AUGUST 29 2018 #lessonthirteen

DO NOT SHARE. THIS INFORMATION IS PART OF A TRIAL AND MUST NOT BE DISTRIBUTED BEYONG THIS GROUP. DO NOT MAKE A COPY ANY OF THE INFORMATION IN THIS LESSON.THIS INFORMATION WILL BE MADE PUBLIC FOLLOWING THE TRIAL. AFTER READING, WRITE “READ” IN THE COMMENTS SECTION.

EDITED TO ADD – TNI will not provide optimum results unless your child uses the entire protocol, Daytime Formula and Polyphenol Formula with EGCG and Curcumin. The benefits will vary from child to child but all should see significant improvement.

If you are using products not included in the protocol, these may interfere with the benefits.

Most citations used are taken from the NLM database and are in the public domain.

Last week we discussed the role of RCAN1 in activating the region of the gene encodein g MicroRNA 132 and how important that microRNA is to the brain. We discussed how RCAN1 also hyper phosphirlates CREB. We covered the importance of down regulating RCAN1, something we may not be able to completely accomplish. We talked about the difficulty in down regulating RCAN1 because it is extremely sensitive to environmental agents. Simple exposure to second hand smoke can cause this gene to over express. We do not know what else may trigger RCAN1. Complete control of this gene in today’s society may never be possible but you cannot ignore it and must do the best you can.

Lastly, we introduced the addition of Luteolin/Rutin. This combination will possibly help stabilize MicroRNA 132 and both are powerful anti inflammatory agents. Lycopene has been proven to down regulate RCAN1. CREB can be regulated through use of PQQ. See last weeks lesson for supporting research.

Today, we will discuss the rest of the problem and explore the rationale for the solution.

The next thing we need to discuss is role of acetylcholine in the human brain and body.

WHAT IS ACETYLCHOLINE?

Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals, including humans, as a neurotransmitter -a chemical message released by nerve cells to send signals to other cells – neurons, muscle cells, and gland cells. This is extremely important in that glands deprived of sufficient Ach cannot properly function. This includes the release of hormones, such as human growth hormone, melatonin, testosterone, estrogen and even insulin. It has been determined that ACh of nonneuronal origin is acts as a autocrine or paracrine hormone synthesized and secreted in the lungs. Acetylcholine is the neurotransmitter used at the neuromuscular junction. It is the chemical that motor neurons of the nervous system release in order to activate muscles. This neurotransmitter is active in every muscle, even in the tiny muscles of the human eye.

Again, this is extremely important when discussing how this neurotransmitter, or lack thereof, contributes to the numerous difficulties often associated with Down syndrome.

With insufficient acetylcholine choline, your child cannot grow properly, he or she is more susceptible to diabetes. The gut has very poor motility without this neurotransmitter functioning normally, learning and memory are greatly impaired.

FOR A COMPLETE DESCRIPTION OF ACH, STOP HERE AND READ THE FOLLOWING

https://en.m.wikipedia.org/wiki/Acetylcholine

We have known for more than twenty years that acetylcholine is low in Down Syndrome. To compensate research has suggested supplementation of choline. We did so two years before the first study was even published. Yet, even though supplementing choline has been helpful, it has not accomplished what we hoped it would.

In researching the issue with gut motility, we looked at neurotransmitters. Neurotransmitters are important in every aspect of gut function from absorption to motility. S. Jill James, in 1997, theorized that a primary cause of poor gut motility in DS is serotonin. She suggested the inclusion of a serotonin re-uptake inhibitor such as Prozac in the Protocol. This actually worked fairly well for quite a few kids, but still gut motility and function remained a troubling issue.

STOP HERE AND READ THE FOLLOWING

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772764/

The question of why acetylcholine is too low in DS has not yet been fully addressed. By this project, we have put those pieces together and have now learned why acetylcholine is low. But more importantly, we now know how to correct this problem.

The following is a brief list of human processes regulated, at least in part by acetylcholine. Though there are numerous studies in every category, I have provided one to reduce the amount of reading. Beside each title I referenced issues associated with DS.

Acetylcholine Is an Autocrine or Paracrine Hormone Synthesized and Secreted by Airway Bronchial Epithelial Cells – Chronic upper respiratory disorders

https://academic.oup.com/endo/article/145/5/2498/2878537

Cholinergic Effects on Human Gastric Motility – Chronic constipation and malabsorption

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1727654/pdf/v045p00346.pdf

The Role of Acetylcholine in Learning and Memory – Cognition and Cognitive decline

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659740/

The M4 muscarinic acetylcholine receptor play a key role in the control of murine hair follicle cycling and pigmentation – What role does this play in Alopecia?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2017094/

An Acetylcholine Receptor Keeps Muscles in Balance – The role of Acetylcholine in both gross and fine motor skills

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789318/

Physiological functions of the cholinergic system in immune cells – Ach deficiency results in poor immune function

https://www.sciencedirect.com/science/article/pii/S1347861317300695?via%3Dihub

Choline Deficiency Attenuates Body Weight Gain and Improves Glucose Tolerance in ob/ob Mice – Obesity and Down syndrome

https://www.hindawi.com/journals/jobe/2012/319172/

Involvement of Brain Catecholamines and Acetylcholine in Growth Hormone Deficiency States
– Why don’t our children grow well?

https://link.springer.com/article/10.2165/00003495-199141020-00002

Cholinergic neurotransmission and olfactory function in obstructive sleep apnea syndrome: a TMS study. What are the implications for OSA in Down syndrome?

https://www.ncbi.nlm.nih.gov/pubmed/28899520

Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet – Why our children are more susceptible to diabetes than non DS children

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113066/

The role of visual cortex acetylcholine in learning to discriminate temporally modulated visual stimuli – Visual learning and Down Syndrome

https://www.frontiersin.org/articles/10.3389/fnbeh.2013.00016/full

Add to these the direct impact of low acetylcholine and MicroRNA 132 llevels on FOXP2, the human speech gene. We know that histamine plays a crucial role in speech by activating neuron growth and migration. But that is not the only issue regarding speech in Down syndrome. We certainly can see how a failure of acetylcholine at the neuromuscular junction of the human tongue could make forming words very difficult. Further, the muscles of the lungs, throat and mouth also depend upon activation by acetylcholine.

FOR FURTHER INFORMATION ON THE FUNCTION OF MICRORNA 132 PLEASE READ THE FOLLOWING.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660991/

These represent only a few of the difficulties associated with Down syndrome which may indeed be linked to acetylcholine deficiency. Why the, if we supplement Choline are our children still deficient?

The answer may be tightly associated with the levels of MicroRNA 132, which is related to the over expression of RCAN1 and the inactivity or hyper phisphorlation of CREB. However, it is unclear whether over expressed RCAN1 is the sole cause of aberrant MicroRNA 132. MicroRNA 132 regulates an enzyme called acetylcholinesterase. Acetylcholinesterase breaks down the neurotransmitter acetylcholine at the synaptic cleft (the space between two nerve cells) so the next nerve impulse can be transmitted across the synaptic gap Abbreviated AChE.

Because MicroRNA 132 is unstable in Down syndrome, it may explain why Acetylcholinesterase is hyper active in DS.  This enzyme breaks down acetylcholine before the the next nerve impulse can be transmitted. This reduces the function of this incredibly important neurotransmitter significantly. The result of this loss of acetylcholine is spelled out in the studies posted above. Only dietary and supplemented choline prevent this neurotransmitter from complete failure. However, as we have seen, simply supplementation of choline or acetylcholine will never be sufficient. It also falls prey to the overactivity of acetylcholinesterase. In order to fix this problem with choline alone, your child would need a constant 24/7 supply, something that is both impractical and impossible.

(NOTE: Though existing studies on MicroRNA levels in DS, including those measuring MicroRNAs not mapped to C21 have never reported over expressed  levels of mRNA 132, a recent paper indicated elevated 132 in DS cells. However, the activity and inactivity of associated pathways and proteins cannot confirm and argued against these findings. We will continue to look for the necessary confirming studies and make appropriate protocol adjustments if scientifically proven necessary).

MicroRNA 132 is not over expressed in DS – See chart.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625835/

We have always known that acetylcholine is low in DS but until the identification of MicroRNA 132 the mechanism and extent could only be guessed at. Recognizing the role of MicroRNA 132 gives us a tool for improving the status of acetylcholine in the brain and in muscle.

How can this be done? A functioning cholinergic pathway depends on numerous things. Normal levels of of RCAN1, sufficient CREB activity, normal levels of MicroRNA 132, available choline stores and normal activity of acetylcholinesterase. There are other measures that must be considered. DYRK1A has a negative impact on RCAN1, it must be down regulated. Acetylcholine and Nuropeneprine work closely together in the Hippocampus to effect learning and memory. It must finely tuned. To down regulate DYRK1A we utilize EGCG, to effect stable levels of Nuropeneprine, we rely on Curcumin. It is at this point that I must reiterate that this new addition will have little or no benefit if you fail to follow the entire protocol. You cannot ignore one gene, neurotransmitter or pathway and expect good results. So what can we do to increase the effectiveness of TNI in light of these findings?

1) Follow the current protocol. Do not add to it or deviate from it. This means you may not skip the Polyphenol Formula, your child needs everything in including EGCG and Curcumin.

2) Add equal measures of Luteolin and Rutin. Luteolin has been proven in studies to help stabilize MicroRNA 132. Rutin improves the action of Luteolin permitting the use of less luteolin.

3) Add Huperzine A, an acetylcholinesterase inhibitor to your child’s protocol.

What is Huperzine A and how does it correct this problem?

Huperzine A (HUP A) is a natural, reversible acetylcholinesterase inhibitor. In studies comparing it to pharmaceutical acetylcholinesterase inhibitors, it was found to be both more effective and much safer. When you inhibit this enzyme, acetylcholine remains available at the synaptic cleft permitting the uninterrupted transmission of impulses from neuron to neuron, and from the neuromuscular juncture to the muscles. Over all your child should see global improvement, but that will differ from child to child for reasons we cannot fully understand. We do know that RCAN1 is a very sensitive gene. It responds to numerous substances by expressing its gene product. RCAN1 is over expressed in Alzheimer’s disease even though there is no additional gene. This has been traced to environmental toxins, in particular, cigarette smoke. However, it can over express from things as simple as other supplements, air born toxins, vaccine, numerous medications and many unknown substances. It is a very difficult gene to control. We will, in the future, find better ways to deal with RCAN1. In the meantime, it is possible that a fluctuation in the expression of RCAN1 can lessen a child’s response to Huperzine A. However, it will produce an astounding impact on your child’s function.

Later this week, I will post supporting research and discuss the potential impact on the gut. There are several neurotransmitter involved in gut function. It may be necessary to address more than just acetylcholine. Do not, initially, forego your current regime of preventing constipation when you begin Huperzine A unless your child develops diarrhea. At that time you can begin easing your child off of stimulants but you will always need to keep the stool soft.

Dosage for Huperzine A has been established by research as 3 mcg (micrograms) per kg. Start at 1-1.5 mcg per kg. Once daily. Best given with the Polyphenol Formula, Curcumin and additional Choline. Use NOW Choline/Inositol blend. Dose at 4 mg per kg for best results.

Dosage for Luteolin/Rutin has been established by research as 1.5 milligrams per kg 2x daily. Given a.m. with the Daytime Formula and with second dose given with Huperzine A, Curcumin, Extra Choline and the Polyphenol Formula.

EDITED TO ADD:

Due to lack of long term trials we recommend you give your child a full 48 hour break once a month.

There are far too many studies to post them here. But, they are available on the website for your review.

http://trisomy21research.org/2018/08/29/studies/