The use of Resveratrol and EGCG in Trisomy 21/ Down syndrome

Resveratrol (from grapeskins or Knotweed) and EGCG (from Green tea) have multiple benefits, including supporting cell health, anti-aging benefits, immune response support, healthy inflammatory function, anti-oxidant effects, and brain and neurological support. However,  Resveratrol and EGCG are two phytochemicals with very important roles in TNI (targeted nutritional intervention- the name for the protocol to address gene over-expression caused by Trisomy 21/ Down syndrome.)

Plant polyphenols as natural drugs for the management of Down syndrome and related disorders.    https://www.ncbi.nlm.nih.gov/pubmed/27826066

The polyphenols resveratrol and epigallocatechin-3-gallate restore the severe impairment of mitochondria in hippocampal progenitor cells from a Down syndrome mouse model.  https://www.ncbi.nlm.nih.gov/pubmed/26964795

RESVERATOL

Resveratrol is used in T21 to address Micro RNA 155.An elevation of MicroRNA – 155 causes permeability in the Blood Brain Barrier (BBB), which allows toxins and other things to get to the brain and nervous system tissue.In Trisomy 21/ Down syndrome, people have a minimum of a 30% – 50% over expression. This results in constant access to the brain of toxins that might otherwise be filtered by this barrier. A damaged blood brain barrier will not let everything cross it to enter the brain but neither will it efficiently keep every harmful thing out of the brain. Studies have proven that it reduces 155 by upregulating MicroRNA-633. Since 633 is a tumor suppressor gene, this is a plus.

Studies have confirmed that Resveratrol heals the BBB in Alzheimer’s disease. The mechanism in AD and DS creating the permeable BBB is the same. There is every reason to believe that Resveratrol takes care of this, but it is not know to what degree.

“The homeostasis of the central nervous system (CNS) environment is maintained by the BBB, which separates the brain from the systemic blood circulation. The cerebral capillaries are organized such that the brain is protected from blood-borne compounds, since a strict homeostasis of the neuronal environment and an intact barrier are essential for optimal brain functioning. However, during various neurological diseases the permeability of the BBB may be changed. This review will discuss the role of the BBB and especially of the CEC in various neuroinflammatory diseases.”http://pharmrev.aspetjournals.org/content/49/2/143

Resveratrol also protects from hypoxia, an issue in Ds because of the high amount of sleep apnea in the Ds population.

Protective effect of resveratrol against chronic intermittent hypoxia-induced spatial memory deficits, hippocampal oxidative DNA damage and increased p47Phox NADPH oxidase expression in young rats. http://www.ncbi.nlm.nih.gov/m/pubmed/26940604/

Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer’s disease.  https://www.ncbi.nlm.nih.gov/pubmed/25024312

But there is another issue In Trisomy 21/ Down syndrome where resveratrol is particularly useful.

Resveratrol helps repair telomere shortening by upregulating telomerase. Studies suggest that it does not require large doses to effect telomere length.

Immortalization of epithelial progenitor cells mediated by resveratrol http://www.nature.com/onc/journal/v27/n17/full/1210886a.html

SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene.   http://www.ncbi.nlm.nih.gov/pubmed/22197555

http://munews.missouri.edu/…/1119-natural-compound…/

What does this mean for people with Down syndrome?

It means Resveratrol may be an answer to yet another serious issue in DS.

“It is suggested that telomere repair is directly related to cell survival (fact) and human longevity (both fact and probability). In DS the telomeres are very short in comparison to normal controls and they simply do not repair at the rate seen in the non DS population. Giving our children the ability to repair the telomeres may help prevent rapid aging, Alzheimer’s disease, Leukemia, and other age related diseases, including autoimmune diseases associated in younger people and even small children with DS. One very important result may be giving our children an additional decade or more of healthy life.

The tips of chromosomes (think about the tips of a shoe string) are called telomeres. These prevent the destruction of DNA and serve other purposes. Every time a cell divides telomeres shorten. It’s as it the tips are chipped off during cell division. But the human body produces an enzyme called telomerase that activates and repairs the telomeres instantly. What a miracle. But not for our children. The telomeres shorten but are not easily repaired. In time, they are too short to sustain life and it may well be a major reason for premature death in DS. Remember, on average, our children’s lives are 20 years shorter than a non DS individual. That means that DS is a terminal disease by definition because death is directly related to it. But! Resveratrol upregulates telomerase and allows the repair of telomeres. You can see how critical Resveratrol is for our children.”

-Dixie Lawrence, T21 biochemist and Ds researcher

EGCG

EGCG is used to down regulate DyrK1a, and enhance learning, cognition and memory.

Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A.  https://www.ncbi.nlm.nih.gov/pubmed/19242551

Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome? https://www.ncbi.nlm.nih.gov/pubmed/28203607

Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome. https://www.ncbi.nlm.nih.gov/pubmed/27844057

Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and degrades the amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated as a cause of Alzheimer’s disease.

Neprilysin is low in the brain of both AD and Down syndrome patients. A recent study found that a DYRK1a inhibitor, harmine, upregulated Neprilysin in both DS and AD.

Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts https://www.jstage.jst.go.jp/arti…/…/40/3/40_b16-00825/_html

Harmine, the compound utilized in the above study is not an option for use in DS as there are numerous issues involving both side effects and availability. However, EGCG is very similar in structure and also acts as a DYRK1a inhibitor and has the identical effect on Neprilysin, increasing its levels in the brain.

(-)-Epigallocatechin-3-gallate attenuates cognitive deterioration in Alzheimer’s disease model mice by upregulating neprilysin expression. https://www.ncbi.nlm.nih.gov/pubmed/…

DOSAGE RECOMMENDATIONS

Resveratrol- start with .5 – 1 mg/kg (1 mg of resveratrol per 1 kg of body weight).  Do this does 2 times a day, spaced at lest 8 hours apart.  Gradually increase the dose to 4-5 mg/kg.

EGCG- start with .5-1 mg of EGCG per kg of body weight.  Gradually increase the does anywhere from 3-5 mg.kg.  Some studies and protocols for much higher amounts.

ADDITIONAL CONSIDERATIONS

EGCG needs to be separated from folate (like in NuTriVene) by 4 hours, as EGCG can effect one of the enzymes in the folate pathway.

At doses much higher than we are using in T21, liver and kidney stress have bee noted.  If your child is low in ferritin, be sure to monitor it, and additional supplementation with a high quality iron and adding organ meats to the diet may be warranted- as EGCG can in some cases, have a chelating effect on iron.