The CNS effects of Ginkgo biloba extracts and ginkgolide B
Introduction
Ginkgo biloba (Ginkgoaceae) is an ancient Chinese tree, which has been cultivated and held sacred for its health-promoting properties (Jacobs and Browner, 2000). Over the last decade, substantial scientific evidence has accumulated to suggest that concentrated and partially purified extracts of Ginkgo biloba leaves afford protection against some kinds of neural and vascular damage (Kleijnen and Knipschild, 1992b, Søholm, 1998, Diamond et al., 2000).
EGb-761 is a patented extract from the leaves of the Ginkgo biloba tree. Since the development of this extract in 1964, its effects on an extensive range of disorders and diseases have been investigated. Most notably these include cerebral insufficiency (characterised by symptoms such as memory impairment, poor concentration, depressed mood, anxiety and confusion), Alzheimer’s disease, multi-infarct dementia, stroke, tinnitus, myocardial ischemia, peripheral occlusive arterial disease (POAD) and thrombosis. In addition, its effects on vestibular disorders, antidepressant-induced sexual dysfunction (Wheatley, 1999), traumatic brain injury and hypertension have been studied (see Diamond et al., 2000 for a review). EGb-761 has recently been licensed in Germany for the treatment of cerebral insufficiency and POAD (Le Bars et al., 1997). It is available as an approved over-the-counter medication in western Europe and Ireland, and is sold as a herbal preparation in the United States, Australia and New Zealand (Rai et al., 1991, Tyler, 1993). The aim of this review is to summarise and to critically evaluate the evidence relating to the neuroprotective effects of the Ginkgo biloba extract, EGb-761, which is the most commonly used extract in experimental and clinical studies, and one of its major constituents, ginkgolide B. Ginkgolide B was chosen because of the large number of experimental studies that have evaluated its efficacy.
Marketed under the trade names of Rökan, Tanakan, Tebonin, and Ginkgold, the EGb-761 extract is standardised to contain 24% flavonoids, 7% proanthocyanidins and 6% terpenoids. The flavonoids are primarily flavonol-glycosides of kaempferol, quercetin and isorhamnetin with glucose or rhamnose. The terpenoid fraction consists of a unique group of diterpenes (ginkgolides A, B, C and J) and the sesquiterpene, bilobalide. EGb-761 also contains a number of organic acids including kinurenic, hydroxykinurenic and vanillic acids, which are reported to play a role in the extract’s water solubility (Drieu, 1988, Kleijnen and Knipschild, 1992a, Tyler, 1993). A similar extract, LI 1370 (Kaveri), standardised at 25% flavonoids and 6% terpenoids, is also available (Kleijnen and Knipschild, 1992a).
For the preparation of EGb-761, Ginkgo biloba leaves are harvested while they are still green, then they are dried and subjected to a 15-step extraction procedure. The extraction process begins with an acetone–water mixture, followed by the removal of lipophillic constituents and then the concentration of the active components in the extract (see DeFeudis, 1991 for detailed extraction procedure). It is important to note that many of the constituents of Ginkgo biloba are either not present or present in only small concentrations in EGb-761. For example, the ginkgolic acids, steroids, polyprenols and flavone and flavonol aglycons occur in concentrations of less than 0.1%. Biflavonoids usually do not occur at all (DeFeudis, 1991). Besides the constituents of Ginkgo biloba leaves that either do not occur or occur in only trace amounts in EGb-761, it is also important to realise that the principle constituents of EGb-761 exist in much higher concentrations than in Ginkgo biloba leaves, i.e. it is a highly concentrated extract. For this reason, the effects of the terpenes and flavonoids in EGb-761 may bear little relation to their functions in the Ginkgo biloba tree itself.
Moreau et al. (1988) endeavoured to determine the biological fate of the principal constituents of EGb-761 following oral administration of a -radiolabelled extract in rats. The blood pharmacokinetics were found to be characteristic of a two-compartment model, with a first-order absorption phase and a half-life of approximately 4.5 h. The peak plasma concentration (22.5 neq./mg) occurred 1.5 h following administration, while a second peak (12.8 neq./mg), observed at 12 h, indicated possible enterohepatic cycling or absorption of metabolites. High radioactivity in the stomach and small intestine at 3 h post-administration suggested that these organs were the sites of absorption. Radioactivity was also concentrated and retained in eye, glandular and neuronal tissue. At 72 h post-administration, 38% of the initial dose had been exhaled in carbon dioxide, while 21 and 29% were excreted in the urine and faeces, respectively. An important limitation of this study, however, was that the -radioactive label was not evenly distributed between the constituents of the extract. In fact, no radioactivity whatsoever was found in the terpenoid component. Given this information, the data obtained from this study may relate to some of the flavonoids and proanthocyanidines contained within EGb-761, but they do not reflect the pharmacokinetics of the whole extract.
Biber and Koch (1999) examined the pharmacokinetics of ginkgolides A and B along with bilobalide following oral dosing of EGb-761 in rats. Single doses of 30, 55 and 100 mg/kg were administered and the resultant plasma levels were measured using gas chromatography/mass spectrometry. For the 30 mg/kg dose, peak plasma concentrations were 68, 40 and 159 ng/ml for ginkgolides A, B and bilobalide, respectively. For each of the constituents, a linear dose–response relationship was observed. The time taken to reach these maximum concentrations ranged from 0.5 to 1 h and the half-lives were 1.7 h (ginkgolide A), 2 h (ginkgolide B) and 2.2 h (bilobalide).
Kleijnen and Knipschild (1992a) reported unpublished data obtained from human clinical studies in which EGb-761 had been administered orally. These data indicated that, following an 80 mg dose of EGb-761, the bioavailability of ginkgolides A and B was at least 80%, while the bioavailability of ginkgolide C was negligible. The half-lives for ginkgolides A and B were 4 and 6 h, respectively. Following a 120 mg dose of EGb-761, bilobalide exhibited a half-life of 3 h with 70% bioavailability. Approximately 70% of ginkgolide A, 50% of ginkgolide B and 30% of bilobalide were excreted unchanged in the urine.
It appears that pharmacokinetic assessment of EGb-761 is complicated by the fact that it contains many active ingredients. Additive, antagonistic or synergistic interactions between the various constituents of EGb-761 are likely to exist. To date, a systematic pharmacokinetic evaluation of all of the constituents following various routes of administration remains to be conducted.
Section snippets
Cognition
Cognition-enhancing drugs (also referred to as nootropics or ‘smart drugs’) are purported to facilitate attentional abilities and the acquisition, consolidation and retrieval of information (Sarter, 1991). Extracts of Ginkgo biloba have prematurely achieved the status of ‘smart drugs’, with claims to this effect often printed on its packaging in health food stores and supermarkets. The evidence that EGb-761 has cognition-enhancing properties in healthy humans and animals appears controversial
Cerebral insufficiency
Cerebral insufficiency is a commonly used term that essentially describes a non-specific, age-related decline in mental function (Winter, 1998). The 12 symptoms claimed to be typical of cerebral insufficiency include memory difficulties, impaired concentration, decreased energy, confusion, tiredness, decreased physical performance, depression, anxiety, tinnitus, headache and dizziness. While these symptoms are frequently linked with decreased cerebral circulation, often no explanation for
Peripheral effects of EGb-761
In addition to the multitude of effects that EGb-761 has on the CNS, Ginkgo biloba extracts have numerous peripheral effects. In particular, the vasoactive properties of EGb-761 (see Koch and Chatterjee, 1993 for a review) have led to its licensing for the treatment of POAD and intermittent claudication (Kleijnen and Knipschild, 1992a).
Adverse effects of EGb-761
To date, no serious adverse effects attributable to EGb-761 treatment have been reported in clinical trials. Infrequently, patients have developed allergic skin reactions, mild gastro-intestinal upset and headache (Kleijnen and Knipschild, 1992b, Kanowski et al., 1996, Le Bars et al., 1997). A small number of case studies have reported the occurrence of spontaneous bleeding in individuals taking Ginkgo biloba extracts. Intracerebral haemorrhage was reported in a 78-year-old woman concurrently
Ginkgolide B
Ginkgolides are a unique group of diterpenes that occur naturally in the leaves of the Ginkgo biloba tree. They are also found, albeit to a lesser extent, in standardised extracts of Ginkgo biloba. The Institut Henri Beaufour uses the nomenclature BN-52020, BN-52021 and BN-52022 to refer to ginkgolides A, B and C, respectively. All are highly selective and competitive PAF receptor antagonists; however, ginkgolide B is by far the most potent (Braquet, 1987). Ginkgolides J (BN-52024) and M
PAF
PAF is an alkylphospholipid produced by a variety of cells throughout the body. It is one of the most potent lipid mediators known, producing effects at picomolar concentrations (for reviews see Braquet et al., 1987, Venable et al., 1993). The term ‘platelet-activating factor’ was introduced by Benveniste et al. (1972) when they isolated a lipid factor that caused potent aggregation of rabbit platelets. Muirhead (1980) identified a similar lipid factor in the kidney that lowered blood pressure,
Ca2+ and immediate early gene expression
PAF-induced intracellular Ca2+ mobilisation has been demonstrated in neurohybrid NCB-20 cells preloaded with the Ca2+ indicator Fura-2 (Yue et al., 1991). PAF application produced a fast, transient increase in Ca2+, followed by a decline to basal level. The addition of BN-52021 resulted in a concentration-dependent inhibition of the PAF-induced Ca2+ increase.
IEGs undergo fast and transient activation via numerous extracellular signals. Squinto et al. (1989) discovered a PAF-induced activation
Ischemia
It has been proposed that oxygen free radical attack on phospholipids containing a polyunsaturated fatty acyl residue in the sn-2 position, results in fragmentation of the residue, leading to the unregulated production of mediators that have the approximate structure and mimic the biological action of PAF (Zimmerman et al., 1995). These products, which are less potent than PAF, effectively stimulate the PAF receptor and their effects are inhibited by PAF receptor antagonists and PAF
Peripheral effects of ginkgolide B
In addition to the aforementioned central effects, ginkgolide B has a multitude of peripheral effects, which have been reviewed in detail by others (see Koltai et al., 1991a, Koltai et al., 1991b, Koltai et al., 1994; Braquet et al., 1991 for reviews). In particular, ginkgolide B has exhibited beneficial actions in thrombosis, myocardial ischemia and gastrointestinal ulceration. Clinical trials investigating the therapeutic effects of ginkgolide B in allergy (asthma and skin disorders), burn
Adverse effects of ginkgolide B
Clinical experience with ginkgolide B is relatively limited; however, no serious adverse effects directly attributable to ginkgolide B have been reported to date. Of the mild adverse reactions that have been described, hiccups, headache, drowsiness and asthenia were the most frequently reported (Guinot, 1994).
Conclusions
The Ginkgo biloba extract, EGb-761, has been shown to have antioxidant effects, to increase cerebral blood flow and to modulate a number of neurotransmitter systems, including serotonin, noradrenaline, dopamine and acetylcholine. Although there is some evidence to support the idea that EGb-761 can enhance cognitive function in neurologically-intact humans and animals, many studies suffer from methodological flaws such as a lack of double-blind protocols. Overall, the evidence that EGb-761 can
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