We know that lack of memory is the problem with Down syndrome.
Let’s Change That!
**The top part of this page explains the logic of using Ginkgo Biloba. To read the supporting studies scroll down to the bottom of the page.
Ginkgo Biloba is the key! It opens the door to memory!
Without it, the rest of the protocol will have no major effect on intelligence.
We can’t stress this strongly enough. Everything else depends on this bridge!
Memories are made of this
It didn’t take long for the scientists at Stanford to sort through the problems of the DS mouse and pinpoint a major dysfunction in their brain. The memory switches never got turned on. It is important to realize that all learning depends on memory and a lack of creating long term memory may explain much of the difficulty individuals with DS have in learning. Let us take you into the laboratory and you can see for yourself an excellent example of scientific deduction that led to this conclusion.
Long-Term Potentiation (LTP)
Mice can be trained to solve simple tasks. For example, if a mouse is placed in a pool of milky water, it will swim about until it finds a hidden platform to climb out on. With repetition, the mouse soon learns to locate the platform more quickly. Presumably it does so with the aid of visual cues placed around the perimeter of the pool because it cannot see or smell the platform itself. Down syndrome mice cannot learn this task no matter how many times they try. This suggests that neurons in their brains are not suitable for this type of learning.
What is going on?
When the mouse finds the platform he gets a little blip in his brain. Then the second time he finds it he gets a much bigger blip, and continues to get a big blip every time he finds it after that. This process is called Long Term Potentiation, (LTP). With a Down syndrome mouse he would get a little blip the first time, the second time, the third time, etc. Always the same result! No LTP! We know LTP is a major factor in forming memories, in mice and in humans, and without it learning is highly restricted. Think back to your school days when you were trying to memorize something for a test; what you were doing is activating LTP in your brain with repetitive stimulus. It’s called recall.
Our purpose for this review is to give you a little insight into the research process. If nothing else it will give you more confidence in the process and the recommendations that are forthcoming. So we would like to take you stepwise through how the mystery of insufficient LTP in Down syndrome was unraveled.
Action in the brain can be related to traffic at a major intersection. Because there is so much traffic it requires a signal light to keep order, and allow cars to pass without hitting each other. Everyone knows green light is go; red light is stop. It is basically the same in the brain except we use different names. Of course, there are no lights involved, just two different chemicals, and the signal given depends on which one is in action.
You might think because you are awake and alert all day that the most used signal is the excitatory, but this is not the case. In fact it is just the opposite – by a wide margin 95 to 98% are inhibitory. Peeling away all the incidental stimuli that you come in contact with is a big job, but when it is done you can operate with a clear mind on the specific things you are interested in. Some extreme examples of this are having a conversation at a crowded cocktail party, doing your homework with the TV on, going to sleep, etc.
On the other end of this switching system is a receiver. It is called an NMDA receptor. This also had to be checked.
Stepwise the researchers analyzed the DS mice system by system. They found the following:
- The excitatory synaptic transmission is normal in the DS mice.
- The NMDA receptor is normal in DS mice.
- Excessive inhibitory transmission which restricts synaptic activation of the excitatory receptors is the cause for the failure to induce LTP in DS mice.
You may not realize it but this discovery has turned the Down syndrome world upside down. All efforts to date have been aimed at increasing the excitatory transmission. In Down syndrome the brain activity is low, and the person is mentally challenged; the obvious answer is to increase the excitatory activity. But, the work at Stanford says its the other side of the system that needs to be addressed– reduce the inhibitory activity.
The researchers at Stanford have demonstrated that an excess of inhibitory signals is the problem. In other words, there are too many red lights in the system and making the green lights greener doesn’t help. We have to turn off some of the red lights.
Research has clarified the mystery. They have given us a well defined objective. It now looks more like a medical problem that should respond to the proper medication than an insurmountable mass of confusion. An extensive literature search has uncovered a short list of products that demonstrate this type of restrictive activity on inhibitory transmission. They will be reviewed and tested.
It would appear that we are close to our first treatment program earlier than we could have expected. While Stanford is now working on a small group of pharmaceutical products testing which will be the best fit, this band of diligent parents scoured the internet and found a good treatment option.
The drug classification is called a GABA antagonist. It goes against the GABA receptor and turns off some or all of the red lights. Stanford used a chemical in its study that shut the GABA receptor down 100%. We just want to turn the volume down, not off. The best internet searcher in the world, a mother from Cincinnati found a study out of the University of Sidney, which compared the chemical Stanford used in its study to a fairly common herb, Ginkgo Biloba. The study looked at how each of the chemicals worked and found they did the same things. Except for one important difference. The Ginkgo Biloba did not turn the red lights off 100% no matter what dose you take.
Ginkgo Biloba has been used in Chinese medicine for about 5000 years. It has no major side effects. If you put Ginkgo Biloba into a search engine, you will see that they say it improves memory by increasing blood flow. We don’t think anyone knew how it worked, just that it improved memory in some people, but the lab in Sydney is the first to show us how it worked.
There is no doubt that with improved memory will come increased learning and ability to participate in social activities. Memory is a fundamental requirement to understanding and learning and this will lead to many more improvements in all areas. We all live busy lives but we would love to hear your stories.
Dose matters. Let me say that again. Dose Matters!!! If you don’t take enough, you don’t see much difference. The receptor acts like a light switch if the switch is only half way on, there is no light. You have to flip the switch. But the good news is, more doesn’t hurt you. If you take too much, you have wasted a little money and you might possibly get an upset stomach.
We have anecdotally worked out about 3 mg per pound for the extract formula of Ginkgo Biloba. For example, a 75 lb child would take 220 mg. That may seem like a lot but the active ingredient is only 3 % of the whole. The biloba (active ingredient) is only 7mg of a 220 mg dose. We have found that maintaining that dosage throughout the day is very beneficial. It keeps the GABA at bay. That is why we suggest giving the ginkgo 2 times per day both morning and evening.
We recommend that you use ginkgo in the capsule form. If your child has trouble swallowing pills, you can open up the capsules into food (applesauce, pudding, mashed potatoes, etc.) The liquid form is very difficult to dose correctly. The companies will even tell you that it is extremely difficult to dissolve the ginkgo into liquid. The dosage that the bottle recommends will seem very high because it is mostly water. You will have a much easier time dosing with the capsules, whether your child swallows the pills or not.
This website is not intended to give medical advice only medical information. Everyone needs to make decisions for himself but it would have been selfish and unfair of us not to use the new media to share our successes.
Neurobiology of Disease
Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down Syndrome
Alexander M. Kleschevnikov,1 Pavel V. Belichenko,1 Angela J. Villar,3 Charles J. Epstein,3 Robert C. Malenka,2 and William C. Mobley1
1Department of Neurology and Neurological Sciences, and the Institute for Neuroscience, and 2Nancy Pritzker Laboratory, Department of Psychiatry, Stanford University Medical School, Stanford University, Stanford, California 94305, and 3Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143
Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABAA receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.
Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome.
Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC.
Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Palo Alto, California 94304-5485, USA.
Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABAA antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABAA antagonists may be useful therapeutic agents for this disorder.
PMID: 17322876 [PubMed – in process]
Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an
antagonist at recombinant a1h2g2L GABAA receptors
Shelley H. Huanga, Rujee K. Dukea, Mary Chebibb, Keiko Sasakic,
Keiji Wadac, Graham A.R. Johnston
Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia
Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan
Herbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia
The sesquiterpene trilactone bilobalide is one of the active constituents of the 50:1 Ginkgo biloba leaf extract widely used to enhance memory and learning. Bilobalide was found to antagonize the direct action of g-aminobutyric acid (GABA) on recombinant a1h2g2L GABAA receptors. The effect of bilobalide on the direct action of GABA at a1h2g2L GABAA receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp method was evaluated and compared with the effects of the classical GABAA receptor competitive antagonist bicuculline and noncompetitive antagonist picrotoxinin. Bilobalide (IC50 = 4.6F0.5 AM) was almost as potent as bicuculline and pictrotoxinin (IC50 = 2.0F0.1 and 2.4F0.5 AM, respectively) at a1h2g2L GABAA receptors against 40 AM GABA (GABA EC50). While bilobalide and picrotoxinin were clearly noncompetitive antagonists, the potency of bilobalide decreased at high GABA concentrations suggesting a component of competitive antagonism.
D 2003 Elsevier Science B.V. All rights reserved.
This website is not intended to give medical advice only medical information. Everyone needs to make decisions for himself but it would have been selfish and unfair of us not to use the new media to share our successes