Action Of Ginkgo Biloba Extract Research Articles

Препараты гинкго билоба: по пути открытий в клинической нейрофармакологии

В статье приведены наиболее актуальные и современные данные об основных механизмах действия экстракта гинкго билоба: нейромедиаторных, нейрометаболических и вазотропных эффектах. Популярность экстракта гинкго билоба в неврологии связана с его эффективностью и безопасностью.

Застосування екстракту гінкго білоба в системі реабілітації хворих, які перенесли інсульт

Стаття присвячена актуальній проблемі лікування хворих, які перенесли інсульт. Розглянуто склад і механізм дії екстракту гінкго білоба, а також дані про ефективність і безпеку екстракту у хворих, які перенесли транзиторну ішемічну атаку або гостре порушення мозкового кровообігу, що дає авторам підставу рекомендувати включення екстракту гінкго білоба в систему фармакологічної реабілітації хворих на ішемічний інсульт.

Cardioprotective Action of Ginkgo biloba Extract against Sustained β-Adrenergic Stimulation Occurs via Activation of M2/NO Pathway.

Ginkgo biloba is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of Ginkgo biloba on cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of Ginkgo biloba-mediated neuroprotection, we aimed to investigate whether Ginkgo biloba extract (GBE) promotes cardioprotection via activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M2) and downregulation of β1-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection in vivo, we performed in vitro studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs via activation of M2/NO pathway uncovering a new mechanism involved in the cardioprotective action of Ginkgo biloba.

The chemopreventive effect of Ginkgo biloba extract 761 against cisplatin ototoxicity: a pilot study

The purpose of this study was to evaluate, by using distortion product otoacoustic emission test, the action of Ginkgo biloba extract 761, which has a known antioxidant property, as a possible otoprotective against cisplatin induced hearing loss. This prospective and double blinded study was conducted on individuals that were to begin cisplatin treatment in a tertiary university center. They were randomized and allocated in two groups: control group (CG) (n = 07) receiving placebo and cisplatin and study group (SG) (n = 08) receiving Ginkgo biloba extract 761 (240 mg/day) and cisplatin. This prospective study was conducted on individuals that were treated by cancer with cisplatin (CDDP) in a tertiary University center. Both groups were instructed to ingest the either placebo or Ginkgo biloba extract 761 before the first cisplatin dose. They were rated and followed up for approximately 90 days. The maximum cumulative cisplatin dosage was 300 mg/m(2). The ototoxic effect was measured with distortion product otoacoustic emissions. Distortion product otoacoustic emissions were recorded before the first cisplatin cycle, 30, 60 and 90 days after the treatment. The average of the amplitude of the signals were calculated and used for comparisons between the groups. Comparisons were made between baseline measurements and those recorded after maximum cumulative CDDP dose. The control group showed smaller distortion product otoacoustic emissions mean amplitudes and smaller signal/noise ratio than the study group (p < 0.05). Ginkgo biloba extract 761 probably has antioxidant properties, and might play otoprotective effect against cisplatin ototoxicity in these patients.

Long-Term Feeding of Ginkgo biloba Extract Impairs Peripheral Circulation and Hepatic Function in Aged Spontaneously Hypertensive Rats

We previously demonstrated that Ginkgo biloba extract (GBE) produces an anti-hypertensive effect via enhanced vasodilation responses in young spontaneously hypertensive rats (SHR) and hepatic hypertrophy occurs with increased cytochrome P450 (CYP) mRNA expression in young rats. In the present study, to clarify whether these actions of GBE are observed in older rats, we investigated cardiovascular functions and hepatic CYP protein expressions in aged SHR fed a control diet or a diet containing 0.5% GBE for 4 weeks. In aged SHR, GBE feeding significantly increased liver weight per 100 g body weight without changing the body weight. Furthermore, significant increases in alanine aminotransferase level in serum and marked increase in CYP2B protein expression in the liver were observed in aged SHR fed GBE. On the other hand, GBE feeding did not affect blood pressure, but significantly reduced heart rate and blood flow velocity in tail arteries of aged SHR. Furthermore, GBE feeding did not affect contractile response to phenylephrine, relaxation responses to not only sodium nitroprusside but also acetylcholine, and protein levels of endothelium nitric oxide synthase and soluble guanylate cyclase in aortas of aged SHR. These results suggested that long-term GBE feeding impairs peripheral circulation due to bradycardia and hepatic function in aged SHR. Thus, in the elderly population with hypertension, the use of GBE may need to be assessed for effects on heart rate and liver function.

Evaluation of the effect of Ginkgo biloba extract (EGb 761) on the myenteric plexus of the small intestine of Wistar rats

The aging process causes a reduction in the myenteric neuronal population, related to oxidative stress, resulting in malfunctioning of the digestive tract. The purpose of this study was to evaluate the action of Ginkgo biloba extract (EGb 761), an important antioxidant drug, on the myenteric plexus of the jejunum and ileum of rats after treatment for 120 days. Fragments of the jejunum and ileum were collected from three groups of rats: a 90-day-old group (group Y), a 210-day-old group (group A), and a 210-day-old group treated daily with the extract EGb 761 (50 mg/kg body weight) (group TA). The analysis was carried out by using the myosin-V immunohistochemical technique. Neuronal densities were estimated, and a study of the neuronal profile area of 500 neurons from each group was carried out. In the jejunum, there was a significant neuronal population reduction of 17% only in group A compared with group Y. In the ileum, there was a significant neuronal reduction of 36% in group A compared with group Y, and a significant reduction in group TA of 20%. The difference in the reduction between groups A and TA in the ileum was also significant. In the jejunum, only group A showed a significant increase in neuronal profile area, but in the ileum, there was a significant increase in both groups A and TA. A daily dose of 50 mg/kg body weight of Ginkgo biloba extract has a significant neuroprotector effect on the myenteric plexus of the ileum during the aging process in rats.

Paradoxical effects of ginkgolide B on cardiomyocyte contractile function in normal and high-glucose environments

Ginkgo biloba extract is a natural product used widely for cerebral and cardiovascular diseases. It is mainly composed of terpene lactones (ginkgolide A and B) and flavone glycosides (eg quercetin and kaempferol). To better understand the cardiac electromechanical action of Ginkgo biloba extract in normal and diabetic states, this study was designed to examine the effect of ginkgolide B on cardiomyocyte contractile function under normal and high-glucose environments. Isolated adult rat ventricular myocytes were cultured for 6 h in a serum-free medium containing either normal (NG; 5.5 mmol/L) or high (HG; 25.5 mmol/L) glucose with or without ginkgolide B (0.5-2.0 microg/mL). Mechanical properties were evaluated using the IonOptix MyoCam system. Contractile properties analyzed included peak shortening (PS), maximal velocity of shortening/relengthening (+/-dl/dt), time-to-PS (TPS) and time-to-90% relengthening (TR90). Levels of essential Ca(2+) regulatory proteins sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), phospholamban (PLB) and Na(+)-Ca(2+) exchanger (NCX) were assessed by Western blotting. Ginkgolide B nullified HG-induced prolongation in TR90. However, ginkgolide B depressed PS, +/-dl/dt and shortened TPS in NG and HG cells. Ginkgolide B also prolonged TR90 in NG cells. Western blot analysis revealed that HG upregulated SERCA2a and downregulated PLB expression without affecting that of NCX. Ginkgolide B disrupted the NG-HG response pattern in SERCA2a and NCX without affecting that of PLB. Ginkgolide B affects cardiomyocyte contractile function under NG or HG environments in a paradoxical manner, which may be attributed to uneven action on Ca(2+) regulatory proteins under NG and HG conditions.

Age-related changes in the vasodilating actions of Ginkgo biloba extract and its main constituent, bilobalide, in rat aorta

Background Age-related modulation in vasodilating actions induced by Ginkgo biloba extract (GBE) and bilobalide, a main constituent of GBE, were examined using rat aorta ring strips. Methods Wistar rats from 5 to 25 weeks old were used, and the isolated aorta ring strips were fixed in Krebs–Henseleit solution. Results GBE and bilobalide concentration-dependently dilated norepinephrine (NE)-induced vasoconstriction in all aged rats. The vasodilating actions generally decreased in accordance with aging. GBE at 1 mg/ml decreased from 28.4±3.8% ( n=5) in 5-week-old rats to 23.7±7.1 ( n=7) in 25-week-old rats, but not significantly. GBE (3 mg/ml)-induced vasodilation was maximum by 73.7±2.1% ( n=4, P<0.001) in 10-week-old rats. GBE had the marked vasodilation at younger ages and further decreased it with developing ages. In the rats older than 20 weeks, however, GBE tended to rather increase the strength of vasodilating action. On the other hand, the vasorelaxation induced by 30 μmol/l bilobalide significantly decreased from 11.8±1.4% ( n=4) in 5-week-old rats to 2.3±1.5% ( n=5, P<0.01) in 25-week-old rats, and by 100 μmol/l from 20.2±3.4% ( n=4) to 5.6±2.5% ( n=5, P<0.01), respectively. Bilobalide had the similar age-related actions. The age-dependent attenuation was produced milder by bilobalide than by GBE. At lower concentrations, however, bilobalide caused the weak vasocontriction in 20- and 25-week-old rats. Conclusion GBE and bilobalide possess a similar characteristic for age-related modification, clinically suggesting the more effective actions of GBE for elder persons.

Mechanisms for the vasodilations induced by Ginkgo biloba extract and its main constituent, bilobalide, in rat aorta

Vasodilating actions of Ginkgo biloba extract (GBE) and bilobalide, a main constituent, were examined using rat aorta ring strips. GBE at the concentration ranges from 0.03 to 3 mg/ml had a potent concentration-dependent relaxation, reaching 70 ± 4.5% (n = 6, P < 0.001) at 3 mg/ml. Bilobalide at 0.1 to 100 μM also caused the relaxation in a concentration-dependent manner. At 100 μM, bilobalide caused dilation by 17.6 ± 3.9% (n = 7, P < 0.05). NG-monomethyl-L-arginine acetate (L-NMMA)(100 μM), an NO synthesis inhibitor, reduced the vasodilation of GBE (3 mg/ml) to 57.6 ± 2.5% (n = 6, P < 0.05), and was accompanied with a decrease in the rate of relaxation. Tetraethylammonium (TEA)(100 μM), a Ca 2+-activated K + channel inhibitor, also decreased the GBE (3 mg/ml)-induced relaxation to 63.1 ± 4.6% (n = 6), but not significantly. Indomethacin tended to reduce the GBE (3 mg/ml)-induced vasorelaxation to 67.3 ± 4.1% (n = 6). In contrast, the vasorelaxation of GBE (3 mg/ml) was strongly attenuated to 53 ± 6.1% (n = 7, P < 0.05) in Ca 2+-free medium. Similarly, the vasorelaxation induced by bilobalide significantly decreased both by pretreatment with NO inhibitor (L-NMMA) and in Ca 2+-free solution. These results indicate that the relaxation induced by GBE would be due to the inhibition of Ca 2+ influx through the Ca 2+ channel and the activation of NO release, and might be in part due to the inhibitions of Ca 2+-activated K + current and PGI 2 release, in the endothelium and aortic vascular muscles. Bilobalide possesses the similar mechanisms for the vasodilation.

Induction of glutathione synthesis in human keratinocytes by Ginkgo biloba extract (EGb761).

The objective of the present study was to characterize the action of Ginkgo biloba extract (EGb761) and its sub-fractions on glutathione homeostasis in a human keratinocyte cell culture model. Cells were incubated with EGb761, its purified flavonoid (quercetin, kaempferol, rutin) or terpenoids (gingkolides A, B, C, J, bilobalide) constituents or the vehicle for up to 72 hours. Incubation of keratinocytes with the purified flavonoids or terpenoids did not affect cellular GSH levels. However, EGb761 treatment (up to 200 microg/ml) resulted in a dose-dependent increase of cellular GSH. Western blot analysis of extracts from cells treated with EGb761 revealed increased levels of the catalytic subunit of gamma-glutamylcysteinyl synthetase (gamma-GCS), the rate-limiting enzyme in GSH synthesis. The abundance of mRNA for the catalytic subunit (assayed by RT-PCR) was also increased by the treatment with EGb761. Increased levels of cellular GSH by EGb761 were also observed in other cell lines including those from human bladder and liver as well as in murine macrophages indicating that the induction of gamma-GCS mRNA, protein and GSH may be an ubiquitous effect of EGb761 in mammalian cells.

Effects of Ginkgo biloba extract on cognitive function and blood pressure in elderly subjects

In this randomized, double-masked study, we assessed the effects of a Ginkgo biloba (GB-8) extract on elderly volunteers with age-related cognitive dysfunction. A total of 260 subjects were tested to obtain a homogeneous group of 60 elderly subjects with mild-to-moderate cognitive impairment, as defined by a clinical rating scale. The subjects were allocated to one of three groups and received either GB-8 40 mg or 80 mg or placebo three times daily for 3 months. Before therapy was started and after 1 and 3 months of treatment, standardized testing of attention, concentration, and memory was performed. The subjects completed self-assessments before and after 3 months of therapy, and arterial blood pressure was measured at the same intervals. Clinical ratings were done before and after 3 months of treatment. Six subjects withdrew from the study, whereas 54 subjects (31 women and 23 men; mean age, 74 years; age range, 61 to 88 years) completed the study. After randomization, the groups were similar with respect to age, social class, level of education, and demographic characteristics. Objective test results showed that attention, concentration, and short-term verbal memory improved significantly in subjects receiving the low-dose (standard) treatment. Similar improvements were seen in the results of the self-assessment test and the clinical rating. Diastolic blood pressure decreased significantly during low-dose treatment. Treatment with the GB-8 extract was found to improve objective measures of cerebral function in elderly subjects with mild-to-moderate cognitive impairment; the improvement appeared to be clinically relevant. The possible antihypertensive action of Ginkgo biloba extract is sufficient to warrant further investigation

Effect of the antioxidant action of Ginkgo biloba extract (EGb 761) on aging and oxidative stress.

Aging is responsible for oxidative damage to DNA, protein, lipid, and other macromolecules linked to tissue alterations. The resultant damage contributes significantly to degenerative diseases, to include those of the brain, sensorial tissues, and cardiovascular system. To protect cellular components from oxyradical attack, especially lipoperoxidation, a substantial interest in the use of antioxidants has evolved. A free radical scavenger, Ginkgo biloba extract (EGb 761) may be effective in fighting the oxidative stress related to aging. Many data support the efficacy of EGb 761 in biological model systems. In aging processes, EGb 761 may ameliorate the mitochondria respiratory chain function by quenching the superoxide anion, and the hydroxyl and peroxyl radicals. It protects the brain by facilitating the uptake of neurotransmitters and by reducing ischemia-reperfusion episodes and level of apoptosis. Moreover, in sensorial tissues, EGb 761 reduces apoptosis in the olfactive bulb and in the retinal pigmented epithelium of the eye, and protects against the lipoperoxidation alteration of the retina that results in a decrease of the electroretinogram response. In the cardiovascular system, by a direct effect on oxidative low density lipoproteins, EGb 761 may decrease atherosclerosis evolution, and is shown to accelerate cardiac mechanical recovery after ischemia-reperfusion. In conclusion, the antioxidant effects of EGb 761 noted in many experimental data, may explain the therapeutic efficacy observed in clinical trials of the elderly. These beneficial properties seem in part to come from the activity of EGb 761 constituents, such as flavonoids and terpens.

Ginkgo biloba attenuates oxidative stress in macrophages and endothelial cells

The action of Ginkgo biloba extract (GBE) as an antioxidant was studied using various models of oxidative stress in macrophages and vascular endothelial cells. GBE was incubated with murine macrophages (J774) at 37°C and 5% CO 2 for 1 h; oxidative burst was triggered by zymosan. The intensity of fluorescence was measured directly in 96-well plates using a computerized microplate fluorometer at 485 nm excitation and 530 nm emission. GBE exhibited both time- and concentration-dependent suppression of oxidative burst. Confluent monolayers of bovine pulmonary artery endothelial cells (PAEC) were preincubated with different concentrations of GBE for 16 h, washed, and then exposed to an organic oxidant tert-butyl hydroperoxide (tBHP) for 2 h. Lipid peroxidation products of PAEC were determined by measuring thiobarbituric acid-reactive substances (TBARS). Cell injury was assessed by measuring the release of intracellular lactate dehydrogenase (LDH), and cell viability was determined by the methylthiazol tetrazolium (MTT) assay, tBHP increased production of TBARS in PAEC. Preincubation with GBE inhibited the increase of TBARS induced by tBHP. GBE protected biomembranes from oxidative injury by decreasing intracellular LDH leakage from PAEC. MTT assay showed that GBE minimized loss of cell viability induced by oxidative injury. The extensive antioxidant effect of GBE may be valuable to the prevention and treatment of various disorders related to free radical-induced pathology.

Superoxide anion scavenging effect and superoxide dismutase activity ofGinkgo biloba extract

Ginkgo biloba extract is known to be efficient in diseases associated with free radical generation. The purpose of this work was to study, under in vitro conditions, the action of Ginkgo biloba extract (Gbe) against superoxide anion (O2-.), which is directly or indirectly implicated in cell damage. Gbe appears to have both an O2-. scavenging effect and also a superoxide dismutase activity. Its antiradical effect was demonstrated by low temperature electron spin resonance and in a non-enzymatic system (phenazine methosulfate-NADH), and its enzymatic activity was shown by polarographic determination.

Sympathetic nerves protect against blood-brain barrier disruption in the spontaneously hypertensive rat.

SUMMARY The cerebral vessels of spontaneously hypertensive rats (SHR) are reported to have an in­ creased luminal size and decreased wall thickness after chronic sympathetic denervation. In order to evaluate a possible physiological significance of this observation, we studied blood-brain barrier protein transfer in two month old SHR and their normotensive controls, Wistar-Kyoto (WKY), during profound vasodilation stimuli one month after a unilateral superior cervical ganglionectomy. Our hypothesis was that during acute vaso­ dilation, protein transfer, which is dependent on vessel tension (tension = pressure X radius/wall thickness), would be greater in the vasculature of the chronically denervated (De) than in contralateral innervated hemi­ sphere (In). Vasodilation was induced with acute hypertension (norepinephrine) and seizures (bicucilline). Immediately prior, the cervical trunk to the innervated hemisphere was sectioned to prevent acute sympathetic neuronal effects. Protein transfer was assessed qualitatively with Evans blue dye and quantitatively with radio­ iodinated albumin. Successful chronic denervation was demonstrated by the absence of histofluorescence in De. Evans blue dye staining of SHR (n = 3) cerebral hemispheres was greater in De than in In. Radioiodinated albumin protein transfer was elevated in SHR De compared to In in each of eight animals studied (De-In = 0.16 ± 0.04%*, *p < 0.01); WKY (n = 8) De protein transfer was not different from In (De-In = 0.07 ± 0.05%). These results suggest that the trophic influence of sympathetic nerves on SHR cerebral vessels con­ tributes to protection of the blood-brain barrier during hypertension and seizures.