By David N. Leff

Any well-stocked pharmacy or health food store will display up to 22 varieties of a traditional Chinese herbal medicine called Ginkgo biloba. In pills, potions or capsules, these non-prescription, over-the-counter botanical remedies sport self-explanatory brand names such as: IntelliQ Capsules, Nature¿s Reward, One-A-Day Memory, Right Choice and Quanterra Mental Sharpener Tablets.

Ginkgo biloba is a tall tree, native to China, Japan and Korea, that grows 80 feet high or higher, and can live for centuries or longer. Its fan-shaped, twin-lobed leaves and yellow seeds carry the ingredients that Chinese folk healers infused as a tea for asthma, tinnitus aurium, hypertonia and angina pectoris.

Modern customers count on ginkgo biloba products to enhance their memory and mental acuity ¿ among other ills of old age.

Bio-organic chemist Coran Watanabe, a postdoctoral fellow at the Scripps Research Institute in La Jolla, Calif., has a word of caution for consumers who rely chronically on such medicaments: ¿People should tell their doctors that they take herbal remedies, especially prior to a surgical operation. Because there are a lot of negative effects. If you have a mixture with some other medication that you¿re taking, some of these things can affect the anesthetics, or cause formation of blood clots, so your doctor will probably advise you to stop taking the product for two weeks or so before undergoing surgery. Because an herbal remedy is all natural, people don¿t think about it in terms of a medicine.¿

She observed that ¿people eating ginkgo against forgetfulness claim that the herb enhances memory. That¿s why we chose to study it. Scripps sponsors our experiments, with funding from NIH grants.¿

Watanabe is first author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated June 5, 2001. Its title: ¿The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba.¿ The article¿s senior author is bio-organic chemist Peter Schultz, a professor on the Scripps faculty, who directs the Genomic Institute of the Novartis Research Foundation, in La Jolla.

Ginkgo Diet Made Mouse Genes Jump

In their analysis of the herbal remedy¿s effects, Watanabe told BioWorld Today, ¿What we did was to start 20 mice on a four-week diet of ginkgo or no ginkgo. We just put it in their chow. Then, we profiled changes in messenger RNA expression levels in the hippocampus and the cerebral cortex of those animals, using oligonucleotide gene chip arrays. The chips allowed us to look across 6,000 full-length genes and 6,000 expressed sequence tags [EST].

¿Of the approximately 12,000 combined genes and ESTs on the array,¿ Watanabe said, ¿only 10 changed in expression level by threefold or more, and all were up-regulated. Actually,¿ she pointed out, ¿there was only one gene that changed its expression in the hippocampus [center of learning and memory]; the other nine were in the cortex. All of these genes were up-regulated ¿ increased in expression.¿

That one hippocampal change was in a gene that encodes a protein called transthyretin, implicated in protection from Amyloid-beta. Its expression level went up 16-fold.

¿We couldn¿t specify what kinds of changes we were looking for,¿ Watanabe observed, ¿but we found that a lot of them were involved in neurological functions that could potentially have therapeutic value with respect to Alzheimer¿s disease [AD]. However, it¿s difficult to say that without confirmatory studies, so we¿ll be following up with a mouse study in the Novartis mouse model for AD. Among the changes that we saw was transthyretin, expressed in the hippocampus. Transthyretin binds Amyloid-beta, which creates the senile neuritic plaques that are one hallmark of AD. Neurofibrillary tangles that cluster inside the neurons of AD patients are also hallmarks.

¿There were some other effects as well,¿ Watanabe said. ¿Phosphorylation of an AD-associated protein called tau gives rise to neurofibrillary tangles. We saw significantly enhanced expression of tau. But an accompanying phosphatase aborted that phosphorylation.

¿These are encouraging results, she allowed, ¿but we really need to do more studies. That¿s why we¿re undertaking initial neurophysiology mouse experiments. We¿re just taking normal mice and putting the ginkgo directly into artificial cerebrospinal fluid, then looking at long-term memory or seizure activity. We¿re looking at old mice and young mice, and hoping to publish within the next few months.

¿The next step will be to repeat the feeding, then do the learning and behavior in the Novartis model for AD, which mimics Alzheimer¿s disease,¿ she said. ¿If you look at year-old Novartis mice, they have those plaques seen in AD. So we¿d really like to feed them for a year, then see whether there¿s any reduction in plaque formation.¿

No Adverse Indications Yet

So far, the co-authors haven¿t encountered any out-and-out negative or toxic effects in their ginkgo analysis. ¿One thing we were kind of worried about,¿ Watanabe said, ¿at least with respect to gene changes, was prolactin. Both growth hormone and prolactin were up-regulated in our gene profile, and they¿re quite similar ¿ both are considered growth hormones. Prolactin, it¿s said, can cause male impotence. But I¿ve never see anybody reporting that they have problems with that.

¿Because so many people are consuming these natural products,¿ she said, ¿we¿re also interested in other herbal remedies as well, such as Echinacea ¿ a popular cold remedy. We¿re going to do multiple studies, and if we see something really promising, we want to go and isolate the active agent. Then we have a chance of making a therapeutic drug, and if we find there are negative side effects, hopefully we can eliminate that by purification. That says the angle is being able to isolate the active agent and figure out the drug target ¿ asking what it is targeting. If we can figure that out, then if the drug isn¿t optimal, we can always modify that compound.¿

The PNAS paper concludes: ¿We have shown here that a variety of neuronal genes are induced in the hippocampus and cortex by dietary supplementation with ginkgo biloba. However, it is not clear what these changes in mRNA expression have on brain function. Further studies will be required to fully investigate both possible beneficial and harmful effects of ginkgo biloba.¿

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