In Europe, leaf preparations of Ginkgo biloba L. (Ginkgoaceae) were used for the treatment of circulatory disorders in the 1960s, and they are now a popular herbal remedy with a reputation for alleviating memory problems. In Iran, Ginkgo biloba has been used traditionally to improve memory associated with blood circulation abnormalities. The use of Ginkgo biloba in TCM dates back for centuries, and the Pharmacopoeia of the People’s Republic of China (2005) includes G biloba seeds as a remedy for cough and asthma and to reduce leukorrhoea and urination.
There has been extensive research to determine any pharmacological basis which might explain the reputed effects of Ginkgo biloba on memory, and a number of clinical studies have also been conducted. Much of this research has used a standardised extract of Ginkgo biloba known as EGb 761, which contains flavonoid glycosides and terpenoid lactones amongst various other constituents. This extract has shown a variety of activities relevant to improving cognitive function, particularly neurodegenerative-related disorders such as Alzheimer’s disease, thus indicating that the extract may have a number of different modes of action. EGb 761 has shown favourable effects on cerebral circulation and neuronal cell metabolism and on the cholinergic system, and it has antioxidant activity. EGb 761 reduced apoptosis both in vitro and in vivo, and it was neuroprotective against nitric oxide- and beta-amyloid-induced toxicity in vitro, with the latter effect being associated with the flavonoid fraction (CP 205). Ginkgolides, the main constituents of the non-flavonoid fraction of EGb 761, are neuroprotective against hypoxia-induced injury in cortical neurons.
EGb 761 also protected mitochondria from beta-amyloid-induced toxicity and modulated synaptic and mitochondrial plasticity in vitamin E-deficient rodents. Other studies showed EGb 761 and the terpenoid lactone bilobalide to protect against ischemia-induced neuronal death, and they reduced mitochondrial gene expression in vivo. Furthermore, bilobalide reduced both glutamate and aspartate release in cortical slices, indicating a neuroprotective action. One mechanism to explain a neuroprotective action of bilobalide is that it acts as an antagonist at GABAa receptors.
Some Ginkgo biloba leaf constituents, including some flavonoids (e.g. quercetin) and terpenoids (e.g. bilobalide and ginkgolides A, B and C), have been associated with a vasodilatory action, which could also benefit memory function. Anti-inflammatory activity is also associated with Ginkgo biloba and its components. Ginkgolide B antagonises platelet-activating factor (PAF), ginkgetin, a biflavone from Ginkgo biloba leaves, inhibits phospholipase A2, and ginkgetin and the biflavone mixture downregulate COX-2 expression. The antiox-idant properties of Ginkgo biloba extract have shown potential relevance in modulating Alzheimer’s disease pathology in vivo. An extract reduced oxidative stress resulting from senile plaques in vivo and progressively reversed structural changes in dystrophic neurites associated with senile plaques, thus indicating that neurotoxicity associated with the senile plaques in Alzheimer’s disease could be partially reversible with antioxidant therapies such as Ginkgo biloba extract. Some evidence suggests that Ginkgo biloba and its components quercetin, kaempferol and isorhamnetin may also have estrogenic activity in some circumstances, but any physiological relevance of this effect is unclear.
These activities, and perhaps other modes of action yet to be elucidated, might explain the effects on cognition observed when Ginkgo biloba extracts have been tested in vivo. Extracts have been shown to enhance cognition in both young and old rats, to improve short-term memory in mice and spatial learning and memory in rats with aluminium-induced brain dysfunction, to reduce cognitive impairment and hippocampal damage after ischemia in rats and to attenuate scopolamine-induced amnesia in rats, perhaps indicating modulation of cholinergic function. This hypothesis is supported by another study in which a standardised Ginkgo biloba extract containing 24% flavone glycosides inhibited acetylcholinesterase activity both in vitro and ex vivo at doses which correlated with effects against scopolamine-induced deficits in a passive avoidance test in mice. In another study, the antagonistic effect of Ginkgo biloba extract on spatial memory deficits in rodents was attributed to cholinergic activity but was also suggested to be partly due to a histaminergic mechanism of action.
The clinical efficacy of Ginkgo biloba extracts (including EGb 761) has been evaluated in several studies including double-blind, placebo-controlled, multicentre trials with administration to both Alzheimer’s disease and healthy subjects. Although these trials have indicated that Ginkgo biloba can modestly improve cognitive ability, some of the data need to be interpreted with caution since some results were based on self-assessment questionnaires rather than more objective methods of analysis. Ginkgo biloba extract is also being investigated for any role it may have in the prevention of Alzheimer’s disease. In another randomised, double-blind, placebo-controlled trial, 120mg Ginkgo biloba extract was administered twice daily to assess if it could improve cognitive performance in multiple sclerosis patients. Although this extract was not found to significantly improve cognition in this study, it was suggested to influence some cognitive processes such as mental flexibility.
Ginkgo biloba is probably one of the most studied herbal remedies for alleviating memory problems, and there is substantial evidence, both pharmacological and clinical, to encourage further study on its potential in the treatment of some cognitive disorders. As is often typical with herbal products, the active compounds need to be characterised, appropriate doses need to be established and both short-and long-term safety needs to be evaluated. Clinical trials to date have generally shown oral administration of Ginkgo biloba to be well tolerated, with no serious adverse effects. It is also important to consider potential drug interactions, particularly as patients requiring therapies to improve cognition may be already taking a number of other medicines. One study showed that Ginkgo biloba supplementation in Alzheimer’s disease patients taking donepezil (5 mg/d) did not have a major impact on the pharmacokinetics and pharmacodynamics of donepezil, although the use of Ginkgo biloba with antiplatelet or anticoagulant medicines may increase the risk of haemorrhage.