Friday, November 17, 2006

Ginkgo May Protect Against Alzheimer’s Protein

Ginkgo biloba may protect neurons from the toxic effects of Я-amyloid protein, a major constituent of the senile plaques found in the brains of Alzheimer’s disease patients. Researchers at McGill University in Canada showed that a standardized extract of ginkgo biloba could protect cells taken from the hippocampus, a region of the brain involved in memory formation, from the cytotoxic, or “cell-killing,” effects of Я-amyloid.

The researchers grew hippocampal cells in a dish, then exposed these cultured cells to Я-amyloid. Without any protection, the cells died, but when the researchers added a standardized extract of ginkgo biloba developed in 1964 by a German pharmaceutical company, the hippocampal cells were able to withstand the exposure to Я-amyloid.

The ginkgo extract used in the study is known as EGb 761 and has been standardized to contain specific percentages of its chemical components: 24% flavonoids, 6% terpenoids, 5-10% organic acids, and >0.5% proanthocyanidins. This extract and its components have been used in hundreds of research studies. In this study, both EGb 761 and its flavonoid component were shown to be neuroprotective, with the flavonoid component being somewhat less protective than the whole extract. However, the terpenoid components tested in the study did not protect against Я-amyloid toxicity.

Although the neurotoxic mechanisms of Я-amyloid are not fully understood or agreed upon, a popular theory is that beta-amyloid triggers the production of free radicals known as reactive oxygen species (ROS).

Since the flavonoid component has been shown to have antioxidant and free radical scavenging activities, these results indicate that the neuroprotective effects of the ginkgo biloba extract may be due, at least in part, to its antioxidant properties. Since the terpenoid components tested did not protect against beta-amyloid toxicity, the neuroprotective effects of EGb 761 are probably not attributable to the anti-inflammatory properties that have been previously demonstrated for the terpenoids.

Oxidative stress has been implicated in many disease processes, including neurodegeneration in Alzheimer’s disease and after stroke and trauma. It occurs when free radicals are produced at a higher rate than they can be eliminated by the cell’s antioxidant defenses. Massive release of the excitatory neurotransmitter glutamate into the extracellular fluid occurs, and its reuptake is slowed.

There are two types of cell death that can be triggered by oxidative stress. Necrotic cell death occurs within 24 hours of injury and involves increased permeability (leakiness) of the cell membrane, resulting in the cell swelling then bursting, an event called cell lysis. Apoptosis, or programmed cell death, is also known as delayed cell death and involves the activation of a series of cell events that result in mitochondrial injury, DNA fragmentation and cell shrinkage and death.

Cell survival was increased at all concentrations of EGb 761 used, with the amount of protection increasing (dose-dependently) as the concentration of EGb 761 increased from 10 micrograms per milliliter to 100 micrograms per milliliter. The highest concentration provided complete protection. Using this concentration, the researchers in the McGill University study investigated whether EGb 761 was protective against apoptotic cell death induced by beta-amyloid. They found that co-treatment with EGb 761 inhibited apoptosis of hippocampal neurons for 24 hours in a medium containing Я-amyloid fragments. This occurred even when the EGb 761 was not added to the cells until 8 hours after exposure to Я-amyloid began.

Previous clinical trials of ginkgo biloba extract with Alzheimer’s patients have shown some improvements in memory and cognition and positive changes in EEG profiles. Ginkgo has also been shown to produce an improvement in mood in some studies. Although most studies have lasted for at least 4 weeks, several studies have demonstrated effects within 1 to 3 hours of administration.

While ginkgo is considered to be relatively safe, 4.4% of patients in 25 clinical studies experienced side effects, including gastrointestinal upset, headaches, sleep disturbances, dizziness, and skin eruptions. Four case studies of adverse events have been reported for individuals who were taking ginkgo extract. Two cases of subdural hematoma, one case of subarachnoid hemorrhage, and one case of spontaneous hyphema (bleeding into the anterior eye chamber) have been reported. Therefore, caution is advised, particularly when taking anticoagulants in addition to ginkgo biloba. As with any medication, herbal or otherwise, side effects should not be ignored.

Other naturally occurring substances with antioxidant effects that have been shown to protect neurons from Я-amyloid toxicity are Vitamin C, Vitamin E, glutathione, melatonin, estrogen, and progesterone. A complex system of antioxidant enzymes, metal chelators, and low molecular weight reductants (Vitamin C, Vitamin E, and glutathione) detoxify free radicals under normal physiological conditions. Under normal conditions, glutathione and Vitamin C replenish each other and Vitamin E from their radicals. During oxidative stress, however, the body’s antioxidant defenses are overcome, low molecular weight reductants are depleted (oxidized), and cellular structures are damaged by free radicals. Administration of antioxidant compounds helps replenish the body’s antioxidant system and boosts scavenging of free radicals.

Ginkgo biloba extract, as well as other naturally occurring compounds with antioxidant activity, may be beneficial in the treatment of Alzheimer’s disease and dementia due to stroke or cerebrovascular insufficiency. Specific precautions should be observed with any of these substances, however. For example, melatonin should be used with caution in individuals with high blood pressure. Since Vitamin E is fat soluble and accumulates in the body tissues over time, doses over 800 IU per day should not be taken without a physician’s supervision. Depending on dose, a two- to three-fold increase in the risk of stroke has been associated with estrogen supplementation. Since the body’s production of progesterone rises from 20 milligrams per day between ovulation and the end of the regular menstrual cycle to 400 milligrams per day during pregnancy, when most women are their healthiest, administration of this hormone appears to have a low risk factor. Considered to be relatively nontoxic, Vitamin C has been administered in doses up to several grams per day. While there is considerable variation with individuals, an excess of Vitamin C can result in diarrhea, which is easily corrected by reducing the dose.

Supplementation with ginkgo, the antioxidant vitamins, and flavonoids such as quercetin, with observation of indicated precautions holds promise as a preventive measure against the debilitating consequences of oxidative stress. Women over 35 may also benefit from progesterone, which is absorbed best transdermally—through the skin. Even more important is the inclusion of plenty of fresh fruits and vegetables in the diet and the avoidance of foods, such as saturated fats, that increase oxidative stress.

Source Article:

S Bastianetto, C Ramassamy, S Dorй, Y. Christen, J. Poirer, and R. Quirion. The ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by Я-amyloid. European Journal of Neuroscience, 12: 1882-1890, 2000.

Other Sources:

BJ Diamond, SC Shiflett, N. Feiwel, RJ Matheis, O. Noskin, JA Richards, and NE Schoenberger. Ginkgo biloba extract: mechanisms and clinical indications. Archives of Physical Medicine and Rehabilitation, 81: 668-678, 2000.

JX Wilson. Antioxidant defense of the brain: a role for astrocytes. Canadian Journal of Physiology and Pharmacology, 75: 1149-1163, 1997.

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