Fengming Wu

Ginkgo biloba extract in Alzheimer's disease: from action mechanisms to medical practice.

Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, is one of the most popular herbal supplements. Numerous preclinical studies have shown the neuroprotective effects of EGb761 and support the notion that it may be effective in the treatment and prevention of neurodegenerative disorders such as Alzheimer’s disease (AD). Despite the preclinical promise, the clinical efficacy of this drug remains elusive. In this review, possible mechanisms underlying neuroprotective actions of EGb761 are described in detail, together with a brief discussion of the problem of studying this herb clinically to verify its efficacy in the treatment and prevention of AD. Moreover, various parameters e.g., the dosage and the permeability of the blood brain barrier (BBB), impacting the outcome of the clinical effectiveness of the extract are also discussed. Overall, the findings summarized in this review suggest that, a better understanding of the neuroprotective mechanisms of EGb761 may contribute to better understanding of the effectiveness and complexity of this herb and may also be helpful for design of therapeutic strategies in future clinical practice. Therefore, in future clinical studies, different factors that could interfere with the effect of EGb761 should be considered.

Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt.

BACKGROUND The pathogenic accumulation of amyloid β peptide (Aβ), a natural occurring peptide processed from beta-amyloid precursor protein (APP), is considered to play a key role in the development of Alzheimers disease (AD). Ginsenoside Rg1, an active component in ginseng, has been identified as a phytoestrogen and also found to be neuroprotective. However, it is unknown whether Rg1-induced estrogenic activity intervenes in APP processing, and improves memory performance. METHODS Using HT22 cells and SH-SY5Y cells stably expressing the Swedish mutant APP (APPsw), this study investigated whether Rg1 intervened in APP metabolism through estrogenic activity. Using the ovariectomized (OVX) rats to mimic age-related changes in postmenopausal females, this study also tested the long-term effect of Rg1 on APP metabolism. RESULTS The in vitro study demonstrated that Rg1 increased extracellular secretion of soluble amyloid precursor protein α (sAPPα), enhanced α-secretase activity and decreased extracellular release of Aβ. These effects of Rg1 could be prevented by inhibitors of protein kinase C (PKC), Extracellular-Signal Regulated Kinase/Mitogen-Activated Protein Kinase (ERK/MAPK) and Phosphoinositide-3 kinase (PI3K)/Akt pathways. Inhibition of endogenous estrogen receptor (ER) activity abrogated Rg1-triggered release of sAPPα, increase of α-secretase activity, and activation of ERK and Akt signaling. In addition, Rg1 promoted phosphorylation of ERα at Ser118 residue. The in vivo study demonstrated that 8-week Rg1 treatment of OVX rats increased sAPPα levels and decreased Aβ content in the hippocampi, and improved the spatial learning and memory. GENERAL SIGNIFICANCE Rg1 might be used to slow or prevent AD, in particular in postmenopausal females.

Ginkgo biloba extract EGb761 protects against aging-associated mitochondrial dysfunction in platelets and hippocampi of SAMP8 mice

Standardized Ginkgo biloba extract, EGb761, has been shown to possess polyvalent properties, such as anti-oxidation, anti-apoptosis and anti-inflammation. Recently, it has also been proposed to have direct protective effects on mitochondria. The effects of EGb761 make it a potential anti-aging drug. Despite that, the ‘anti-aging’ effect of EGb761, particularly its effect on the central nervous system, is still inconclusive. Using two age groups (3-week-old and 40-week-old) of SAMP8 mice (a senescence-accelerated strain of mice), the effects of EGb761 on mitochondrial function in platelets and hippocampi were investigated in this study. It was found that mitochondrial functions, evaluated as cytochrome c oxidase (COX) activity, mitochondrial ATP (adenosine-5′-triphosphate) content and mitochondrial glutathione (GSH) content, decreased with age. EGb761 protected against mitochondrial dysfunction in platelets of young and old mice, suggesting a peripheral effect of this herb in the prevention and treatment of age-associated degeneration. In contrast, in hippocampi, protective effects of EGb761 were observed only in the old mice, probably due to an age-associated increase in the permeability of the blood brain barrier (BBB). Therefore, while EGb761 has a potential anti-aging effect, its central effect can be affected by in vivo factors such as the BBB permeability. A better understanding of the in vivo pharmacological actions of EGb761 may contribute to a better understanding of the effectiveness and complexity of this drug.

H2O2 and PAF mediate Aβ1-42-induced Ca2+ dyshomeostasis that is blocked by EGb761

Calcium (Ca2+) dyshomeostasis may be of pivotal importance in mediating the neurotoxic action of amyloid beta peptide (Abeta), but the mechanism whereby Abeta disrupts Ca2+ homeostasis remains unclear. Using hippocampal neuronal cultures, the present study investigated possible mechanisms underlying Ca2+ dyshomeostasis induced by the oligomeric form of Abeta1-42 and two possible mediators of its toxicity, hydrogen peroxide (H2O2) and platelet-activating factor (PAF). It was found that, both H2O2 and PAF were able to reproduce each of the events induced by oligomeric Abeta1-42, including (a) Ca2+ influx via N-methyl-D-aspartic acid (NMDA) receptors, (b) enhancement of Ca2+ response to NMDA via activation of protein kinase C (PKC), (c) the increase of extracellular concentrations of glutamate and (d) the increase in cytosolic free Ca2+ ([Ca2+]i). Moreover, each of these events could be blocked by Ginkgo biloba extract EGb761, a free radical scavenger with PAF antagonism, and by quercetin, a constituent with well-established free radical scavenging property. In contrast, ginkgolide B, another constituent of EGb761 with well-established PAF-antagonizing activity protected the neurons against Ca2+ dyshomeostasis induced by Abeta1-42 and PAF, but not by H2O2. These results suggested the possibility that Abeta1-42-induced Ca2+ dyshomeostasis might be mediated by formation of toxic mediators such as H2O2 and PAF. Therefore, increased production of toxic mediators such as H2O2 and PAF in the brain may be critical in the pathological mechanism of neurodegenerative diseases, particularly Alzheimers disease (AD), and may serve as major therapeutic targets for these diseases.

Incorporation of β-sitosterol into mitochondrial membrane enhances mitochondrial function by promoting inner mitochondrial membrane fluidity

Recent findings suggest that mitochondrial membrane fluidity could influence mitochondrial energy metabolism. β-sitosterol (BS) is a common plant sterol that is prevalent in plant oils, nuts, cereals and plant food products. Its chemical structure is very similar to that of cholesterol. As a cholesterol analog, BS is highly lipid soluble and largely resides in the membranes of cells or organelles where it may have an influence on the membrane fluidity. The present study reports that, with the cholesterol chelator 2-hydroxypropyl-β-cyclodextrin (HPβCD) as its carrier, BS is able to increase the fluidity of the inner mitochondrial membrane (IMM) without affecting the fluidity of the outer mitochondrial membrane (OMM), and consequently to increase the mitochondrial membrane potential (∆Ψm) and mitochondrial ATP content. It has been previously proposed that a therapeutical boost in adenosine triphosphate (ATP) levels in mitochondria may be beneficial for neurodegenerative diseases such as Alzheimer’s disease (AD). Given that dietary administration of plant sterols could increase brain BS concentrations, these results may provide a better understanding of the beneficial effects of plant sterol-enriched nutrients on neurodegenerative diseases such as AD.

Bilobalide regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway.

Bilobalide (BB) is a sesquiterpenoid extracted from Ginkgo biloba leaves. An increasing number of studies have demonstrated its neuroprotective effects. The neuroprotective mechanisms may be associated with modulation of intracellular signaling cascades such as the phosphatidyl inositol 3-kinase (PI3K) pathway. Using differentiated SH-SY5Y cells, this study investigated whether BB modulation of intracellular signaling pathways, such as the protein kinase C (PKC) and PI3K pathways, contributes to amyloid precursor protein (APP) metabolism, a key event in the pathogenesis of Alzheimers disease (AD). We demonstrated in this study that BB enhanced the secretion of α-secretase-cleaved soluble amyloid precursor protein (sAPPα, a by-product of non-amyloidogenic processing of APP) and decreased the β amyloid protein (Aβ, a by-product of amyloidogenic processing of APP) via PI3K-dependent pathway. The PI3K pathway mediated the rapid effect of BB on APP processing possibly via regulation of intracellular APP trafficking. After longer time BB incubation (12h), this effect was reinforced by PI3K pathway-mediated up-regulation of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, an α-secretase candidate). Given the strong association between APP metabolism and AD pathogenesis, the ability of BB to regulate APP processing suggests its potential use in AD prevention.

β-sitosterol inhibits high cholesterol-induced platelet β-amyloid release

Recently, increasing evidence has linked high cholesterol to the pathogenesis of Alzheimer’s disease (AD), suggesting that cholesterol may be a target for developing new compounds to prevent or treat AD. Plant sterols, a group of sterols enriched in plant oils, nuts, and avocados, have the structure very similar to that of cholesterol, and have been widely used to reduce blood cholesterol. Due to their cholesterol-lowering property, plant sterols such as β-sitosterol may also influence cholesterol-depending functions including its role in AD development. Using human platelets, a type of peripheral blood cells containing the most circulating amyloid precursor protein (APP), this study investigated the effect of β-sitosterol on high cholesterol-induced secretion of β amyloid protein (Aβ). It was found that β-sitosterol effectively inhibited high cholesterol-driven platelet Aβ release. In addition, β-sitosterol prevented high cholesterol-induced increase of activities of β- and γ-secretase, two APP cleaving enzymes to generate Aβ. Additional experiments showed that high cholesterol up-regulated lipid raft cholesterol. This effect of cholesterol could be suppressed by β-sitosterol. These findings suggest that β-sitosterol is able to inhibit high cholesterol-induced Aβ release probably through maintenance of membrane cholesterol homeostasis. Given that dietary plant sterols have the potential of penetrating the blood–brain barrier (BBB), these data suggest that plant sterols such as β-sitosterol may be useful in AD prevention.