Inhibition of amyloid-β aggregation and caspase-3 activation by the
            <i>Ginkgo biloba</i>
            extract EGb761

Luo, Yuan; Smith, Julie V.; Paramasivam, Vijaykumar; Burdick, Adam J.; Curry, Kenneth J.; Buford, Justin P.; Khan, Ikhlas A.; Netzer, William J.; Xu, Huaxi; Butko, Peter

doi:10.1073/pnas.182425199

Cited by 379 publications

(270 citation statements)

References 37 publications

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“…6 As Ab is toxic to neurons, 7 the main targets for therapeutic intervention of the Ab cascade include the inhibition of Ab production, the inhibition of Ab aggregation and fibril formation, in addition to the inhibition of the consequent inflammatory responses caused by the Ab deposition. In this context, several substances are known to inhibit Ab fibrillogenesis in vitro, including laminin, 6,8 melatonin, 9 nordihydroguaiaretic acid, 10 polyphenols, 11 site-directed monoclonal antibodies, 12 a1-antichymotrypsin, 13 Ginkgo biloba extract, 14 type IV collagen 15 and b-sheet breaker peptides. 16 Nevertheless, an effective therapeutic approach that interferes directly with the neurodegenerative process in AD is eagerly awaited.…”

Section: Introductionmentioning

confidence: 99%

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Dinamarca¹,

Cerpa²,

Garrido

et al. 2006

Mol Psychiatry

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The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid b-peptide (Ab). In the present work, we have determined the effect of hyperforin an acylphloroglucinol compound isolated from Hypericum perforatum (St John's Wort), on Ab-induced spatial memory impairments and on Ab neurotoxicity. We report here that hyperforin: (1) decreases amyloid deposit formation in rats injected with amyloid fibrils in the hippocampus; (2) decreases the neuropathological changes and behavioral impairments in a rat model of amyloidosis; (3) prevents Ab-induced neurotoxicity in hippocampal neurons both from amyloid fibrils and Ab oligomers, avoiding the increase in reactive oxidative species associated with amyloid toxicity. Both effects could be explained by the capacity of hyperforin to disaggregate amyloid deposits in a dose and time-dependent manner and to decrease Ab aggregation and amyloid formation. Altogether these evidences suggest that hyperforin may be useful to decrease amyloid burden and toxicity in AD patients, and may be a putative therapeutic agent to fight the disease.

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Section: Introductionmentioning

confidence: 99%

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Dinamarca¹,

Cerpa²,

Garrido

et al. 2006

Mol Psychiatry

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“…Protective effects in both systems were linked to a modulation in signaling through protein kinase C and/or modulation of cell survival/cell cycle genes (4,6). Much evidence also exists to support the potential beneficial and neuromodulatory effects of flavonoid-rich ginkgo biloba extracts, such as EGb 761, in the central nervous system (7)(8)(9). Clinical trials with EGb 761, which contains kaempferol and quercetin, have indicated beneficial effects on brain function, particularly in connection with age-related dementias and Alzheimer's disease (9,10).…”

mentioning

confidence: 99%

Modulation of Pro-survival Akt/Protein Kinase B and ERK1/2 Signaling Cascades by Quercetin and Its in Vivo Metabolites Underlie Their Action on Neuronal Viability

Spencer

Rice‐Evans

Williams

2003

Journal of Biological Chemistry

309

224

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Much recent interest has focused on the potential of flavonoids to interact with intracellular signaling pathways such as with the mitogen-activated protein kinase cascade. We have investigated whether the observed strong neurotoxic potential of quercetin in primary cortical neurons may occur via specific and sensitive interactions within neuronal mitogen-activated protein kinase and Akt/protein kinase B (PKB) signaling cascades, both implicated in neuronal apoptosis. Quercetin induced potent inhibition of both Akt/PKB and ERK phosphorylation, resulting in reduced phosphorylation of BAD and a strong activation of caspase-3. High quercetin concentrations (30 M) led to sustained loss of Akt phosphorylation and subsequent Akt cleavage by caspase-3, whereas at lower concentrations (<10 M) the inhibition of Akt phosphorylation was transient and eventually returned to basal levels. Lower levels of quercetin also induced strong activation of the pro-survival transcription factor cAMP-responsive element-binding protein, although this did not prevent neuronal damage. O-Methylated quercetin metabolites inhibited Akt/PKB to lesser extent and did not induce such strong activation of caspase-3, which was reflected in the lower amount of damage they inflicted on neurons. In contrast, neither quercetin nor its O-methylated metabolites had any measurable effect on c-Jun N-terminal kinase phosphorylation. The glucuronide of quercetin was not toxic and did not evoke any alterations in neuronal signaling, probably reflecting its inability to enter neurons. Together these data suggest that quercetin and to a lesser extent its O-methylated metabolites may induce neuronal death via a mechanism involving an inhibition of neuronal survival signaling through the inhibition of both Akt/PKB and ERK rather than by an activation of the c-Jun N-terminal kinase-mediated death pathway.

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“…EGb 761 contains flavone glycosides (quercetin, kaempferol, isorhamnetin) and terpene lactones (ginkgolides and bilobalide) and has antioxidant and free radical-scavenging activities [21]. Translational studies have also shown its potential to inhibit amyloid-aggregation and consecutive mitochondrion-initiated apoptosis, and indicated that direct neuronal damage may actually be mediated by the amyloid toxicity [22]. …”

Section: Pharmacological Treatment Of MCImentioning

confidence: 99%

Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer's Disease

Karakaya

Fußer²,

Schröder³

et al. 2013

Current Neuropharmacology

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Mild cognitive impairment (MCI) is a syndrome which, depending on various neurobiological, psychological and social factors, carries a high risk of developing into dementia. As far as diagnostic uncertainty and the heterogeneous underlying pathophysiological mechanisms are concerned, only limited therapeutic options are currently available. Clinical trials involving a wide range of substances have failed to show efficacy on primary and secondary outcome parameters. Most results reflect not only a lack of effectiveness of drug therapy but also methodological constraints in true prodromal Alzheimer´s disease (AD) based on clinical criteria. Biomarkers may help to identify MCI as a prodromal phase of dementia, so it is important to use them to improve specificity of case selection in future studies. For MCI as a prodromal syndrome of AD, clinical trials with disease modifying drugs that target underlying pathological mechanisms such as amyloid-beta accumulation and neurofibrillary tangle formation may help develop effective treatment options in the future. Alternative pharmacological approaches are currently being evaluated in ongoing phase 1 and phase 2 studies. Nevertheless, a lack of approved pharmacotherapeutic options has led to specific interventions that focus on patient education and life-style related factors receiving increasing attention.

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Inhibition of amyloid-β aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761

Cited by 379 publications

References 37 publications

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

Modulation of Pro-survival Akt/Protein Kinase B and ERK1/2 Signaling Cascades by Quercetin and Its in Vivo Metabolites Underlie Their Action on Neuronal Viability

Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer's Disease

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