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Nutrients, age and cognitive function.

Many nutrients or indices of nutritional status are associated with cognitive functioning, although the size of the effects on cognitive performance may be small. Results from recent studies, however, seem consistently to indicate that supplementation with beta-carotene and alpha-tocopherol, substances that promote antioxidant vitamins A and E, respectively, can be beneficial to cognitive function in elderly people. Folate rather than vitamin B12 appears to be associated with cognitive functioning. Furthermore the daily intake of ginkgo biloba extract can enhance cognitive performance and has been proved to delay cognitive decline in dementia. A proper dietary composition with regard to the ratio of carbohydrates to proteins, as well as the inclusion of sufficient micronutrients, seems to be favourable in the maintenance of cognitive function in the elderly. Glucose can enhance cognitive function, but a rapid decline of glucose levels may impair cognitive function or may induce feelings of lack of energy. Low doses of caffeine may also enhance cognitive function, although most studies on caffeine and cognition, as with studies on glucose and cognition, have not been carried out in elderly individuals. The effects of nutritional supplements are modest but do not seem to be very different from those of medicinal or investigational cognition-enhancing or anti-dementia drugs.

Aged↗

Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants.

Ginkgo biloba extract (EGb) from the world's oldest living tree has been reputed to ameliorate cognitive decline in the elderly and slow cognitive deterioration in patients with dementia of the Alzheimer's type. EGb remains as one of the most popular plant extracts to alleviate symptoms associated with a range of cognitive disorders such as Alzheimer's disease, vascular dementia and age-related amnesic conditions. EGb is known to contain a range of chemically active components that have antagonistic effects on platelet-activating factor, free-radical scavenging activity and direct effects on the cholinergic neurotransmitter system. Recently there has been much speculation, that EGb may act as a 'smart drug' or nootropic agent in the healthy young to improve intelligence. We conducted a 30-d randomized, double-blind, placebo-controlled clinical trial in which 61 participants were administered a battery of validated neuropsychological tests before and after treatment. Statistical analysis indicated significant improvements in speed of information processing working memory and executive processing attributable to the EGb.

Adult↗

Identification of Gingko biloba flavonol metabolites after oral administration to humans.

An extract of Ginkgo biloba leaves (EGb) was given to healthy volunteers. Urine samples were collected for 3 days, and blood samples were withdrawn every 30 min for 5 h. The samples were purified through SPE C18 cartridges and analyzed by reversed-phase LC-diode array detection for the presence of EGb metabolites. Only urine samples contained detectable amounts of substituted benzoic acids, i.e., 4-hydroxybenzoic acid conjugate, 4-hydroxyhippuric acid, 3-methoxy-4-hydroxyhippuric acid, 3,4-dihydroxybenzoic acid, 4-hydroxybenzoic acid, hippuric acid and 3-methoxy-4-hydroxybenzoic acid (vanillic acid). In contrast to rats no phenylacetic acid or phenylpropionic acid derivatives were found in urine, thus indicating that in humans a more extensive metabolism takes place. As for rats the metabolites found in human urines accounted for less than 30% of the flavonoids given. The same procedure was applied to blood samples, and no metabolites could be detected.

Benzoates↗

Safety of dietary supplements: chronotropic and inotropic effects on isolated rat atria.

We investigated the effects of dietary supplements on atria isolated from male Wistar rats. The examined supplements, which are increasingly used in Japan, those were Ginkgo biloba extract (GBE), catechins, isoflavones, sodium iron chlorophyllin and sodium copper chlorophyllin. GBE at 100-1000 microg/ml significantly increased the beat rate and the contractile force. Catechins at 1-100 microg/ml significantly potentiated the contractile force but did not effect the beat rates. However, isoflavones, sodium iron and sodium copper chlorophyllins did not change the contractile force or the beat rates. To identify the active ingredient of GBE, ginkgolide B, quercetin and amentoflavone on the atria were tested. Ginkgolide B weakened the contractile force. Quercetin potentiated the contractile force at only 30 microg/ml. Amentoflavone significantly increased the beat rate. From these findings, amentoflavone and quercetin were considered to be the principal ingredients of GBE producing the positive chronotropic and inotropic actions, respectively. In the case of catechins, (-)-epigallocatechin gallate (EGCg), one of the principal ingredients, produced inotropic actions. These findings suggest that there are some dietary supplements which affect cardiac function, such GBE and catechins.

Animals↗

Stimulation of astrocytes affects cytotoxic brain edema.

Cytotoxic brain edema has been produced in rats by subacute intoxication with triethyltin (TET). Some animals were allowed to recover spontaneously, others were post-treated with an extract of Ginkgo biloba (EGB) for 1 to 4 weeks, beginning 3 days after intoxication was stopped. The time course of the resolution of the edema was studied biochemically and morphologically by light microscopy, histochemistry and electron microscopy (EM). Morphometric evaluation showed that the spontaneous reabsorption of TET-induced edema was very slow: it was evident only 2 weeks after ending TET administration and it required more than 4 weeks to be completed. EGB therapy markedly decreased the vacuolation, as well as the abnormal levels of water and sodium contents, 1 week after beginning the treatment. Less influence of EGB was observed at the later stages. During spontaneous recovery, astroglial cells in the edematous white matter of TET-intoxicated animals showed short and swollen processes containing few organelles, low levels of NADH- and NADPH-tetrazolium reductase activities and glial fibrillary acidic protein (GFAP)-immunofluorescence for about 2 weeks. During EGB therapy the astrocytes regained their cellular processes, containing intense oxidative enzyme activities and GFAP-immunofluorescence as early as after 1 week of treatment. In the EM, astrocytes often appeared hypertrophic, surrounding myelin vacuoles and displaying phagocytosis of myelin debris. We conclude that EGB can accelerate the reabsorption of TET-induced cerebral edema and improve the astroglial reaction.

Animals↗

Specific inhibition of PAF-acether-induced platelet activation by BN 52021 and comparison with the PAF-acether inhibitors kadsurenone and CV 3988.

BN 52021 is a chemically defined substance extracted from Ginkgo biloba leaves. Its inhibitory potency was tested on washed human platelets prepared so as to render them specifically sensitivity either to adenosine 5'-diphosphate (ADP), arachidonic acid (AA) or PAF-acether. Its activity and specificity were compared with those of two other reported inhibitors of PAF-acether effects: Kadsurenone and CV 3988. PAF-acether-induced aggregation of washed human platelets was concentration dependently inhibited by BN 52021 (IC50: 2.22 +/- 0.79 microM against 7.5 nM PAF-acether (n = 3)). Under the same experimental conditions the aggregation triggered by ADP was not modified and that induced by AA was marginally affected. The PAF-acether EC50 in platelet-rich plasma was increased 5- and 46-fold with 1 microM and 5 microM of BN 52021 respectively. This strongly suggested that the mechanism of action of BN 52021 is of the competitive type. Analysis of [3H]PAF-acether binding showed that BN 52021 as well as unlabelled PAF-acether prevented [3H]PAF-acether binding to intact washed platelets. In washed human platelets Kadsurenone affected only PAF-acether-induced aggregation (IC50: 0.8 +/- 0.4 microM (n = 3)), whereas CV 3988 inhibited the aggregation induced by ADP, AA and PAF-acether (IC50 were 10.2 +/- 2.3 microM; 2.2 +/- 0.1 microM; 1.0 +/- 0.1 microM respectively (n = 3). In contrast, up to 30 microM, CV 3988 was a specific antagonist of PAF-acether-induced platelet aggregation in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗

Peroxidation of synaptosomes alters the dopamine uptake complex but spares the exocytotic release of dopamine.

Synaptosomes, prepared from the striata of mice, and incubated for 1 h in a Krebs-Ringer medium with the peroxidative combination of ascorbic acid (0.1 mM)/Fe2+ (1 microM), lose their ability to take up [3H] dopamine. This effect is associated with a decrease in binding of the dopamine uptake inhibitor [3H] GBR 12783. The free radical scavenger trolox C (0.1 mM) and the Ginkgo biloba extract EGb 761 (10 micrograms/ml) prevent both effects. Although submitted to these peroxidative conditions after loading with [3H] DA, superfused synaptosomes retain their ability to release [3H] DA when depolarized by high potassium concentrations (40 mM). This release is higher than that observed when synaptosomes are incubated without ascorbic acid/Fe2+, and does not seem to depend upon peroxidation, since it is also observed when incubation is performed in the presence of the free radical scavengers EGb 761 (10 micrograms/ml) and trolox C (0.1 mM).

Analysis of Variance↗

Oxidative stress in diabetic retina.

The authors describe the alterations usually associated with diabetic retinopathy. They concern the classical thickening of the basal membrane of retinal capillaries and the associated modification of retinal vessel permeability. These alterations correspond to the blood-retinal barrier disruption. The authors then discuss the participation of oxygenated free radicals in the pathogenesis of diabetic retinopathy. They report several experimental studies establishing such a participation and finally describe their own results obtained on a model of retinas isolated from alloxan-induced diabetic rats. After one month of evolution, the electroretinograms (ERG) recorded on isolated retinas from diabetic rats had an amplitude about 20% lower than the controls, whereas after two months of diabetes, this decrease was about 60%. Under these conditions, the authors tested the protective properties of Ginkgo biloba extract (EGb 761) on their model. They observed that in EGb-treated animals (100 mg/kg/day), the ERG had a significantly (p less than 0.001) greater amplitude than untreated animals after two months of diabetes evolution. In conclusion, the authors discuss the possible utilization of a free radical scavenger, such as EGb 761, in the prevention of the retinal impairment in diabetes.

Animals↗

In vivo inhibition of plasma protein leakage and Salmonella enteritidis-induced mortality in the rat by a specific paf-acether antagonist: BN 52021.

The effects of BN 52021, a new specific paf-acether receptor antagonist and the total Ginkgo Biloba extract (GBE 761) from which this product was isolated, were studied in the rat on paf-acether-induced permeability and cell number changes and on endotoxin-induced lethality. Their activities were compared to those of cyclooxygenase, 5-lipoxygenase and phospholipase A2 inhibitors. BN 52021 given s.c. or orally exerted a dose-related inhibition of paf-acether deleterious effects as well as of endotoxin lethality whereas the other drugs tested were poorly effective. These results strongly suggest paf-acether involvement in endotoxic and septic shock.

Animals↗

Influences of Ginkgo biloba on cyclosporin A induced lipid peroxidation in human liver microsomes in comparison to vitamin E, glutathione and N-acetylcysteine.

The in vitro effect of cyclosporin A (CsA) on lipid peroxidation in human liver microsomes was investigated, and efforts were made to prevent the resulting toxic effect of CsA. Microsomes were prepared from human liver resection material and incubated with CsA (0, 10, 30, 100, 300, 1000 micrograms/mL) for one hour (pH 7.4, 37 degrees, 95% O2, 5% CO2). Subsequently the resulting concentrations of malondialdehyde equivalents (MDA) were determined, a breakdown product of lipid peroxidation. Furthermore the duration of incubation was varied (0, 15, 30, 60, 90 min) using a CsA concentration of 300 micrograms/mL. CsA was shown to stimulate MDA-formation to up to 10-fold of the control value in both a time and concentration dependent manner. The dosage dependent experiment stated above was repeated, adding alpha-tocopherol (vitamin E, 1 mM), reduced glutathione (GSH, 1 mM), N-acetylcysteine (0.1, 0.3, 1, 3 mM), and Ginkgo biloba extract (Gbe, 15, 50, 150 micrograms/mL), respectively, to the medium of incubation. Vitamin E, a potent radical scavenger, proved to inhibit lipid peroxidation almost totally. Both GSH and N-acetylcysteine were also able to prevent lipid peroxidation, suggesting that the antioxidant effect of GSH might be caused by its thiol group and does not depend on the integrity of the whole molecule. Gbe inhibited CsA induced lipid peroxidation in a concentration dependent manner. This effect of Gbe was diminished yet not totally abolished when FeCl3 was added to the medium of incubation, whereas N-acetylcysteine even slightly enhanced CsA stimulated lipid peroxidation in the presence of iron. These results suggest that Gbe might be able to prevent radical mediated damage to human membranes caused by CsA.

Acetylcysteine↗

Expression of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), and Bcl-2 protooncogene protein by Müller (glial) cells in retinal light damage of rats.

In retinal light damage, degeneration of photoreceptors may cause alterations of glial (Müller) cells. We performed immunocytochemical studies on Müller cells isolated from retinae of rats exposed to enhanced illumination for 24 months, a procedure which leads to complete loss of photoreceptor cells. One group of rats was fed daily with Ginkgo biloba extract (EGb 761, an established free radical-scavenger) during the last 8 months of life when the remaining photoreceptors (about 50%) die. We found that (1) Müller cells respond to photoreceptor damage by increased expression of glial fibrillary acidic protein, (2) Müller cells reduce expression of glutamine synthetase when the major glutamate-releasing neurons are lost, and (3) the application of exogenous free radical scavengers prevents the expression by Müller cells of the protooncogene protein Bcl-2, a molecule assumed to activate endogenous free radical-scavenging activities.

Animals↗

Intratympanic dexamethasone injection effects on transient-evoked otoacoustic emission.

PURPOSE: To investigate the effects of intratympanic dexamethasone injection, which is done because of tinnitus, on transient evoked otoacoustic emission (TEOAE) and so determine whether given dexamethasone cause any damage in the inner ear. PATIENTS AND METHODS: Twenty-six patients, aged between 32 and 75, with subjective tinnitus, were randomly selected. The selected patients were the ones whose improvement had not been achieved through minimum 6 months' medical therapy (eg, Ginkgo biloba extract EGb 761, betahistidine, and trimetazidin) and who were free of systemic or otolaryngologic disease (hypertension, diabetes mellitus, hypo/hypertyroidi, hypercholesterolemia, Meniere disease, and otosclerosis). Before and after the injections, audiometry including high-frequency tinnitus matching and TEOAE tests were done. The injections of 4 mg/mL dexamethasone were done 5 times in fixed protocols on days 0, 2, 4, 6, and 8. After each injection, the patients were kept supine for 60 minutes with the head turned 45 degrees to opposite ear. Paired t test was used to compare the beginning and final measurements. RESULTS: Temporary pain and vertigo attacks which lasted at most for 15 minutes occurred in some patients only during injections. Neither infection nor persistent perforation occurred in any patients. After the management, there was no significant difference on patient's pure tone averages ( P = .067) and high-frequency averages ( P = .592). When the obtained TEOAE results before and after management were compared, the only significant increase was detected in the reproducibility values ( P = .042). There was no significant difference in other TEOAE parameters which are stimulus stability, stimulus intensity, and overall signal-to-noise ratio ( P > .05). There is no fixed criteria for rejecting a response solely on the reproducibility. However, a high value of the reproducibility (or increase in reproducibility) is always meaningful. CONCLUSION: Intratympanic dexamethasone used for management in many indications, primarily in Meniere and tinnitus patients, was found to increase the reproducibility values of otoacoustic emission. Despite the fact that there was not a reasonable increase in the responses coming from the outer hair cells, the result was considered positive for the study as the responses did not decrease. It is found out that 4 mg/mL dexamethasone given intratympanically does not adversely affect the outer hair cell function as measured by otoacoustic emission. Within the limits of this study, dexamethasone appears to be safe when given intratympanically.

Adult↗

Effects of Ginkgolide on the development of NOS and AChE positive neurons in the embryonic basal forebrain.

Extract of Ginkgo biloba (EGb) has been therapeutically used for several decades to increase peripheral and cerebral blood flow so as to prevent cardiovascular and neurovascular diseases. However, the role of EGb in neuroprotective effects has received much attention recently. In this study, we investigated the effect of EGb on the development of NOS and AChE positive neurons in the rat embryonic basal forebrain. The results showed that treated with EGb, the OD of MTT staining analysis, and the numbers, the cell sizes and circumferences of NOS and AChE positive neurons were greatly promoted. These data suggest that EGb had similar effects of the neurotrophins such as NGF and BDNF in promoting the development of NOS and AChE positive neurons in the rat embryonic basal forebrain.

Acetyl Coenzyme A↗

Central role of PKCdelta in glycoxidation-dependent apoptosis of human neurons.

Accumulation of advanced glycation end products (AGEs) induces alterations in the intracellular redox balance, leading cells to functional injury. Current literature reports that intracellular signaling triggered by the interaction of AGEs with their specific receptors RAGEs depends on the cell type and the state of activation/stress. In this work, NT2 human neurons were exposed for 48 h to glycated fetal serum containing 750-3000 pmol/ml pentosidine; the treatment induced an increase in apoptosis rate linear with AGE concentration up to 1500 pmol/ml, but necrotic death was elicited with the highest AGE amount employed (3000 pmol/ml pentosidine). Pentosidine at 1500 pmol/ml, which was the concentration responsible for the highest apoptotic effect (40% of apoptotic neurons), was able to determine early generation of intracellular reactive oxygen species and increase in RAGE levels. Under these conditions, protein kinase C (PKC) delta activity was increased approximately 2-fold, and DNA binding activity of redox-sensitive transcription factor activator protein-1 (AP-1) was enhanced 2.5-fold. A relationship among oxidative stress, PKCdelta activity, AP-1 activation, and apoptosis was demonstrated by pretreating neurons with 500 muM vitamin E, with 20 mug/ml Ginkgo biloba extract, or with 3 muM Rottlerin, inhibitor of PKCdelta; these pretreatments were able to protect neurons from the glycoxidation-dependent effects.

Acetophenones↗

Sensitive and selective liquid chromatography-electrospray ionization mass spectrometry analysis of ginkgolide B in dog plasma.

As an important active constituent of Ginkgo biloba extract, ginkoglide B is a highly selective and competitive PAF receptor antagonist which has been widely used in clinical applications. A novel high-performance liquid chromatography-electrospray ionization mass spectromentry (LC-ESI-MS) method was developed for the determination of ginkgolide B in dog plasma. After liquid/liquid extraction with ether and high-performance liquid chromatography (HPLC) gradient separation with 0.01% of ammonia water (v/v)-methanol as the mobile phase, the deprotonized anions [M-H](-1) at m/z 423 of ginkoglide B, and [M-H](-1) at m/z 492 of internal standard (IS) glibenclamide were analyzed by LC-ESI-MS in selected ion monitoring (SIM) mode. Chromatographic separation was achieved in less than 9 min and calibration curve was linear over a concentration range of 0.1-20 ng/ml. The described assay method was successfully applied to the pre-clinical pharmacokinetic study of ginkoglide B. After intragastric administration of ginkgolide B to beagle dogs, C(max) and T(max) of ginkgolide B were 43.8 +/- 6.24 ng/ml and 0.5 h, respectively, and the elimination half-life (t(1/2)) was 2.85 +/- 0.54 h.

Animals↗

Bilobalide prevents ischemia-induced edema formation in vitro and in vivo.

EGb761, a standardized extract of Ginkgo biloba, has neuroprotective properties in animal models of ischemia, an activity that is partially attributed to its constituent, bilobalide. EGb761 has also been reported to inhibit edema formation induced by toxins such as triethyltin. The goal of this study was to test the activity of pure bilobalide to prevent edema formation in models of ischemia. Oxygen-glucose deprivation (OGD) in rat hippocampal slices served as a model of in vitro-ischemia. OGD caused cellular edema formation as indicated by an increase of slice water contents in 30 min. Bilobalide (1-10 microM) reduced slice water contents in ischemic slices in a concentration-dependent manner. As a model of in vivo-ischemia, we performed middle cerebral artery occlusion (MCAO) in mice. Permanent MCAO caused cell death and swelling of the ischemic hemisphere within 24 h. Pretreatment of the mice with bilobalide (10 mg/kg i.p.) reduced infarct area by 43% (as judged by 2,3,5-triphenyl-tetrazolium chloride (TTC) staining) and edema formation by 70% (as judged by hemispheric enlargement). In parallel experiments, pretreatment with bilobalide also reduced forebrain water contents in the ischemic hemisphere by 57%. As an alternative model of brain edema formation, we used water intoxication to increase brain water content; bilobalide, was, however, inactive in this model. We conclude that bilobalide strongly and specifically attenuates edema formation in models of brain ischemia in vitro and in vivo. Bilobalide may be therapeutically effective in brain edema which occurs secondarily to large hemispheric stroke and traumatic brain injury in humans.

Animals↗

Complementary therapy for the treatment of glaucoma: a perspective.

Although neuroprotective strategies and pharmaceutical agents have been initiated in the treatment of numerous disorders of the central and peripheral nervous systems, including trauma, epilepsy, stroke, Huntington disease, amyotrophic lateral sclerosis,and AIDS dementia, none have yet been applied to the treatment of glaucoma. A prospective, placebo-controlled, multi-institutional trial of memantine is underway. One would not expect the treatment modalities that form the bases of nonpharmaceutical, traditional medical systems to be used to lower IOP. Glaucoma was unknown when these medicinal treatments were developed over the centuries. Their primary use is in improving the cardiovascular and immune systems and in what is now called neuro-protection. Rather than single compounds that target a specific receptor and have demarcated side effects in other systems, plant products are a blend of many compounds and, according to those most versed in them, they achieve a balanced therapy, helping in specific symptomatic complexes while reducing side effects through ameliorating effects in other areas. It is not insignificant that, now that the rain forests are rapidly dwindling, together with their inhabitants and the knowledge of medicinal plants (especially in South America), the pharmaceutical companies are spending large amounts of money in a sudden, almost frantic attempt to gather the knowledge about rainforest plants before all has been completely lost. Proof of effects clinically in a chronic disease such as glaucoma remains largely lacking, and controlled trials are unlikely to be initiated, except perhaps through the National Institutes of Health, because these compounds have been in the public domain for many years. Perhaps those as yet unknown or un-recorded are patentable and perhaps these include drugs known only to small surviving communities of hunter-gatherers, which explains the pharmaceutical interest in these areas. When more accurate and rapid means of assessment of progression of glaucomatous damage than perimetry and optic nerve head photography are eventually developed and trials can be reduced in time, number of subjects, or even the use of nonhuman subjects for the bulk of studies, studies could be done for verification of effect of various compounds and also comparative studies. At the present time, GBE is the best documented of all the complementary medicinal agents and seems to have the greatest potential value. Ginkgo biloba extract has numerous properties that theoretically should be beneficial in treating non-IOP-dependent mechanisms in glaucoma. Its multi-ple beneficial actions, including increased ocular blood flow, antioxidant activity, platelet activating factor inhibitory activity, nitric oxide inhibition, and neuroprotective activity, combine to suggest that GBE could prove to be of major therapeutic value in the treatment of glaucoma.

Complementary Therapies↗

[Stevens-Johnson syndrome/toxic epidermal necrolysis treated with intravenous immunoglobulins].

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are part of the same disease spectrum, but are differentiated by the degree of skin detachment. In TEN, more than 30 % of the body's surface area is affected; thus, it is a serious process, whose frequency is estimated at 1.2-6 cases per million population/year. We describe the case of a 75-year-old male who suffered from SJS which evolved into TEN, probably because of the ingestion of ginkgo biloba extract. He was treated with intravenous immunoglobulins (Ig IV) at a dose of 0.5 g/kg/day for five consecutive days, with favorable progress and no significant side effects. It is evident that isolated cases do not justify the systematic use of this treatment, but they may help build up experience.

Aged↗