Ginkgo biloba is one of the world’s oldest living tree species, earning it the name ‘living fossil’. Its existence can be traced back more than 200 million years and it was commonly found in North America and Europe before the Ice Age. Ginkgo was first introduced into Europe in 1690 by the botanist Engelbert Kaempfer, who described it as the ‘tree with duck feet’. Ginkgo has been used medicinally for many centuries and is now one of the most popular therapeutic agents prescribed in Europe by medical doctors. It has been estimated that in Germany and France, prescriptions for ginkgo make up 1% and 1.3%, respectively, of total prescription sales. Also popular in the United States, it was the top selling herbal medicine in 1999 with sales of US$148 million.
Adiantifolia, Arbre aux quarante ecus, bai guo ye, duck foot tree, fossil tree, gin-nan, icho, Japanese silver apricot, kew tree, maidenhair tree, salisburia, silver apricot, tempeltrae, temple balm, yinhsing
Botanical Name / Family
Ginkgo biloba (family Ginkgoaceae)
Plant Parts Used
In modern times the leaf is used, but traditionally the nut was also used.
Important constituents present in the leaves are the terpene trilactones (i.e. ginkgolides A, B, C and J and bilobalide), many flavonol glycosides, biflavones, proanthocyanidins, alkylphenols, simple phenolic acids, 6-hydroxykynurenic acid, 4-O-methylpyridoxineand polyprenols.
There has been some interest in ginkgo alkylphenols (ginkgolic acids) because of their allergenic properties, so most manufacturers limit the concentration of alkylphenols to 5 ppm.
Clinical note — Ginkgo extract used in practice
The standardised ginkgo extract is made from dried ginkgo leaves extracted in 60% acetone. Only a fraction of the leaf matter is extracted, 98% is not extracted. Of the 2% extracted the flavones account for 25%, the ginkgolides 3% and the bilobalide 3%. The remaining 69% is not specified. The drug ratio may vary from 35:1 to 67:1 (average ratio 50:1). This means that, on average, it takes 50 kg dried leaf to produce 1 kg of extract. Standardised ginkgo extract (e.g. EGb 761) must be standardised to 22-27% flavone glycosides, 5-7% terpenes lactones (2.8-3.4% ginkgolides A, B and C, and 2.6-3.2% bilobalide). The content of ginkgolic acids must be less than 5 ppm. Although the standardisation is very specific, the compounds are considered to be marker compounds as the active constituents of Ginkgo biloba have not been fully identified.
The many and varied pharmacological actions of ginkgo preparations are related to the presence of several classes of active constituents.
Ginkgo biloba extract and several of its individual constituents, such as quercetin and kaempferol, have demonstrated significant antioxidant properties in vitro.
The antioxidant effects of Ginkgo biloba have been shown to reduce the effects of UV radiation on skin. When applied topically, ginkgo increases the activity of superoxide dismutase within skin, thereby enhancing the skin’s natural defences.
Vasodilation Ginkgo promotes vasodilation and improves blood flow through arteries, veins and capillaries. Increases in microcirculatory blood flow occur rapidly and have been confirmed under randomised crossover test conditions 1 hour after administration.
Several mechanisms of action are responsible. Currently, these are considered to be: inhibition of NO release, activation of Ca2+-activated K+ (KCa) channels, and increased prostacyclin release.
Various flavonoids including anthocyanosides and Ginkgo biloba extracts have been shown to be effective against experimentally induced capillary hyperfiltration.
There have been several case reports of Ginkgo biloba causing haemorrhage during or after surgery and there is evidence that one of its components, ginkgolide B, is a platelet-activating factor antagonist. However, three placebo-controlled studies have failed to detect a significant effect for Ginkgo biloba on platelet function or coagulation. One was an escalating dose study that found that 120 mg, 240 mg or 480 mg given daily for 14 days did not alter platelet function or coagulation.
Monoamine oxidase (MAO) inhibition
In vitro tests in rat brains suggest that EGb 761 may exert MAO-A and MAO-B inhibitor activity. Tests with isolated constituents kaempferol, apigenin and chrysin have demonstrated these to be potent MAO inhibitors, with greater effect on MAO-A than MAO-B. It is unclear whether MAO inhibition occurs in vivo.
Another in vitro study found that oral EGb 761 significantly increases the uptake of serotonin, but not dopamine, in cerebral cortex samples from mice and another in vivo study identified an anti-aggressive effect mediated by 5-HT2A receptors.
Considering that Ginkgo biloba appears to be as effective as anticholinesterase drugs, several researchers have investigated whether it exerts cholinergic effects. Evidence from behavioural, in vitro and ex vivo tests with Ginkgo biloba has shown both direct and indirect cholinergic activity.
The extract appears to increase the rate of acetylcholine turnover and stimulate the binding activity of ligands to muscarinic receptors in the hippocampus.
Bilobalide in Ginkgo biloba is a competitive antagonist for GABA-A receptors according to in vitro tests (Huang et al 2003). The effect is almost as potent as bicucullineand pictrotoxinin.
Corticosterone In vivo tests have found EGb 761 has stress-alleviating properties mediated through its moderation of corticosterone levels.
Ginkgo biloba leaf extract (EGb 761) has demonstrated neuroprotective effects in a variety of studies ranging from molecular and cellular, to animal and human; however, the cellular and molecular mechanisms remain unclear. Of the constituents studied, it appears that the bilobalide constituent is chiefly responsible for this activity, although others are also involved.
Up until recently, it was believed that theantioxidant, membrane stabilising and platelet-activating factor antagonist effects were chiefly responsible for neuroprotection, but new evidence suggests MAO inhibitor activity and effects at the mitochondria may also be important contributing mechanisms.
Ginkgo biloba extract EGb 761 protects cells against toxicity induced by beta-amyloid in a concentration-dependent manner, according to in vitro tests. More recently in vivo studies have confirmed that ginkgo extract has an anti-amyloid aggregation effect. It appears that ginkgo increases transthyretin RNA levels in mouse hippocampus, which is noteworthy because transthyretin is involved in the transport of beta-amyloid and may provide a mechanism to reduce amyloid deposition in brain. There is also evidence that Ginkgo biloba modulates alpha-secretase, the enzyme that cuts the amyloid precursor protein and prevents amyloidogenic fragments from being produced.
There is evidence from experimental and clinical studies that Ginkgo biloba extract protects tissues from ischaemia/reperfusion damage. According to investigation with an experimental model, EGb 761 could prevent and treat acute cerebral ischaemia, but the effect was most pronounced when administered prophylactically.
Stabilisation and protection of mitochondrial function
Several in vitro tests have demonstrated that EGb 761 stabilises and protects mitochondrial function. These observations are gaining the attention of researchers interested in neurodegenerative diseases as it is suspected that the mitochondria and the phenomenon of mitochondrial permeability transition play a key role in neuronal cell death and the development such diseases.
Immunostimulatory activity has been demonstrated in several experimental models. The beneficial effects of EGb 761 on immune function are based on its antioxidant properties, as well as the cell proliferation-stimulating effect.
The anti-inflammatory activity of ginkgo has been investigated for the whole extract and an isolated biflavonoid component known as ginkgetin, with both forms demonstrating significant anti-inflammatory activity.
Intravenously administered ginkgo extract produced an anti-inflammatory effect that was as strong as the same dose of prednisolone (i.e. 1 mg GBE = 1 mg prednisolone) in an experimental model. Ginkgo extract was also found to significantly reduce the concentration of PGE2, TNF-alpha and NO production in vitro. Studies with subcutaneously administered Ginkgo biloba extract in experimental models have also identified significant anti-inflammatory activity, with the addition of antinociceptive effects. Ginkgetin Ginkgetin showed a stronger anti-inflammatory activity than prednisolonewhen administered by intraperitoneal injection in an animal model of arthritis. Histological examination of the knee joints confirmed the effect. When used topically in an animal model of chronic skin inflammation and pro-inflammatory gene expression, it was found to inhibit ear oedema by approximately 26% and PGE2 production by 30%. Histological comparisons revealed that ginkgetin reduced epidermal hyperplasia, inhibited phospholipase A2, and suppressed COX-2 and iNOS expression.
Studies conducted with various molecular, cellular and whole animal models have revealed that leaf extracts of Ginkgo biloba may haveanticancer (chemopreventive) properties that are related to its antioxidant, anti-angiogenic and gene-regulatory actions. Both the flavonoid and terpenoid constituents are thought to be responsible for many of these mechanisms, meaning that the whole extract is required for activity. Studies in humans have found that ginkgo extracts inhibit the formation of radiation-induced (chromosome-damaging) clastogenic factors and UV-induced oxidative stress, both effects that may contribute to the overall chemopreventive activity. As a result of these observations, there has been a call by some academics for ginkgo to be more widely investigated and used in the prevention and treatment of cancer.
Inhibition of CYP3A4 has been demonstrated in vitro; however, two clinical studies have produced contradictory results.
Evidence from a recent in vitro study that investigated the effect of individual constituents in ginkgo suggests that several constituents found within ginkgo have significant inhibitory activity; however, the principal components (terpene trilactones and flavonol glycosides) do not. Ultimately, the clinical importance of these potential inhibitors will depend on their concentration within a commercial product and the extent of their bioavailability.