal cell viabilityIncreased neuronal cell viability

• Decreased free cholesterol levels, linked to less Decreased free cholesterol levels, linked to less amyloid formationamyloid formation

• Improved cognitive performance in ratsImproved cognitive performance in rats

• Was linked to decreased incidence of AD in Was linked to decreased incidence of AD in French women French women

• Keeps brain cells healthier!Keeps brain cells healthier!

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