Ginkgo Extract EGb Research Articles

Chemoprevention of aflatoxin B_1-induced hepatic oxidative damage and hepatocarcinogenesis in rats by Ginkgo biloba extract EGb 761

Objective To investigate the preventive effect of Ginkgo biloba extract (EGb 761) on hepatocarcinogenesis induced by aflatoxin B_1 (AFB_1) and the mechanism of its antitoxident activity. Methods Seventy-one Wistar rats were divided into at random three groups: group A (AFB_1), group B (AFB_1 + EGb761) and group C (control). The animals in groups A and B were injected with AFB_1 (ip, 100-200 μg/kg body weight, 1-3 times/week). The rats in group B were fed on the food containing EGh761, but thos in groups A and C were fed on the normal food. Liver biopsies were performed on all rats at the 14th, 28th and 42nd week of the experiment, and the animals were sacrificed at the 64th week. Histopathological changes of the liver tissues and the levels of malondialdebyde (MDA) were examined, and the protein expression of 8-hydroxydeoxyguanosine (8-OHdG) was detected by immunohistochemistry staining. Results The incidence of hepatocellular carcinoma (HCC) in group B (26.92%) was significantly lower than that in group A (76.00%) (P<0.01). None HCC developed in group C. The level of MDA in rat's liver tissues in group B was significantly lower than that in group A at four time points (P<0.05), and also significantly lower than that in group C at the 64th week (P<0.05). The expression of 8-OHdG protein in rat liver tissues collected at the week of 28, 42 and 64 in group B was significantly lower than that in group A (P<0.05). Conclusion The extenuation of lipid peroxidation and the inhibition of the expression of 8-OHdGprotein are the potential mechanisms for the chemopreventive effects of EGb761. Key words: Carcinoma,hepatocellular; Ginkgo biloba extract; Aflatoxin B_1; MDA

Ginkgo-Spezialextrakt bei Alzheimer-Demenz gleich wirksam aber verträglicher als Donepezil

Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R, for the GINDON Study Group. Ginkgo biloba extract EGb 761, donepezil or both combined in the treatment of Alzheimer’s disease with neuropsychiatric features: A randomised, doubleblind, exploratory trial. Aging & Mental Health 2009; 13: 183–190

Ginkgo biloba extract EGb761 protects against mitochondrial dysfunction in platelets and hippocampi in ovariectomized rats

Using ovariectomized middle-aged rats to mimic the post-menopausal pathophysiological changes in women, we have previously demonstrated that estrogen withdrawal and age-related decrease in the functional reserve of mitochondria might co-operate to induce persistent mitochondrial dysfunction, which may be critical in inducing degenerative processes in the brain later in post-menopausal women. The standardized Ginkgo biloba extract EGb761 has long been considered a natural antioxidant. More recently it has also proposed to have direct protective effects on the mitochondria. In this work, effects of EGb761 on mitochondrial function in platelets and hippocampi of ovariectomized and sham-operated rats were investigated. It was found that EGb761 protected against the decrease of cytochrome c oxidase (COX) activity, mitochondrial ATP (adenosine-5’-triphosphate) content and mitochondrial glutathione (GSH) content in both platelets and hippocampi of ovariectomized rats, suggesting its peripheral and central effects against estrogen withdrawal-induced degeneration. In contrast, in sham-operated rats, EGb761 increased mitochondrial GSH content in platelets but failed to show similar effect on hippocampi, suggesting that EGb761 may help to enhance the functional reserve of mitochondria, but this effect was limited to the outside of the central nervous system. EGb761 displayed similar effects on platelets and hippocampi of ovariectomized rats but showed differential effects on platelets and hippocampi of sham-operated rats, possibly because estrogen withdrawal induced an increase of blood brain barrier (BBB) permeability. Therefore, while EGb761's effect may be limited to the outside of the nervous system under normal physiological conditions, EGb761 may be a potential protective agent against central neurodegeneration in post-menopausal women.

Improvement of auditory discrimination learning by Ginkgo biloba extract EGb 761 ®

The effect of oral application of Ginkgo biloba extract EGb 761 ® on auditory discrimination learning in Mongolian gerbils was investigated using discrimination tasks with three different degrees of difficulty and two protocols for administration starting 2 weeks prior to or at the beginning of training. In comparison to placebo-treated controls we observed significant improvement of learning performance in EGb 761 ® treated gerbils in discrimination tasks of all degrees of difficulty, from the easiest to the most demanding. EGb 761 ® has been reported to increase the extracellular concentration of dopamine in prefrontal cortex of rats which plays a major role in the type of discrimination learning used in the present study. We, therefore, suppose that EGb 761 ® improves discrimination learning through its effect on the dopaminergic system.

Ginkgo-Spezialextrakt EGb 761® in der Behandlung der Demenz: Evidenz für Wirksamkeit und Verträglichkeit

The Ginkgo biloba extract EGb 761 interferes with pathomechanisms relevant to dementia, such as Abeta aggregation, mitochondrial dysfunction, insulin resistance, and hypoperfusion. The efficacy of EGb 761 in the treatment of dementia (Alzheimer's disease and vascular dementia) has been studied in 10 randomised, controlled, double-blind clinical trials. In three of the four large trials conducted in accordance with recent recommendations EGb 761 was significantly superior to placebo with respect to cognitive performance and one or more further (global, functional or behavioural) outcomes demonstrating the clinical relevance of the findings. The findings from the six smaller trials are in line with those of the large trials. One trial was inconclusive, but of questionable external validity due to uncommonly rigorous patient selection. Subgroup analyses of this study together with the findings from the most recent clinical trial suggest that EGb 761 may be most beneficial to patients with neuropsychiatric symptoms, who actually constitute the majority of dementia patients. Delay in symptom progression, rates of clinically significant treatment response and numbers needed to treat (NNT) found for EGb 761 are in the same range as those reported for cholinesterase inhibitors. In an exploratory trial comparing EGb 761 and donepezil, no statistically significant or clinically relevant differences were seen. Hence, EGb 761 has its place in the treatment of dementia.

Efficacy and tolerability of Ginkgo Biloba extract EGb 761® in different types of dementia: Analyses of a randomized controlled trial

Background and aims: Ginkgo Biloba extract EGb 761® has been found effective in the treatment of dementia with neuropsychiatric features. Secondary analyses of a randomized controlled trial were performed to find out whether treatment effects differ by type of dementia. Methods: 395 patients aged 50 years or above, suffering from dementia with neuropsychiatric features, were treated with EGb 761® (240 mg/day) or placebo for 22 weeks. Patients scored 35 or below on the TE4D, a screening test for dementia, below 6 on the Clock–Drawing Test (CDT) and between 9 and 23 on the SKT, a cross-culturally validated cognitive test battery.

The Effects of Ginkgo Biloba Extract EGb 761 on Mechanical and Cold Allodynia in a Rat Model of Neuropathic Pain

Neuropathic pain is chronic pain that is caused by an injury to the peripheral or central nervous system. The symptoms of neuropathic pain are continuing pain, hyperalgesia, and allodynia. Ginkgo biloba extract is an oriental herbal medicine that has various pharmacological actions. We examined the effect of Ginkgo biloba extract, EGb 761, on the mechanical and cold allodynia in a rat model of neuropathic pain. Male Sprague-Dawley rats were prepared by tightly ligating the left L5 and L6 spinal nerves. All the rats developed mechanical and cold allodynia 7 days after surgery. Fifty neuropathic rats were assigned into five groups for the intraperitoneal administration of drugs. The study was double-blind and the order of the treatments was randomized. Normal saline and EGb 761 (50, 100, 150, and 200 mg/kg) were administered, respectively, to the individual groups. We examined mechanical and cold allodynia at preadministration and at 15, 30, 60, 90, 120, 150, and 180 min after intraperitoneal drug administration. Mechanical allodynia was quantified by measuring the paw withdrawal threshold to stimuli with von Frey filaments of 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 15.0, and 26.0 g. Cold allodynia was quantified by measuring the frequency of foot lift with applying 100% acetone. We measured the locomotor function of the neuropathic rats by using the rotarod test to reveal if EGb 761 has side effects, such as sedation or reduced motor coordination. The control group showed no differences for mechanical and cold allodynia. For the EGb 761 groups, the paw withdrawal thresholds to mechanical stimuli and withdrawal frequencies to cold stimuli were significantly reduced versus the preadministration values and versus the control group. The duration of antiallodynic effects increased in a dose-dependent fashion, and these were maintained for 120 min at the highest dose (P < 0.05). Only at the highest dose (200 mg/kg) did EGb 761 reduce the rotarod performance time. We conclude that Ginkgo biloba extract, EGb 761, attenuates mechanical and cold allodynia in a rat model of neuropathic pain, and it may be useful for the management of neuropathic pain.

Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against β-amyloid peptide-induced toxicity in SH-SY5Y cells

Ginkgo biloba extract EGb761 has been shown to protect against β-amyloid peptide (Aβ)-induced neurotoxicity but the specific mechanisms remain unclear. In the present study, effects of EGb761 and two of its constituents, quercetin and ginkgolide B, on the cytotoxic action of Aβ (1–42) were tested with human neuroblastoma SH-SY5Y cells. We found that EGb761 was able to block Aβ (1–42)-induced cell apoptosis, reactive oxygen species (ROS) accumulation, mitochondrial dysfunction and activation of c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling pathways. Both quercetin and ginkgolide B may be involved in the inhibitory effects of EGb761 on JNK, ERK1/2 and Akt signaling pathways. Ginkgolide B also helped to improve mitochondrial functions but quercetin failed to show this effect. Additional experiments suggest that, protective effects of EGb761 against Aβ toxicity may be associated with its antioxidant and platelet activating factor (PAF) antagonist activities. Quercetin but not ginkgolide B is one of the constituents responsible for the antioxidant action of EGb761. Both quercetin and ginkgolide B may be involved in the PAF antagonist activity of EGb761. Overall, actions of individual EGb761 components provide further insights into direct mechanisms underlying the neuroprotective effects of EGb761.

Table of Contents

AbstractMetabolic Effects Linked to 2nd‐Generation Antipsychotics in Alzheimer's PatientsStudy Compares Ginkgo Biloba and Donepezil for Alzheimer's DiseaseClozapine Plasma Levels May Increase With Addition of IsoniazidAripiprazole Prescribing Patterns in Clinical PracticeSleep Disorders in the Elderly: Guidance for CliniciansResearch on Ginkgo Biloba Extract EGb 761 for Alzheimer's DiseaseCilostazol With Donepezil for Moderate ADBapineuzumab Highest Dose Dropped in Phase 3 AD TrialsDopamine Agonists and Compulsive BehaviorsGalantamine and NightmaresNew Approvals

Expression of heat shock proteins 70 in spinal cord and dorsal root ganglia after neurotomy of rat sciatic nerve and the effect of extract of ginkgo biloba

Objective To study the expression of heat shock protein 70 (HSP 70) in spinal cord and dorsal root ganglia after peripheral nerve injury and the influence of Ginkgo biloba extract EGb 761 on HSP 70 expression, and investigate the mechanism of the protective effect of EGb 761 after peripheral nerve injury in rats. Methods One hundred and forty-four male adult SD mrs were randomly divided into three groups, sham operation group ( n= 48), sciatic nerve transection group ( n = 48) and sciatic nerve transection and EGb 761 hours, 12 hours, 1 day, 2 days, 4 days, 7 days, 14 days and 28 days postoperatively, spinal cord of L4-L6 were harvested. Immunohistochemistry analysis was done to measure the expression of HSP 70 in anterior horns of Lt-L6 spinal cord and dorsal root ganglia. Results In normal rats' spinal cord anterior horn and dorsal root ganglia, HSP 70 was expressed. After rat sciatic nerve transection, the expression of HSP 70 increased quickly.This elevated expression lasted for a period of time, and then returned to the normal level. After being intervened by EGb 761, HSP 70 expression during the early postoperative period was lower compared with the group not being intervened. At the later period, the expression increased and lasted for a longer time. Conclusion Ginkgo biloba extract( EGb 761 ) can enhance the expression of HSP 70 after peripheral nerve injury. This could be the mechanism of the neuroprotective and neurotrophic effect of Ginkgo biloha extract. Key words: Nerve regeneration; Spinal cord; Ganglia, spinal; Heat shock proteins; Ginkgohiloha extract EGb 761

Efficacy and tolerability of Ginkgo biloba extract EGb 761 ® by type of dementia: Analyses of a randomised controlled trial

Secondary analyses of a randomised controlled trial were performed to find out whether treatment effects of Ginkgo biloba extract EGb 761 ® differed by type of dementia. Three hundred ninety-five patients aged 50 years or above, with dementia with neuropsychiatric features were treated with EGb 761 ® (240 mg/day) or placebo for 22 weeks. Patients scored between 9 and 23 on the Short Syndrome Test (SKT), a cross-culturally validated cognitive test battery. Their total score on the Neuropsychiatric Inventory (NPI) was at least 5. Efficacy was assessed by the SKT test battery (primary outcome measure), the Verbal Fluency Test, the Clock-Drawing Test, the NPI, the Hamilton Rating Scale for Depression (HAMD), and the Gottfries–Bråne–Steen Scale (GBS). Applying standard research diagnostic criteria 214 patients were diagnosed with Alzheimer's disease (probable AD or possible AD with cerebrovascular disease) and 181 with probable vascular dementia (VaD). Under EGb 761 ® treatment the SKT total score improved by − 3.0 ± 2.3 and − 3.4 ± 2.3 points in patients with AD and VaD, respectively, whereas the patients on placebo deteriorated by + 1.2 ± 2.5 and + 1.5 ± 2.2 points, respectively ( p < 0.01 for both drug–placebo differences). Significant drug–placebo differences were found for all secondary outcome variables with no major differences between AD and VaD subgroups. The rate of adverse events tended to be higher for the placebo group.

Ginkgo biloba extract EGb 761®, donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: A randomised, double-blind, exploratory trial

Objective: This randomised, double-blind exploratory trial was undertaken to compare treatment effects and tolerability of EGb 761®, donepezil and combined treatment in patients with AD and neuropsychiatric features. Method: We enrolled 96 outpatients, aged 50 years or above, who met the NINCDS/ADRDA criteria for probable AD, scored below 36 on the TE4D, a screening test for dementia, below 6 on the Clock-Drawing Test (CDT) and between 9 and 23 on the SKT, a cross-culturally validated cognitive test battery. They scored at least five on the 12-item Neuropsychiatric Inventory (NPI). EGb 761® (240 mg per day), donepezil (initially 5 mg, after 4 weeks 10 mg per day) or EGb 761® and donepezil combined (same doses) were administered for 22 weeks. Results: Changes from baseline to week 22 and response rates were similar for all three treatment groups with respect to all outcome measures (SKT, NPI, total score and activities-of-daily-living sub-score of the Gottfries–Bråne–Steen Scale, Hamilton Rating Scale for Depression, CDT and Verbal Fluency Test). An apparent tendency in favour of combination treatment warrants further scrutiny. Compared to donepezil mono-therapy, the adverse event rate was lower under EGb 761® treatment and even under the combination treatment. Conclusion: These exploratory findings helped to develop three hypotheses that will have to be proven in further studies: (1) there is no significant difference in the efficiency between EGb 761® and donepezil, (2) a combination therapy will be superior to a mono-therapy with one of both substances and (3) there will be less side effects under a combination therapy than under mono-therapy with donepezil.

Effects of Gingko Extract (EGb761) on oxidative damage under different conditions of serum supply

Standardized Ginkgo biloba extract EGb761 is known to have multivalent properties such as anti-oxidation and anti-apoptosis. In this study, we determined in rat pheochromocytoma (PC12) cells effects of EGb761 treatment on oxidative damage under three different conditions of serum supply: normal growth medium (NGM), serum deprivation (SE) and serum deprivation followed by re-supply (SERS). It was found that, under the condition of serum deprivation, oxidative damage induced less cell death than the condition of serum supply. This appears to be related to inhibition of mitochondrial metabolism. Moreover, after serum deprivation, serum re-supply exacerbated cell necrosis, possibly through enhancement of oxidative damage. EGb761 could attenuate oxidative damage under the condition of serum supply whereas no protective effect on serum-depleted cells was observed. These results suggest that, there is a synergistic effect between trophic factors and EGb761. EGb761 treatment may protect cells from possible oxidative damage induced by the trophic factors. On the other hand, trophic factors appear to strengthen the protective effect of EGb761. To fully understand the synergistic interaction between antioxidants and trophic factors will help to sort out rational use of drugs in clinic practice.

Gene Regulatory Effects of Ginkgo biloba Extract and Its Flavonol and Terpenelactone Fractions in Mouse Brain

The standardised Ginkgo biloba extract EGb761 is known for its potential beneficial effects in the prevention and therapy of neurodegenerative disorders including Alzheimer’s disease (AD). However, the molecular mechanisms and the specific role of its constituents are largely unknown. The aim of the present feeding trial was to investigate the effects of EGb761 and its major constituents on the expression of genes encoding for proteins involved in the pathogenesis of AD in mouse brain. Six month old C57B6 mice were fed semi synthetic diets enriched with either EGb761 or one of its main fractions, flavonols and terpenelactones, respectively, over a period of 4 weeks. Thereafter, mRNA of α-secretase, neprilysin, amyloid precursor protein (App), App binding protein-1 and acetylcholine esterase was quantified in hippocampus and cortex. EGb761 and its flavonol fraction had no effects on relative mRNA levels of the respective genes in mouse brain. However, the terpenelactone fraction significantly decreased the mRNA levels of App in the hippocampus. Taken together, a 4 week dietary treatment with EGb761 or its main fractions had only moderate effects on mRNA levels of AD related genes in cortex and hippocampus of mice.

&lt;emph type="ital"&gt;Ginkgo biloba&lt;/emph&gt; Extract and Preventing Alzheimer Disease

GINKGO BILOBA LEAVES AND EXTRACTS ARE WIDELY used over-the-counter preparations marketed in the United States as food supplements or nutraceuticals, and as such, explicit health claims are not listed in their labeling. In other countries and in the popular press, G biloba is advocated for the treatment of a broad and seemingly ever-increasing range of medical conditions. The extract used in the Ginkgo Evaluation of Memory (GEM) study reported in this issue of JAMA by DeKosky and colleagues and in many other clinical and preclinical studies is Ginkgo extract EGb 761 (Schwabe Pharmaceuticals, Karlsruhe, Germany). The extract is standardized to contain 2 major constituents: 22% to 27% flavonoids and 5% to 7% terpene lactones (ginkgolides and bilobalide). Unique to G biloba trees, the terpene lactones consist of several ginkgolides and bilobalide. The flavonoids and ginkgolides have protean biological activity in preclinical research. The flavonoids are active as antioxidants and appear neuroprotective. Ginkgolide B is a potent antagonist of the platelet activating factor receptor. Ginkgolides A and J variously inhibit hippocampal neuron dysfunction and neuronal cell death caused by amyloid beta protein-42 (A 42). Ginkgolides A and J decrease A 42-induced pathological behaviors, enhance neurogenesis in animal models of Alzheimer disease, and inhibit A aggregation, providing considerable rationale for G biloba extracts as potential treatments for Alzheimer disease. Some of the components of G biloba extract are as active in preclinical models of neurodegeneration and Alzheimer disease as new drug candidates being developed by pharmaceutical companies and some research universities. The GEM trial involved 3069 participants who were not cognitively impaired or had mild cognitive impairment and were randomized to receive EGb 761 (120 mg twice daily) or identically appearing and tasting placebo and were followed up for the onset of dementia. The main results were that use of EGb 761 over the median follow-up period of 6.1 years did not delay the onset of dementia due to any cause including Alzheimer disease specifically. The hazard ratios for all-cause dementia (1.12 [95% confidence interval {CI}, 0.94-1.33]) and for Alzheimer disease (1.16 [95% CI, 0.971.39]) numerically favored placebo and the lower limits of the 95% CIs were not compatible with any potentially meaningful level of dementia risk reduction. The investigators also found no favorable effects of EGb 761 for reducing cardiovascular serious adverse events or total mortality, 2 of 4 secondary outcomes. The relationship of ginkgo extract use and cardiovascular disease is potentially more complex, however, in that the 25% of participants with cardiovascular disease prior to randomized treatment showed increased risk for developing dementia with EGb 761 treatment (hazard ratio, 1.56 [95% CI, 1.14-2.15], P=.006). Moreover, the infrequently occurring serious adverse events of hemorrhagic stroke favored placebo—8 events with placebo vs 16 events with EGb 761—although the difference was not statistically significant. Furthermore, this difference appeared inconsistent with the similarly infrequent incidence of vascular dementia (by definition dementia subsequent to stroke) that favored EGb 761, 17 placebo cases vs 7 with EGb 761 (hazard ratio,0.41 [95% CI, 0.17-0.98], P=.05). These 2 latter observations may be the result of chance, often seen in post hoc analyses of very few events. The former observation, however, suggests that at least in patients aged 75 years or older with cardiovascular disease, G biloba may have risks and the decision to use this agent should be carefully considered. Although DeKosky and colleagues do not report results of their 2 other secondary outcomes—overall cognitive decline and functional disability—it is unlikely that a trial with no difference in dementia outcomes would yield significant benefits in the cognitive and functional impairments that define the dementia outcomes. Nevertheless, the effects of EGb 761 on actual cognitive test scores and daily function ratings are important because individuals without cognitive impairment who use G biloba may expect it to noticeably improve their intellectual function over the short term but not necessarily to prevent Alzheimer disease or other dementia over the long term.

Effect of a short- and long-term treatment with Ginkgo biloba extract on Amyloid Precursor Protein Levels in a transgenic mouse model relevant to Alzheimer’s disease

Several clinical trials have reported beneficial effects of the Ginkgo biloba extract EGb761 in the prevention and therapy of cognitive disorders including Alzheimer’s disease (AD). The aim of the present long-term feeding trial was to study the impact of dietary EGb761 on Amyloid precursor protein (APP) metabolism in mice transgenic for human APP (Tg2576). Tg2576 mice were fed diets with and without EGb761 (300 mg/kg diet) for 1 and 16 months, respectively. Long-term treatment (16 months) with EGb761 significantly lowered human APP protein levels by ∼50% as compared to controls in the cortex but not in the hippocampus. However, APP levels were not affected by EGb761 in young mice. Current data indicate that APP seems to be an important molecular target of EGb761 in relation to the duration of the Ginkgo biloba treatment and/or the age of the animals. Potential neuroprotective properties of EGb761 may be, at least partly, related to its APP lowering activity.

Ginkgo biloba extract EGb® 761 exerts anti‐angiogenic effects via activation of tyrosine phosphatases

The standardised Ginkgo biloba extract EGb 761 (Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany) is one of the most widely used herbal remedies. Indications for this extract range from dementia to peripheral vascular disease, based on well-documented vascular effects. Surprisingly, the actions of EGb 761 on angiogenesis as a function of vascular cells have not been investigated to date. The anti-cancer activity of EGb 761 in vitro and epidemiological data showing reduced risk for ovarian cancer in regular users have prompted us to investigate this issue. We show an anti-angiogenic profile of EGb 761 in vitro (inhibited proliferation, migration and tube formation of endothelial cells) and in vivo in the chicken chorio-allantoic membrane (CAM) assay. An analysis of the underlying mechanisms indicates inhibition of growth factor-induced extracellular signal-regulated kinase (ERK) phosphorylation by EGb 761. Inhibitory effects of EGb 761 on ERK as well as of the upstream kinases map-erk-kinase (MEK) and rapidly growing fibrosarcoma (Raf)-1 could be completely reversed by pre-treatment with sodium vanadate (inhibitor of tyrosine phosphatases). Sodium vanadate also reversed the EGb 761-induced inhibition of endothelial cell migration. Focusing on tyrosine phosphatases upstream of the Raf-MEK-ERK cascade, we identified the tyrosine phosphatase Src homology-2 domain-containing phosphatase 1 (SHP-1) as one target of EGb 761. SHP-1 was rapidly activated by EGb 761, and silencing SHP-1 (siRNA) abrogated reduction of endothelial proliferation by EGb 761. In summary, we identify EGb 761 as a potent anti-angiogenic drug. The underlying mechanism is the activation of protein tyrosine phosphatases, leading to inhibition of the Raf-MEK-ERK pathway. These findings provide a rational basis for using EGb 761 for an additional therapeutic indication: anti-angiogenesis-based tumour prevention and adjuvant therapy.

Effects of ginkgo biloba extract EGb761 on expression of RAGE and LRP-1 in cerebral microvascular endothelial cells under chronic hypoxia and hypoglycemia

Alzheimer's disease (AD), characterized by accumulation of amyloid-beta protein (Abeta) in brain parenchyma, is closely associated with brain ischemia. Decreased clearance of Abeta from brain is the main cause of Abeta accumulation in sporadic AD. However, the mechanisms underlying ischemia-mediated AD pathogenesis remain unclear. The receptor for advanced end glycation products (RAGE) and low-density lipoprotein receptor-related protein-1 (LRP-1) expressed at blood brain barrier (BBB) are actively involved in Abeta clearance. RAGE is thought to be a primary transporter of Abeta across BBB into the brain from the systemic circulation, while LRP-1 mediates the transport of Abeta out of the brain. Ginkgo biloba extract EGb761, a traditional Chinese medicine, has been widely used in the treatment of AD. To investigate the effects of EGb761 on the expression of RAGE and LRP-1 in endothelial cells in response to ischemic injury, we cultured bEnd.3 cells, an immortalized mouse cerebral microvessel endothelial cell line, under a chronic hypoxic and hypoglycemic condition (CHH) to mimic ischemic injury of BBB, and then treated with EGb 761. We found that EGb 761 markedly ameliorated the damage (evaluated by MTT assay) from CHH. Moreover, we demonstrated that CHH led to a significant increase in the expression of RAGE both at the mRNA and protein levels at all times (24, 36, and 48 h), conversely; CHH induced a dramatic decrease in LRP-1 mRNA and protein expression at both 36 and 48 h. The results indicated that CHH has differential effects on the expression of RAGE and LRP-1. Furthermore, EGb761 significantly reversed CHH-induced upregulation of RAGE expression and downregulation of LRP-1 expression. Our findings suggest that EGb761 favor clearance of Abeta via regulating the expression of RAGE and LRP-1 during brain ischemia. This may provide a new insight into a possible molecular mechanism underlying brain ischemia-mediated AD pathogenesis, and potential therapeutic application of EGb 761 in treatment of AD.

Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers

Heat shock response, mediated by heat shock proteins, is a highly conserved physiological process in multicellular organisms for reestablishment of cellular homeostasis. Expression of heat shock factors and subsequent heat shock protein plays a role in protection against proteotoxicity in invertebrate and vertebrate models. Proteotoxicity due to beta-amyloid peptide (Abeta) oligomerization has been linked to the pathogenesis of Alzheimer's disease. Previously, we demonstrated that progressive paralysis induced by expression of human Abeta(1-42) in transgenic Caenorhabditis elegans was alleviated by Abeta oligomer inhibitors Ginkgo biloba extract and its constituents [Wu, Y., Wu, Z., Butko, P., Christen, Y., Lambert, M.P., Klein, W.L., Link, C.D., Luo, Y., 2006. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J. Neurosci. 26(50): 13102-13113]. In this study, we apply a protective heat shock to the transgenic C. elegans and demonstrate: (1) a delay in paralysis, (2) increased expression of small heat shock protein HSP16.2, and (3) significant reduction of Abeta oligomers in a heat shock time-dependent manner. These results suggest that transient heat shock lessens Abeta toxicity by diminishing Abeta oligomerization, which provides a link between up regulation of endogenous chaperone proteins and protection against Abeta proteotoxicity in vivo.

O3-04-03: A 240-mg once-daily formulation of Ginkgo Biloba extract EGb 761 ® is effective in both Alzheimer's disease and vascular dementia: Results from a randomized controlled trial

O3-04-03: A 240-mg once-daily formulation of Ginkgo Biloba extract EGb 761 ® is effective in both Alzheimer's disease and vascular dementia: Results from a randomized controlled trial