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[The effect of Ginkgo biloba extract on neurophysiological and psychometric measurement results in patients with psychotic organic brain syndrome. A double-blind study against placebo].

The range of typical symptoms of cerebro-organic syndrome such as dizziness, memory and concentration loss, and orientation disorders can either be measured objectively within a clinical trial or can be observed subjectively. Thirty-six patients with classical symptoms of organic syndrome were recruited into a placebo-controlled double-blind trial in which the therapeutic effect of Ginkgo biloba extract EGb 761 (rökan) was measured by the following objective criteria: quantified EEG, saccadic eye movements and psychometric tests (Wiener Determination Test, Number Connection Test). Following 2 weeks' wash-out, 40 mg. EGb 761 was administered 3 times daily (= 120 mg daily dose) for 8 weeks. The control group received placebo capsules of identical external appearance. The tests listed above were carried out prior to treatment and after 4 and 8 weeks' therapy with the exception of quantitative EEG which was recorded at the beginning and end of treatment only. Patients presenting with pathological findings for at least two of the four test criteria were admitted to the trial. Patients receiving unpermitted supplementary medication or suffering from acute cardiovascular disturbances or digestive and metabolic disorders were excluded from the trial. A highly significant difference could already been seen after 4 weeks of therapy and also after 8 weeks in the results of both the saccadic test and the psychometric tests compared to the placebo control group. Saccade duration was shortened and the latency reduced. In parallel, the number of correct answers given in the Wiener Determination Test and Number Connection Test increased significantly compared to the control group. (ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Ginkgo biloba extract regulates differentially the cell death induced by hydrogen peroxide and simvastatin.

Several human diseases have been associated with the overproduction of reactive oxygen species (ROS) and subsequently various antioxidants emerged as potential therapeutic agents that scavenge ROS. As an oxidative stress model of human disease, we used hydrogen peroxide (H2O2) to study effect of ROS on C6 glioma cells as a surrogate for astrocytes. H2O2 induced dose- and time-dependent apoptotic cell death which was preceded by growth arrest, and transiently activated the signalling proteins ATF-2, ERK1/2 and AKT in C6 glioma cells. While several antioxidants failed to block H2O2-induced apoptosis of these cells, Ginkgo biloba extract (EGb) totally prevented the cell death and growth inhibition induced by H2O2. Interestingly, EGb did not prevent the activation of ATF-2, ERK1/2 and AKT induced by H2O2 excluding the role of these factors in the pro-apoptotic effect of H2O2. We have previously shown that the lipid-lowering drug, simvastatin, causes apoptotic cell death in C6 glioma cells [Koyuturk M, Ersoz M, Altiok N. Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase. Neurosci Lett 2004;370(2-3):212-7]. However, in parallel experiments with H2O2, EGb was unable to prevent cell death induced by simvastatin suggesting the involvement of separate signalling pathways between H2O2 and simvastatin. Thus, EGb and other plant flavonoids might have potential as protective agents against apoptosis through scavenging ROS upon cerebral or myocardial diseases associated with free radical generation.

Activating Transcription Factor 2↗

Inhibition of type 4 phosphodiesterase by rolipram and Ginkgo biloba extract (EGb 761) decreases agonist-induced rises in internal calcium in human endothelial cells.

The effects of Gingko biloba extract EGb 761 on 5 isolated, vascular, cyclic nucleotide phosphodiesterase (PDE) isoforms were evaluated. EGb 761 preferentially inhibited PDE4 (IC(50)=25.1 mg/L), the isoform that is mainly present in endothelial cells, in a competitive manner (K:(i)=12.5 mg/L). Because changes in cyclic nucleotide levels may affect intracellular calcium ([Ca(2+)](i)) levels in endothelial cells, we examined the effects of EGb 761 on both resting [Ca(2+)](i) levels and agonist-induced rises in [Ca(2+)](i) in single human umbilical vein endothelial cells (HUVECs) in culture. The effects of EGb 761 were compared with those of rolipram, a selective PDE4 inhibitor that increases cellular cAMP levels, and the cAMP analogue dibutyryl cAMP (db-cAMP). EGb 761 (20 and 100 mg/L), rolipram (50 micromol/L), and db-cAMP (100 micromol/L) significantly inhibited histamine-, ATP-, and thrombin-induced [Ca(2+)](i) increases in HUVECs without modifying resting [Ca(2+)](i) levels. Similar results were obtained by using a Ca(2+)-free bath solution. EGb 761 (100 mg/L), but not rolipram (50 micromol/L) or db-cAMP (100 micromol/L), also inhibited Ca(2+) influx into cells having thapsigargin-depleted internal Ca(2+) stores and bathed in a Ca(2+)-free external solution. Our results are consistent with an inhibition of PDE activity that causes a reduction of agonist-induced increases in [Ca(2+)](i) in HUVECs, mainly by inhibition of Ca(2+) mobilization from internal stores. It thus may be that the cardiovascular effects of EGb 761 involve inhibition of PDE4 activity and subsequent modification of Ca(2+) signaling in endothelial cells.

3',5'-Cyclic-AMP Phosphodiesterases↗

[Effects of Ginkgo biloba extract on a cerebral ischemia model in gerbils].

Certain anatomical characteristics peculiar to the gerbil make it the animal model best adapted to experimental pathology studies of acute ischaemia. In this animal species, devoid of any substitute vertebro-basilar vascular tissue, unilateral ligature of the carotid artery produces a cerebral ischaemia with neurological signs (well quantifiable), metabolic perturbations (especially mitochondrial) and cerebral oedema development closely resembling the symptoms revealed by physiopathology in human clinical studies. Using this model and under the experimental conditions described, clear-cut, highly significant results were obtained with Ginkgo biloba, whether by oral or intravenous administration. These results were normalization of mitochondrial respiration, diminution of cerebral oedema, correction of the accompanying ionic perturbations, and practically total functional restoration revealed by a normal neurological index in the gerbils treated with Ginkgo biloba extract.

Animals↗

[Cerebral glucose consumption. The effect of Ginkgo biloba extract].

Deoxyglucose is transported under the same conditions as glucose from blood to cerebral tissue. Deoxyglucose-6-phosphate, which cannot be neither metabolized nor eliminated, accumulates in cells. This accumulation is correlated with glucose consumption. In this study, two parameters, transfer rate of deoxyglucose and glucose consumption were measured by means of quantitative autoradiography in two experimental models: normobaric hypoxia and carotid clamping in rats. Normobaric hypoxia induced a decrease in both transfer rate and glucose consumption. Ligature of the carotid artery induced a diminution of glucose consumption greater than that of transfer rate. After administration of Ginkgo biloba extract, glucose consumption was partly reestablished in both experimental models, but the transfer rate of deoxyglucose was increased only in normobaric hypoxia.

Animals↗

In-vivo and in-vitro assessment of the free-radical-scavenger activity of Ginkgo flavone glycosides at high concentration.

Free radicals are involved in numerous skin diseases, especially inflammatory reactions and photosenescence. To identify possible free-radical scavenging by an original terpene-free Ginkgo biloba extract containing 33% Ginkgo flavone glycosides, mostly quercetin and kaempferol derivatives, we studied its activity by means of in-vitro and in-vivo experiments, using superoxide dismutase (SOD) as a positive control. By means of an in-vitro electron-spin resonance (ESR) assay we compared the activity of the Ginkgo extract with that of its two aglycones, quercetin and kaempferol. Quercetin and Ginkgo extract had significant antioxidant properties without pro-oxidant effect. In contrast, kaempferol, above an optimum antioxidant concentration, behaved as a pro-oxidant. The in-vivo experiments were conducted on an anti-inflammatory model. The cutaneous blood flux which reflects the skin inflammatory level was recorded by means of a laser Doppler perfusion imager. The data confirmed the free-radical-scavenging property of both Ginkgo extract and SOD. The Ginkgo extract significantly inhibited (37%) cutaneous blood flux to the same extent as SOD. These data confirmed the antioxidant property of Ginkgo extract. A complementary spin-trapping technique would enable identification of the free radicals involved. This Ginkgo extract should be useful for protection of the skin against free radicals.

Antioxidants↗

Neuroprotective effect of Ginkgo biloba L. extract in a rat model of Parkinson's disease.

The neuroprotective effects of a standardized extract of Ginkgo biloba L. (EGb 761) were investigated on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in the nigrostriatal dopaminergic system of the rat brain. Rats were given a week of pretreatment with daily administrations of EGb 761. Unilateral striatal injection of 6-OHDA was followed by treatment with EGb 761 for a week. Serial measurement of contralateral forepaw adjusting steps revealed a progressive deficit in motor activity. At 8 weeks after 6-OHDA lesion the number of contralateral forepaw adjusting steps was significantly higher in rats that were treated with high doses of EGb 761 (100 mg/kg daily) than in those treated with low doses (50 mg/kg) or with the vehicle. Dopamine neuron loss in the substantia nigra and a depletion in striatal dopamine corresponded with behavioural deficit. These data suggest that the neuroprotective effects of EGb 761 reduce the behavioural deficit in 6-OHDA lesions in rat and also indicates a possible role for the extract in the treatment of Parkinson's disease.

Animals↗

Complexation of Ginkgo biloba extract with phosphatidylcholine improves cardioprotective activity and increases the plasma antioxidant capacity in the rat.

The aim of this work was to compare in the rat the cardioprotective efficacy and the total plasma antioxidant activity of a standardised Ginkgo biloba L. extract (GB) as such (300 mg/kg/day) or complexed with phosphatidylcholine (GB-PC; 1:2 w/w), after a 5 days oral administration. At the end of the treatment, the total plasma antioxidant defence was determined by the TRAP and FRAP assays, and the hearts from all groups of animals subjected to moderate ischemia (flow reduction to 1 ml/min for 20 min) and reperfusion (15 ml/min for 30 min). The recovery of left ventricular developed pressure (LVDP) at the end of reperfusion was 35-40% of the preischemic values in both control and vehicle rats, 50.2% in the GB group and 72.5% in the GB-PC pre-treated animals. Creatine kinase (CK) outflow in the perfusate from the hearts of GB and GB-PC treated animals were restrained to a different extent vs. controls (by 71% GB-PC; by 22% GB); the rate of prostacyclin (6-keto-PGF1 alpha) release was far greater in GB-PC than in GB hearts. In parallel, the GB extract significantly increased the total antioxidant plasma capacity (by 24.5% TRAP; 27.9% FRAP) only when complexed with phospholipids. This indicates an increased bioavailability of phenolic antioxidants when suitably embedded within a lipophilic carrier. The results of this study demonstrate that complexation of Ginkgo biloba with phospholipids induces in the rat, even after a short treatment a greater resistance of the heart to ischemia/reperfusion damage in respect to the native extract, due to an increased plasma antioxidant activity.

Animals↗

Effects of mexiletine, ginkgo biloba extract (EGb 761), and their combination on experimental head injury.

Lipid peroxidation (LP) and brain edema are important factors that produce tissue damage in head injury. The purpose of this study was to investigate the effect of mexiletine, gingko biloba extract (EGb 761), and their combination on LP and edema after moderate head trauma. Forty rats were randomly and blindly divided into four groups of ten animals each: control group (bolus injection of physiological saline), mexiletine group (50 mg/kg per injection), EGb 761 group (30 mg/kg per injection), and mexiletine plus EGb 761 group (50 mg/kg and 30 mg/kg per injection, respectively). The injections were given intraperitoneally at 1 h, 9 h, and 17 h after trauma. Twenty-four hours after injury, the rats were killed, and malondialdehyde (MDA) levels and brain water content were determined. Rats treated with mexiletine, EGb 761, and mexiletine plus EGb 761 had significantly lower MDA levels than the control group (P<0.01). The lowest MDA levels were measured in the mexiletine plus EGb 761 group. However, there was no significant difference in brain water content between treated groups and the control group (P>0.05). These findings show the usefulness of mexiletine and its combination with EGb 761 as a cerebroprotective agent in this model of experimental head injury.

Animals↗

The Ginkgo biloba extract, EGb 761, fails to reduce brain infarct size in rats after transient, middle cerebral artery occlusion in conditions of unprevented, ischemia-induced fever.

There is much biochemical evidence, but very few studies in animal models of stroke in vivo, to suggest that Ginkgo biloba (EGb 761) may offer neuroprotection against regional, ischemic brain damage; additional investigations are needed to ensure future clinical trials. This study reports the effects of EGb 761 given acutely or chronically before ischemia. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h and the brain infarct size was assessed 24 h later. Dipyrone (100 mg/kg, i.p.) was injected 30 min before ischemia, and 2.5 and 5.5 h after ischemia, to reduce ischemia-induced fever. EGb 761 (Tebonin) was given acutely (200 mg/kg, p.o., 60 min before ischemia) or chronically (100 mg/kg, p.o., once daily, for 14 days before ischemia). Acute or chronic treatment with EGb 761, either alone or in combination with dipyrone, did not reduce the infarct size compared with saline alone (p > 0.05). Dipyrone failed to prevent ischemia-induced fever during the intra-ischemic period (p > 0.05 vs saline; p < 0.001 vs sham). In the reperfusion phase, dipyrone reduced fever to normothermic levels in the group treated acutely with EGb 761 (p < 0.01 vs saline, p > 0.05 vs sham) but not after chronic EGb 761 (p < 0.01 vs sham), indicating possible pharmacokinetic interaction. In conclusion, within the context of unprevented, ischemia-induced fever, the present results demonstrate that EGb 761 has no significant effect on brain infarct size.

Animals↗

Clastogenic factors in the plasma of Chernobyl accident recovery workers: anticlastogenic effect of Ginkgo biloba extract.

Clastogenic factors are found in the plasma of persons irradiated accidentally or therapeutically. They persisted in the plasma of A-bomb survivors over 30 years. Clastogenic factors were found in 33 of 47 Chernobyl accident recovery workers (often referred to as liquidators) in a previous study (I. Emerit et al., J. Cancer Res. Clin. Oncol. 120, 558-561, 1994). In the present study, we show that there is a positive correlation between clastogenic activity and dose and that these biomarkers of oxidative stress can be influenced successfully by appropriate antioxidant treatment. With the authorization of the Armenian Ministry of Health, 30 workers were treated with antioxidants from Ginkgo biloba leaves. The extract EGb 761 containing flavonoids and terpenoids was given at a daily dose of 3 x 40 mg (Tanakan, IPSEN, France) during 2 months. The clastogenic activity of the plasma was reduced to control levels on the first day after the end of the treatment. A 1-year follow-up showed that the benefit of the treatment persisted for at least 7 months. One-third of the workers again had clastogenic factors after 1 year, demonstrating that the process which produced clastogenic factors continued. However, the observation that antioxidants do not have to be given continuously is encouraging for intervention trials on a large-scale basis. These appear justified, since clastogenic factors are thought to be risk factors for the development of late effects of irradiation.

Adult↗

The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia.

The epidemic of late life dementia, prominence of use of alternative medications and supplements, and initiation of efforts to determine how to prevent dementia have led to efforts to conduct studies aimed at prevention of dementia. The GEM (Ginkgo Evaluation of Memory) study was initially designed as a 5-year, randomized double-blind, placebo-controlled trial of Ginkgo biloba, administered in a dose of 120 mg twice per day as EGb761, in the prevention of dementia (and especially Alzheimer's disease) in normal elderly or those with mild cognitive impairment. The study anticipates 8.5 years of participant follow-up. Initial power calculations based on estimates of incidence rates of dementia in the target population (age 75+) led to a 3000-person study, which was successfully recruited at four clinical sites around the United States from September 2000 to June 2002. Primary outcome is incidence of all-cause dementia; secondary outcomes include rate of cognitive and functional decline, the incidence of cardiovascular and cerebrovascular events, and mortality. Following screening to exclude participants with incident dementia at baseline, an extensive neuropsychological assessment was performed and participants were randomly assigned to treatment groups. All participants are required to have a proxy who agreed to provide an independent assessment of the functional and cognitive abilities of the participant. Assessments are repeated every 6 months. Significant decline at any visit, defined by specific changes in cognitive screening scores, leads to a repeat detailed neuropsychological battery, neurological and medical evaluation and MRI scan of the brain. The final diagnosis of dementia is achieved by a consensus panel of experts. Side effects and adverse events are tracked by computer at the central data coordinating center and unblinded data are reviewed by an independent safety monitoring board. Studies such as these are necessary for this and a variety of other potential protective agents to evaluate their effectiveness in preventing or slowing the emergence of dementia in the elderly population.

Aged↗

[Cardiovascular protective effects and NO-mediated cerebrovasorelaxant effects of extract of ginkgo biloba leaves].

OBJECTIVE: To examine the anti-free radical related cardiovascular protective effects and NO-mediated cerebrovasorelaxant effects of extract of the leaves of Ginkgo biloba(EGb) in isolated preparations. METHODS: Experiments on the anti-free radical related cardiovascular protective effects were performed in rabbit Langendorff heart and isolated aortic rings damaged by diphenyl-picryl hydyazyl(DPPH). Protective effects of EGb were determined by comparing the results of EGb pretreated group with the DPPH-injured controls. Cerebrovasorelaxant effects of EGb were examined in ring preparations of isolated porcine basilar artery in vitro using tissue bath techniques. RESULTS: EGb protected the isolated rabbit heart from the DPPH-injury to the cardiac contractility and the aortic endothelium from DPPH-attenuated ACh-induced relaxation. EGb concentrationde dependently relaxed the basilar artery and this effect was more significant in endothelium intact rings than those endothelium denuded rings. EGb enhanced the TNS-induced relaxation in basilar artery and this effect was abolished by pretreatment of N-nitro-L-arginine or tetrodotoxin. CONCLUSIONS: EGb exerts cardiovascular protection against DPPH-impaired cardiac contraction in rabbit isolated heart and endothelium-dependent relaxation in the aortic ring of rabbit in vitro. EGb relaxes porcine basilar artery and enhances the TNS-induced relaxation via a NO pathway.

Animals↗

Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba.

A marked increase of choline release from rat hippocampal slices was observed when the slices were superfused with oxygen-free buffer, indicating hypoxia-induced hydrolysis of choline-containing phospholipids. This increase of choline release was suppressed by bilobalide, an ingredient of Ginkgo biloba, but not by a mixture of ginkgolides. The EC50 value for bilobalide was 0.38 microM. In ex vivo experiments, bilobalide also inhibited hypoxia-induced choline release when given p.o. in doses of 2-20 mg/kg 1 h prior to slice preparation. The half-maximum effect was observed with 6 mg/kg bilobalide. A similar effect was noted after p.o. administration of 200 mg/kg EGb 761, a ginkgo extract containing approximately 3% of bilobalide. We conclude that ginkgo extracts can suppress hypoxia-induced membrane breakdown in the brain, and that bilobalide is the active constituent for this effect.

Animals↗