Ginkgo Fails to Enhance Memory in Short-Term TrialNovember 2002
According to the free radical theory of aging, oxygen-derived free radicals are responsible for the age-associated decline in cellular function. Mitochondria have recently been shown to play a key role in cellular aging since these "energy factories" of the cell are major targets for free radical attack. Mitochondrial DNA (mtDNA) is particularly vulnerable and accumulates genetic damage over time. There is abundant experimental evidence that oxidative damage to mtDNA accumulates within both liver and brain mitochondria.
Ginkgo biloba extract is a potent antioxidant and scavenger of most free radical species, such as hydroxyl and peroxyl radicals and superoxide anions, which is likely to enhance its wide-ranging therapeutic benefits. It is known to protect the energy-producing mitochondria within the cells,24 thus enhancing oxygen utilization and cellular respiration.
The aim of an experimental study by Sastre et al.25 was to test whether ginkgo extract could prevent age-associated changes in mitochondria and, if so, to determine whether this effect was due to protection against oxidative stress. In this study, the brain and liver mitochondria of old mice fed ginkgo extract in their drinking water was compared to those of young and old control mice.
The results confirmed that ginkgo prevents age-related changes in mitochondria. Mitochondria from the rats given ginkgo exhibited significantly less genetic damage, peroxide generation and oxidation of the crucial antioxidant glutathione than the untreated old rats. In addition, mitochondria from the old rats given the ginkgo extract resembled those of the young rats much more closely, being similar in size and morphology. The study concluded that standardized ginkgo extract prevents age-related decline in mitochondrial structure and function by protecting mitochondria from oxidative damage.
Membrane-stabilizing activities are also important in the prevention of cell damage and aging, as the health and stability of cell membranes are crucial to the function of the cell. The membranes are vulnerable to lipid peroxidation induced by free radicals.
Oxygen deprivation produces free radicals that can overwhelm the body's own free radical scavengers, such as superoxide dismutase (SOD) and glutathione peroxidase. This leads to peroxidation and damage of membrane lipids. PAF (platelet-activating factor), which also accumulates in the brain during ischemia, stimulates production of additional free radicals. The reperfusion stage, when blood comes back to the oxygen-deprived area, has been shown to cause even more cell damage due to increased lipid peroxidation.
Preventing brain damage from lack of oxygen
Brain cells are more susceptible to free radical damage than other cells because their membranes have a higher content of unsaturated fatty acids (phospholipids) and are particularly vulnerable to peroxidation.
Brain cells are also more susceptible to hypoxia (cerebral ischemia) than any other cells. They require large amounts of energy to function, and when blood supply is restricted there is not enough oxygen and glucose for membrane function and energy production. The result is usually a variety of metabolic changes, such as acidosis, electrolyte shifts, free radical production and increased release of free fatty acids, prostaglandins and neurotransmitters.
Ginkgo extract has shown a remarkable ability to prevent such metabolic disturbances in experimental studies of insufficient oxygen supply to the brain.26
An interesting study on the biochemical events in the rat brain after ischemia27 suggests that lack of oxygen alone cannot initiate peroxidation. This process requires restoration of oxygen supply. It is therefore concluded that the more severe brain damage happens during the reperfusion phase (restoration of circulation) after ischemia. It was shown that administration of ginkgo extract before the ischemic injury prevented reduction of SOD activity and reduced lipid peroxide contents of the mitochondria in the rat brain. This was a clear indicator of the extract's protective effect against post-ischemic injury due to free radical production.
Additional neuroprotective actions
A condition common to many chronic and acute neurological disorders is excitotoxicity-oversensitivity of neurons to the excitatory neurotransmitter glutamate. A series of laboratory experiments28-30 suggests that ginkgo extract can protect neurons from excitotoxicity, preventing glutamate-induced calcium influx leading to cell death.
A study31 showed the protective effect of ginkgo extract on mice injected with a neurotoxin known as MPTP. This neurotoxin brings about a close approximation of Parkinson's disease in humans, monkeys and mice. When the mice were pretreated with ginkgo, the neurotoxicity of MPTP was prevented in a dose-dependent manner.
MPTP selectively damages the dopamine system in the nigrostriatal region affected by Parkinson's disease. When the mice were treated with ginkgo extract after exposure to the toxin, dopamine levels recovered more rapidly. Other studies have shown that ginkgo improves dopamine uptake under conditions of oxidative stress.
Brain metabolism generates hydrogen peroxide, a cytotoxic agent that generates oxidative stress in the brain, contributes to cerebral injury and edema following ischemia, and causes programmed cell death (apoptosis) in cortical neurons (nerve cells). Hydrogen peroxide damages DNA and oxidizes lipids and proteins through reactions that have not been entirely clarified but are thought to involve iron and copper ions.
Interesting studies by Oyama et al.32 and Ni et al.33 demonstrated that ginkgo extract is able to protect neurons from oxidative stress induced by hydrogen peroxide. When neurons were treated with ginkgo extract for one hour before adding hydrogen peroxide, it was highly effective in protecting nerve cells from damage and death.
One study suggests that hydrogen peroxide activates nuclear factor kappa beta in bovine endothelial cells, thus contributing to atherosclerosis, and demonstrates that ginkgo extract blocks this activation.34
Preventing abnormal blood clotting
Another interesting action of ginkgo extract is its inhibition of platelet aggregation and adhesion, which may reduce the risk of thrombus formation. This effect is at least partly exerted by the Ginkgolide terpenes in the extract, which have been shown to be potent inhibitors of platelet-activating factor (PAF). Platelet-activating factor is known to be involved in many inflammatory and allergic processes including bronchial constriction, besides being an activator of platelet aggregation and release of inflammatory components.
A stress antidote
Imagine the potential in our modern world for a compound that reduces the negative effects of stress on the body with no side effects. Ginkgo biloba shows great promise in this direction.
Stress give rise to stress hormones that are both good and bad for us. They are essential for adaptation to acute physical stressors-as in fight or flight situations.35,36 In our mental and emotional stress situations today, however, we usually do not have much use for these hormones. They therefore accumulate in the body and give rise to disease through their immunosuppressive and neurotoxic effects. One of the detrimental effects of glucocorticoid excess is its ability to damage the hippocampus area of the brain. This area is a structure in the limbic system that is critical to cognitive functions such as learning and memory.
Behavioral studies in rats and mice (whose response patterns are very similar to humans) demonstrated that repeated oral administration of ginkgo extract had significant anti-stress effects, determined in several kinds of stress tests.37-39
One study demonstrated that treatment with ginkgo extract decreased serum corticosteroid levels by 50%.40 The remaining 50% may be the normal level in conditions without stress. This theory is supported by the fact that no detrimental effects on either animal or human health were observed. The results indicate that ginkgo does not affect basal adrenal function but controls the stress-induced excess of corticosteroid levels.
In vivo findings that ginkgo extract can enhance adaptation under stressful conditions supports its extensive use in the elderly to improve their capacity to cope with the demands of everyday living.41 An interesting "side effect" of chronic ginkgo treatment in rats42 was the observation that these animals lived significantly longer than the animals that received placebo.
Prevention. . . ginkgo's most important benefit!
Hundreds of scientific studies have confirmed ginkgo's beneficial effects in the human body. Due to its multiple mechanisms of action, ginkgo provides enormous potential protection against our most feared diseases. Aging humans have much to gain from using ginkgo biloba extract as a preventative measure to help maintain neurological and circulatory health.
The fact that one study failed to show improved memory in healthy people who received 40 mg of ginkgo (three times a day) for only six weeks is not relevant to those seeking long-term anti-aging effects. The authors of the JAMA study acknowledge that higher doses of ginkgo for longer periods of exposure might produce the desired effects.
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