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Ginkgo biloba or maidenhair tree is the world's most ancient tree and the only survivor of the family ginkgoaceae1. In fact, it has been referred to as a living fossil by Darwin2. The tree is particularly resistant to infection by bacteria, fungi and invasion by insects and parasites3, and has shown miraculous survival in Hiroshima, where the atomic bomb explosion had killed almost all living animals and plants nearby4. Its natural habitat is China, Japan and Korea, but nowadays it is also cultivated in Europe and America. Medicinal use of ginkgo biloba in China dates back to about 5000 years5 where it was used to treat diseases like asthma, bronchitis and incontinence6. Currently, it is widely used as a food supplement and an anti-oxidant throughout the world. It is available over-the-counter in the United States and can be obtained on prescription in European countries7. A standardized extract of the plant, named EGB 761, is one of the most widely used herbal products in Europe8. It is on top of the seven best selling herbal products in the United States9.
Main constituents of the extract are 24% flovonoid glycosides (quercetin, kaempferol, and isorhamnetin) 6% terpene lactones (ginkgolides A, B, C, J and M and bilobalides) 10-12. Some of the constituents of flavonoids known as proanthocyanidins are potent free radical scavengers in vitro and may contribute to the anti-oxidant property of ginkgo biloba extract13. Quercetin and kaempferol may be the most potent components of the extract involved in ameliorating the neurotoxic effects of Alzheimer's disease14.
Beneficial effects of EGB 751 include its ability to enhance the cognitive activity, decrease stress, improve microcirculation particularly to the brain, counteract hypoxia, protect the integrity of cell membranes, act as an anti-oxidant and free radical scavenger, reduce circulatory levels of glucocorticoids, and counteract the age-related decline in the number of neurotransmitter receptors in brain13.
Neuroprotection offered by ginkgo biloba may be attributed to one of its constituent bilobalides which has the ability to inhibit the release of glutamate and aspartate15-16. Bilobalides and other components of the extract show high affinity for GABAA, GABAB, and CCKA receptors, a factor which may be responsible for its anticonvulsant activity. Moreover, high levels of GABA in hippocampus may be responsible for memory improvement observed in dementia patients treated with the extract1, 17. Anti-stress and anxiolytic effect of ginkgo biloba extract is attributed to its ability to inhibit both MAOA and MAOB18. Kaempferol is the major ingredient that is involved in this respect19. Ginkgo biloba extract offers protection against ischemic injury to brain20 probably by inhibiting the formation of nitric oxide21.
Ginkgo biloba extract protects against oxidative stress-induced mitochondrial damage, which is an important observation in Alzheimer's disease. Acetylcholenesterase inhibitors like donepezil, rivastigmine, and glantamine have been approved by FDA for the improvement of cognitive manifestations of the disease. Research shows that ginkgo biloba extract has an acetylcholenesterase inhibiting activity as well22.
Accumulation of amyloid beta protein is a known pathological finding in Alzheimer's disease. In a recent study it has been demonstrated that EGB 761 regulates the expression of receptor for advanced glycation end products (RAGE) and low density lipoprotein-receptor related protein-1 (LRP-1) in the endothelium of the vessels constituting the blood brain barrier, thus enhancing the clearance of amyloid beta protein23.
In a study conducted by Li and co-workers, there was an increase in the number of neurons in the hippocampus of fetuses of rats which were fed with EGB 761 in the prenatal period. Changes in multiple gene expressions were noted like insulin growth factor II, insulin growth factor binding protein 2, glutathione-dependent dehydroascorbate reductase, DNA binding protein Brn-2, lipoprotein lipase, testosterone repressed prostate message-2 and guanylate cyclase. These findings confirm the neuroprotective property of ginkgo biloba extract24.
Cardioprotective effect of EGB 761 was confirmed in a recent study in which it was observed that platelet activating factor receptors (PAFR), which play an important role in hypoxia, were up-regulated in myocardial cells of neonatal rats in which artificial hypoxia was induced. These receptors were down-regulated to normal levels in cells treated with bilobalides25.
Laboratory rats deficient in MAOA have elevated levels of serotonin and epinephrine and have an aggressive behavior. EGB 761 treated rats showed compromising behavior and decreased aggression26. This signifies the impact of EGB 761 on serotonergic system.
Ginkgolides and bilobalides are shown to affect chloride conduction by manipulating the membrane proteins associated with receptor-gated chloride channels, and this in turn indirectly improves the mitochondrial integrity27.
Encouraging role of Ginkgo biloba extract in memory related disorders like Alzheimer's disease may also be due to its beneficial role in glucose metabolism. It decreases the glucose consumption in different areas of brain like frontoparietal somatosensory area, nucleus accumbens, cerebellar cortex and pons. Therapeutic advantage of the extract in vertigo and related disorders may be attributed to this effect28.
A study of four weeks duration conducted on 66 patients showed improvement in cognitive function in normal subjects without any side effects29. However in another study carried out in Sweden, no improvement in memory was observed in healthy subjects30.
Not all studies support the beneficial effects of ginkgo biloba extract. Some of the studies negate the efficacy of the extract. This may be due to the fact that some of the subjects are the so called responders and the others are non-responders31.
There has been a growing interest in understanding the association of ginkgo biloba with emotional behavior. A study in Japan has confirmed the anxiolytic action of EGB 761 which was particularly attributed to ginkgolide A32. Other effects include prolongation of pentobarbital induced sleep and decrease in caffeine induced excitation11. In another study conducted in India, the researchers have noted that brain concentrations of catecholamines and serotonin and plasma concentrations of corticosterone levels reverted back to normal when ginkgo biloba extract was given to restraint stress-induced rats33.
Ginkgo biloba is found to be beneficial in sexual dysfunction, and in this respect, is more cost-effective with fewer side effects as compared to sildenafil (Viagra)1. Further, it may counteract the impotence as a side effect of SSRIs like fluoxetine (Prozac) 34-35. However this claim could not be replicated in another study carried out by Kang and co-workers36.
Ginkgo biloba is also known for its anti-coagulant properties; ginkgolide B is particularly involved in this respect. This is supposed to be due to its inhibiting effect on platelet activating factor (PAF), which is also found in brain cells, and is involved in decreasing the viscosity of blood and inflammation in brain, thus contributing to the neuroprotective behavior of the extract37. However, cases are reported in which increased bleeding time associated with the use of EGB 761 has even led to intracranial bleeding. But most of the times these bleeding episodes have occurred in those who were already taking some anti-coagulant38.
EGB 761 is now also considered to reduce high blood pressure. The constituent ingredients of the extract show a synergistic action to produce vasodilatation. These effects are promising in the treatment of hypertension generally and in the treatment and prevention of stroke particularly39.
Activated T lymphocytes play important role in inflammatory diseases of heart and brain. EGB 761 has been shown to inhibit many cytokines like tumor necrosis factor-alpha, interleukins and interferon-gamma released by activated T cells. It also downregulates the production of activator protein-1 (AP-1) thereby endorsing the possible role of ginkgo biloba in dealing with the T cell-mediated ailments40.