Feeding an extract of Ginkgo biloba leaves reduced the levels of soluble Aβ oligomers and the pathological effects of amyloid-β (Aβ) expression in a nematode model of amyloid neurotoxicity, according to a new study from Yuan Luo and colleagues at the University of Maryland in Baltimore and collaborators. They used the same preparation which has shown promise in treating the memory loss and cognitive disorders associated with AD, and is now undergoing evaluation in a randomized, placebo-controlled clinical trial for Alzheimer disease (see DeKosky et al., 2006). Their work, published in the December 13 issue of the Journal of Neuroscience, suggests that the neuroprotective actions of Ginkgo biloba may stem more from its ability to disrupt oligomer formation, than from its antioxidant properties.

The extract under study, a standardized formulation called EGb761, is commonly prescribed for AD in Europe, and in the form of a nutritional supplement, is widely used in the United States to enhance memory (see /dis/tre/drt/gingko.asp). The extract is known to have antioxidant properties, and to protect neuronal cells against amyloid toxicity. To probe the molecular action of the extract, first author Yanjue Wu tested it first on transgenic nematodes that have a temperature-sensitive Aβ overexpression construct incorporated into their muscle cells. These worms rapidly develop paralysis when Aβ is turned on with a temperature shift, and the researchers showed that feeding them the extract from birth delayed the onset of paralysis after Aβ induction. Fractionation of the extract showed the most potent activity was associated with Ginkolide A, one of the terpenic lactone compounds specific to the Ginkgo tree.

Next, the researchers looked at nematodes that expressed Aβ in neurons. In these worms, they found behavioral effects of Aβ, namely defects in chemotaxis and altered neurotransmission (as measured by serotonin [5-hydroxytryptamine] hypersensitivity), both of which were normalized by feeding either the EGb 761 extract or the Ginkolide A fraction. The action of Ginkolide A in neuronal pathways is consistent with a previous report that the compound inhibits the effects of Aβ on LTP (Nakanishi, 2005).

The effects of Ginkgo correlated with the loss of oligomeric Aβ species in the worm, as detected by Western blotting with either Aβ- or oligomer-specific antibodies. Whether the Aβ was expressed in muscle or neurons, treatment with Ginkgo diminished oligomers detected by either A11 antibody (see ARF related news story) or NU-4 (Lambert et al., 2006). As oligomers went down, monomers went up, and once more Ginkolide A was most effective of the extract fractions. The treatment did not affect expression of the Aβ transgene, but it did inhibit the appearance of amyloid deposits in the head of the worm. The anti-amyloid activity of Ginkolide A may result from direct binding, as the compound bears some resemblance to other amyloid binders such as Congo red and curcumin.

The Ginkgo extract did have antioxidant activity in the worms, and the researchers showed that treatment caused a decrease in tissue hydrogen peroxide levels in Aβ-expressing worms. But the levels of peroxide did not correlate with paralysis, and reducing peroxide with vitamin C did not correct paralysis or inhibit Aβ oligomerization. In contrast, both paralysis and serotonin hypersensitivity correlated with Aβ load. While the researchers say they cannot rule out a role for the antioxidant activity of Ginkgo in its neuroprotective effects, their results indicate that the extract may have a more direct anti-amyloid activity.—Pat McCaffrey.

Reference:
Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and Ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006 Dec 13;26(50):13102-13. Abstract

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  1. Gingko biloba extract has been extensively used in clinical practice despite overwhelming lack of evidence of its effectiveness for existing disease. Its mechanism of action was believed to be related to antioxidant and anti-inflammatory properties, as well as to neuroprotective and neurotransmission regulatory effects. Despite an elusive mechanism of action, Ginkgo biloba was tested in clinical trials, in some of which a modest improvement in activities of daily living (such as eating and dressing), and social behavior were reported. However, no measurable difference in overall cognitive impairment and memory scores were found. Recently, the National Center for Complementary and Alternative Medicine of the U.S. National Institutes of Health has launched a large, multicenter study to determine if Ginkgo biloba may help prevent or delay the onset of Alzheimer disease or vascular dementia. The trial is currently ongoing.

    Wu and colleagues provided a very nicely designed study where they attempted to dissect effectiveness of particular components of the Gingko biloba extract. Based on their studies in a C. elegans model, they postulated additional neuroprotective and anti-oligomerization properties of the Gingko biloba extract. They found that Ginkolide A is responsible for a majority of the therapeutic benefit. Their results encourage further testing of Ginkolide A in Alzheimer disease transgenic mice. Should Ginkolide A be proven to be effective in reducing the level of Aβ oligomers and preventing memory deficits, it may be tried in human trials. One has to remember, however, that adverse effects associated with Ginkgo biloba extract include increased propensity for bleeding and gastrointestinal irritation. Therefore, the safety profile should be carefully examined along with testing for therapeutic effectiveness of Ginkolide A.

    View all comments by Martin Sadowski

References

News Citations

  1. Amyloid Oligomer Antibody—One Size Fits All?

Paper Citations

  1. . The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006 Jun;27(3):238-53. PubMed.
  2. . Terpene trilactones from Gingko biloba: from ancient times to the 21st century. Bioorg Med Chem. 2005 Sep 1;13(17):4987-5000. PubMed.
  3. . Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem. 2007 Jan;100(1):23-35. PubMed.
  4. . Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006 Dec 13;26(50):13102-13. PubMed.

Other Citations

  1. /dis/tre/drt/gingko.asp

Further Reading

Papers

  1. . Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. Eur J Neurol. 2006 Sep;13(9):981-5. PubMed.
  2. . Alzheimer's disease, the nematode Caenorhabditis elegans, and ginkgo biloba leaf extract. Life Sci. 2006 Mar 27;78(18):2066-72. PubMed.
  3. . A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer's type. Curr Alzheimer Res. 2005 Dec;2(5):541-51. PubMed.
  4. . Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006 Dec 13;26(50):13102-13. PubMed.

Primary Papers

  1. . Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006 Dec 13;26(50):13102-13. PubMed.