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A concise synthesis of ginkgolide M, a minor component of a terpene trilactone fraction from ginkgo biloba roots.

Ginkgolide M (GM), which is found only in the roots of the Ginkgo biloba tree and is an inhibitor of ligand-operated ion channels in the central nervous system, has been prepared in three steps from 10-benzylginkgolide C, an intermediate generated during the isolation and separation of ginkgolides from Ginkgo biloba leaf extract. The described synthetic sequence can be applied to access GM derivatives for biological studies.

Diterpenes↗

[Chemical constituents of the leaves of Ginkgo biloba].

Four compounds were isolated from ethyl acetate extract of the leaves of Ginkgo biloba. Compounds II, III, IV were identified as ginkgolides A, B and C respectively, Compound I, which was obtained from the leaves of G. biloba for the first time, was identified as 3,3'-dimethoxy-4,4'-dihydroxy-stilbene by spectroscopic methods.

Diterpenes↗

The memory-enhancing effects of Ginseng and Ginkgo biloba in healthy volunteers.

RATIONALE: The use of herbal remedies, such as Ginkgo biloba and Ginseng, for improving cognitive performance has become increasingly popular during recent years. Several previous studies have indicated that administration of Ginkgo biloba and Ginseng may improve aspects of learning and memory in healthy volunteers. These results, however, are generally not supported by well-controlled clinical studies. Also, positive results have often been reported from studies investigating effects related to short-term, chronic administration of the extract. Nonetheless, both Ginkgo biloba and Ginseng are marketed as having the capacity to enhance cognitive functions, such as memory and learning, in the long term. OBJECTIVE: This study aimed at investigating whether the use of Ginkgo biloba and Ginseng for a long period of time has positive effects on performance on learning and memory. METHODS: Community-dwelling volunteers ( n=3500) from The Betula prospective cohort study: memory, health, and aging were included in the study. RESULTS: It was found that the use of neither Ginkgo biloba ( n=40) nor Ginseng ( n=86) was associated with enhanced memory performance in any of the eight memory tests examined, relative to control groups either using or not using nutritional supplements. CONCLUSIONS: These findings indicate that use of Ginkgo biloba or Ginseng does not provide any quantifiable beneficial effects on memory performance in the long-term in healthy adult volunteers.

Adult↗

A placebo-controlled, double-blind trial of Ginkgo biloba for antidepressant-induced sexual dysfunction.

The aim of this study was to examine the effect of Ginkgo biloba on antidepressant-induced sexual dysfunction. The Ginkgo biloba (n=19) and the placebo groups (n=18) were divided; each to be administered with Ginkgo biloba and placebo respectively for 2 months by means of a randomized placebo-controlled, double-blind study. The results of this 2 month trial were: (1) there was no statistical significant difference from the placebo at weeks 2, 4 and 8 after medication; (2) in comparison with baseline, both the Ginkgo biloba group and the placebo group showed improvement in some part of the sexual function, which is suggestive of the importance of the placebo effect in assessing sexual function. This study did not replicate a prior positive finding supporting the use of Ginkgo biloba for antidepressant, especially SSRI, induced sexual dysfunction.

Antidepressive Agents↗

Bilobalide and neuroprotection.

In vivo studies have indicated that systemically administered bilobalide, a sesquiterpene trilactone constituent of Ginkgo biloba leaf extracts, can reduce cerebral edema produced by triethyltin, decrease cortical infarct volume in certain stroke models, and reduce cerebral ischemia. In vitro and ex vivo studies indicate that bilobalide has multiple mechanisms of action that may be associated with neuroprotection, including its preservation of mitochondrial ATP synthesis, its inhibition of apoptotic damage induced by staurosporine or by serum-free medium, its suppression of hypoxia-induced membrane deterioration in the brain, and its actions of increasing the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome c oxidase and the ND1 subunit of NADH dehydrogenase. As multiple modes of action may apply to bilobalide, it could be useful in developing therapy for disorders involving cerebral ischemia and neurodegeneration.

Animals↗

Efficacy, safety, and use of ginkgo biloba in clinical and preclinical applications.

Ginkgo biloba is a dioecious tree with a history of use in traditional Chinese medicine. Although the seeds are most commonly employed in traditional Chinese medicine, in recent years standardized extracts of the leaves have been widely sold as a phytomedicine in Europe and as a dietary supplement in the United States. The primary active constituents of the leaves include flavonoid glycosides and unique diterpenes known as ginkgolides; the latter are potent inhibitors of platelet activating factor. Clinical studies have shown that ginkgo extracts exhibit therapeutic activity in a variety of disorders including Alzheimer's disease, failing memory, age-related dementias, poor cerebral and ocular blood flow, congestive symptoms of premenstrual syndrome, and the prevention of altitude sickness. Due in part to its potent antioxidant properties and ability to enhance peripheral and cerebral circulation, ginkgo's primary application lies in the treatment of cerebrovascular dysfunctions and peripheral vascular disorders.

Antioxidants↗

Preparative isolation of terpene trilactones from Ginkgo biloba leaves.

This study investigated and compared some techniques for the preparative isolation of terpene trilactones, including ginkgolides (GA and GB, etc.) and bilobalide (BB), from Ginkgo biloba leaves. The crude Ginkgo biloba L. extracts (GBE) were prepared using an extractor with solvent refluxing operated under an optimal extraction condition. The extraction yield was 20-23% and the purity of terpene trilactones was about 1.0-1.4 wt%. Before the isolation operations, the extracts were dissolved in de-ionized water. The isolation procedures included the method of liquid-liquid extraction and the method of column chromatography. For the method of liquid-liquid extraction using ethyl acetate as the organic solvent operated under the optimal extraction conditions, the purity, concentration ratio, and yield of terpene trilactones were 13.5-18.0%, 15-16, and >99%. For the method of column chromatography, XAD-7HP, XAD-4, and C-18 adsorbents with different polarities were used as the packing materials. Only for the XAD-7HP column, a part of more polar impurities was efficiently separated with the majority of terpene trilactones by a proper step-gradient elution, which resulted in an efficient isolation: the purity, concentration ratio, and yield of terpene trilactones were approximately 20, approximately 15, and approximately 80%. In comparison, the XAD-7HP column achieved the highest purity, but at the expense of the yield of terpene trilactones; on the contrary, the liquid-liquid extraction method, achieving the highest yield but with a slightly lower purity, was proved to be superior to the method of column chromatography in the current isolation stage.

Adsorption↗

Limitation of the deterioration of lipid parameters by a standardized garlic-ginkgo combination product. A multicenter placebo-controlled double-blind study.

The efficacy of a garlic-ginkgo combination product (Allium plus) was analyzed in a randomized placebo-controlled double-blind study under extreme dietary conditions. The Christmas/New Year's season was chosen for this 2 months lasting investigation analyzing whether the known cholesterol lowering effect of garlic was even effective during the period of the year with the most cholesterol-rich meals. 43 patients with elevated total cholesterol levels ranging between 230-390 mg/dl completed the study. There were no significant changes of the total cholesterol values in both treatment groups. Nevertheless the analysis of improvement or deterioration of total cholesterol values revealed a clear difference between verum and placebo. 20% of the patients in the placebo group showed an improvement of their total cholesterol level, while there was a significant greater improvement rate of 35% in the verum group (p < 0.05). The responders of the verum group showed a reduction in the total cholesterol values from 298.5 +/- 53.8 to 293.0 +/- 56.4 mg/dl after 1 month and a total reduction of 10.4% after 2 months to 267.6 +/- 44.4 mg/dl. The difference after 2 months of treatment was significantly different from the starting value (p < 0.05). After the 2 months treatment phase there was a 2 weeks wash-out period. During this period the total cholesterol value returned to 293.5 +/- 90.1 mg/dl showing the effectiveness of garlic treatment, but indicating the need for a continuous long-term therapy.

Anticholesteremic Agents↗

[Long-term treatment of circulatory disturbances of the retina and optic (author's transl)].

Forty-six patients with in most cases severe vascular degenerative retinochoroidal circulatory disturbances or with glaucomatous visual field defects were treated with rökan dragées (160 mg/day for four weeks, then 120 mg/day). The following were checked at monthly intervals to determine the degree of success of the treatment: visual acuity, visual field, funduscopy, pulse rate and blood pressure, sometimes including intraocular pressure, fluorescence angiography and ODG. The results of the treatment are reported and discussed with regard to the largely bad prognosis of these serious disorders.

Aged↗

[Isolation and HPLC analysis of ginkgolic acid].

OBJECTIVE: To isolate ginkgolic acids (GA) from exopleura of Ginkgo biloba and to analyse GA. METHODS: GA were ultrasonic-extracted from exopleura of Ginkgo biloba with petroleum ether, and purified by silica gel column chromatography. The content of GA in sample was determined by HPLC with methanol-3% acetic acid (90:10) as mobile phase at a flow rate of 1 ml/min. UV detection wavelength was set at 310 nm. A HiQ sil C18 column was used at 40 degrees C in analysis. RESULTS: A good linearity was obtained in the range of 1.144-5.720 micrograms (r = 0.9978) for GA. The average recovery of GA was 97.50% with RSD of 1.70%. CONCLUSION: The method may be employed to prepare GA from exopleura of Ginkgo biloba. The analysis method for GA is accurate and reliable, and can be used for determination of GA in sample.

Chromatography, High Pressure Liquid↗

[Study on the comparison of polysaccharides in Ginkgo biloba leaves].

OBJECTIVE: To determine the suitable tree's age, tree's sex and gathering seasons for Ginkgo biloba leaves. METHODS: The twelve different polysaccharides were obtained by extracting and precipitating from Ginkgo biloba leaves and to see if there were differences among them. The concentration of Ginkgo biloba leaf polysaccharides with the highest gain ratio will be determined by HPLC. RESULT: The average gain ratio of Ginkgo biloba leaf polysaccharides was 4.29%, among them the gain ratio of 10-years old female Ginkgo biloba leaf collected in the last ten days of September was the highests, its polysaccharides concentration was 61.5% with RSD = 2.5% (n = 6). CONCLUSION: The gain ratios were different in different Ginkgo biloba leaves and the changing rules provide scientific basis for the GAP of medicinal plants.

Analysis of Variance↗

Ginkgolides, diterpene trilactones of Ginkgo biloba, as antagonists at recombinant alpha1beta2gamma2L GABAA receptors.

Ginkgolides A, B, and C are diterpene trilactones and active constituents of the 50:1 Ginkgo biloba leaf extract widely used in the symptomatic treatment of mild to moderate dementia. Using the two-electrode voltage clamp methodology, these ginkgolides were found to be moderately potent antagonists at recombinant human alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus oocytes. Ginkgolides A, B, and C inhibited the direct action of gamma-aminobutyric acid (GABA) with K(i) values of 14.5+/-1.0, 12.7+/-1.7, and 16.3+/-2.4 microM respectively. Antagonism by these ginkgolides at alpha(1)beta(2)gamma(2L) GABA(A) receptors appears to be noncompetitive as indicated by the nonparallel right shift and reduced maximal GABA response in their GABA concentration-effect curves.

Animals↗

Cognitive and other behavioral effects of EGb 761 in animal models.

Extensive pre-clinical and clinical studies conducted over more than three decades have established that EGb 761 (definition see editorial) represents a polyvalent therapeutic principle that is useful in the therapy of mildly to moderately severe dementia and other cognitive disorders. Besides cognition, other emotional and affective aspects of brain function also seem to benefit from EGb 761 treatment. Extensive behavioural studies in experimental animals are generally in line with clinical data since cognition improvement, stress protection, and antidepressive effects have been identified with this extract in proper animal models. While individual effects in all areas have been reported for adult animals and acute dosing, more pronounced effects are usually seen in aged animals and after subchronic treatment. Specifically, for the cognition improving properties pronounced beneficial effects are mainly present in those situations where cognition was impaired by aging or other noxious stimuli. Since all these conditions are associated with mitochondrial dysfunction, the stabilizing or even protecting effect of EGb 761 on mitochondrial function seems to be a major mechanism associated with many of EGb 761's behavioural effects. Bilobalide is most important in this respect. Moreover, bilobalide and the ginkgolides have recently been shown to affect chloride conductance by interfering with the function of membrane proteins related to receptor-gated chloride channels. These mechanisms are probably associated with behavioural effects requiring acute changes of neuronal activity, but might indirectly also improve mitochondrial function.

Animals↗

Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant alpha1beta2gamma2L GABA(A) receptors.

The sesquiterpene trilactone bilobalide is one of the active constituents of the 50:1 Ginkgo biloba leaf extract widely used to enhance memory and learning. Bilobalide was found to antagonise the direct action of gamma-aminobutyric acid (GABA) on recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptors. The effect of bilobalide on the direct action of GABA at alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp method was evaluated and compared with the effects of the classical GABA(A) receptor competitive antagonist bicuculline and noncompetitive antagonist picrotoxinin. Bilobalide (IC(50)=4.6+/-0.5 microM) was almost as potent as bicuculline and pictrotoxinin (IC(50)=2.0+/-0.1 and 2.4+/-0.5 microM, respectively) at alpha(1)beta(2)gamma(2L) GABA(A) receptors against 40 microM GABA (GABA EC(50)). While bilobalide and picrotoxinin were clearly noncompetitive antagonists, the potency of bilobalide decreased at high GABA concentrations suggesting a component of competitive antagonism.

Animals↗