31 for 21: Oxidative Stress & Down Syndrome

Well, 31 for 21 is coming to a close. I didn't get nearly as many "in-depth" posts up as I may have liked. So, I'll just have to work on that over the next few months :).

Today, I wanted to share a study that came across a DS listserv the other day on Oxidative Stress and Down syndrome.

Oxidative Stress and Down Syndrome: A Route toward Alzheimer-Like Dementia

You can view the full text of the report here.

I wanted to point out a few quotes from the conclusion.

It's already a well established fact that there is increased oxidative stress in Down syndrome, just like this points out.

"Within the context of the reported findings discussed above, we hypothesize that trisomy affects gene/protein expression that results in increased OS conditions and impaired mitochondrial function. These alterations occur early in DS as demonstrated by studies performed on fetal brain and amniotic fluid from DS pregnancy and play an important  role in neurodegeneration."

This is true below and a lot of people may not realize it. It's not just that the overexpression of SOD1 causes increased oxidative stress. It also reduces levels of agents that would counter act that oxidative stress and lowers the antioxidant enzymes.

"OS conditions arise not only from overexpression of SOD1 but also as a consequence of low levels of reducing agents and antioxidant enzymes."

Just thought this was an interesting statement:

"It is now well accepted that OS contribute to neurodegeneration, but in the case of DS and AD, genetic similarities, due to the fact that some of the genes responsible for familial form of AD are encoded by Chr21, provide an interesting field of research for the comprehension of many yet unsolved issues."

This is exactly why targeted nutritional intervention is so entirely important for individuals with DS. We have to combat the low antioxidant levels in DS with plenty of antioxidants!

"Based on this notion, it is possible that using antioxidant nutrients to scavenge oxygen-derived free radicals may modulate some of the complications of DS. "

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Using Evening Primrose Oil, Is it Good or Bad?

Evening Primrose Oil is commonly used as a vegetarian source for essential fatty acids (EFAs): omega 3's, omega 6's, gamma linoleic acid (GLA) & linoleic acid (LA). This used to be commonly be recommended by those in the supplementation world of DS, but then after more current research, the recommendation was reversed.

Dr. Leichtman used to recommend the use of EPO as well (as his website states, but that is out of date), but presently does not recommend it.

When we first started supplementing with TNI, Omega 3's, etc, I remember all the talk of how people used to use EPO and switched to another source. Recently I've been seeing a lot of families starting to use EPO again and it's raised questions and concerns in my mind. Because I recall there being a concern back in the day, but I couldn't remember the exact reason for why.

Well, because my research side of me wants to be informed, I looked up the use of EPO again.

It is true that there are benefits that EPO can give. Andi over at Down Syndrome: A Day to Day Guide shares some good info on her blog here. Since Andi has all the good info on EPO on her blog, I won't explain it all here :).

But, there are also risks involved with giving EPO. Omega 6's are essential fatty acids, but they must be given in moderation, as they can increase oxidative stress.

The two main fatty acids EPO converts to is GLA & LA. Both of these, but particularly, LA have been shown to induce oxidative stress & damage, as well as programmed cell death (apoptosis). While, certain amounts of LA and GLA can have some antioxidant states, they more commonly increase oxidative stress.

There is so much extra oxidative stress in people with Down syndrome due to the overexpressed genes on the 3rd chromosome. In DS, there is not enough antioxidants to battle this already highly oxidant state.

I am hesitant to supplement with a product that is known to increase oxidative stress, however mild it may be. While EPO isn't a very high pro-oxidant vegetable origin of omega 3's, it does still encourage a pro-oxidant state.

While there are no studies, as usual, on EPO in people with DS, you can see a couple studies here and here.

One quote from the discussion of the second study is below,

The possibility arose by in vitro experiments that a high intake of LA would increase oxidative stress in the body is supported by the results of our strictly controlled human experiment... ...although the intake of antioxidants and plasma levels of a-tocopherol of our subjects were well above recommendations.

Flax seeds that are freshly ground are a much better source of vegetarian omega-3's & 6's, but it is harder to quantify. EPO may be okay to give, if it is given in small amounts. I do not feel comfortable giving it at all, therefore we stick with fish oils for our essential fatty acids.




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Why is Glutathione low when Cysteine is high?

A question that I have thought many times, and was also recently asked is, "Why is Glutathione low when Cysteine (a component which makes up Glutathione) is in excess in DS?"

It's a good question. And a hard one at that!

Bottom line - No one really understands it all the way. But, this is what is understood:

There is excess cysteine due to the overexpressed CBS gene. Then there is also the overexpressed SOD1 gene causing a 50% increase in oxidative stress/free radicals. This increase in oxidative stress seems to cause a decrease in Glutathione, as there are not enough antioxidants (Glutathione being one of them) to match the amount of oxidative stress and free radicals which are present.

One of the best studies on the topic is, Homocysteine Metabolism in Children with Down Syndrome: In Vitro Modulation. One quote from the abstract says,

Plasma levels of cystathionine and cysteine were significantly increased, consistent with an increase in CBS activity. Plasma glutathione levels were significantly reduced in the children with DS and may reflect an increase in oxidative stress due to the overexpression of the superoxide dismutase gene, also located on chromosome 21.

 Another good article on this topic is Steven Fowkes article from CERI, Antioxidant Intervention in Down's Syndrome. This article is a few years old (written in 1998), but it is still interesting.




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Supplementing with S.O.D - Is it Good or Bad?

One of my blog readers left a comment on a post mentioning that they give their daughter S.O.D (SuperOxide Dismutase) as a supplement. In the meantime, I have had email correspondance with them and discussed this topic, but I thought it would be helpful to share here as well.

SuperOxide Dismutase itself is sold as a vitamin supplement by a lot of companies. In and of itself, SOD is not bad. It is a powerful antioxidant. But, as with almost anything, too much SOD, causes lots of damage.

The gene for SOD is on the 21st chromosome and is 50% overexpressed in Down Syndrome because of the triplicated chromosome 21.

One example of the increased SOD can be seen in the study, Increased superoxide dismutase and Down's syndrome,

The enzyme superoxide dismutase (SOD) is a constitutive enzyme coded by a gene located in Chromosome 21 (21q22.1). Thus, the tissues from patients with trisomy 21 contain 50% more SOD activity.

This triplication causes an increase in the hydroxyl radical, which causes free radicals. Free radicals then turn into oxidative stress. Oxidative stress causes apoptosis (programmed cell death). 

Because of this, I would not supplement with S.O.D. because it IS in excess in DS.  And the excessive amounts are not helping people with DS, but actually causing many problems.

In Down Syndrome there are not enough antioxidants to combat the increase in oxidative stress, because the antioxidants are low. Zinc is low in DS, because of the overexpressed SOD gene. Glutathione is low because of the overexpressed Glutathione Peroxidase gene.

There are so many other good antioxidants that you can give people with DS, such as Zinc, Vitamin E, Glutathione, Blueberry, Curcumin, Coenzyme Q10,  etc, that I would not want to supplement with a source that is known to be overexpressed in DS.

Is the supplemental form of SOD the same as the form that is overexpressed in DS? I don't know, but personally, I wouldn’t want to risk it. SOD is overexpressed from the time the child is in the womb and throughout their whole life.



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Study shows Low Melatonin in children with Down Syndrome

I thought this was an interesting study. I will bold the most important parts, so you don't have to read through it all to see the conclusion.

Although we do not, a lot of people supplement extra Melatonin to their children with DS to help with sleep. This study is interesting in light of that, as a lot of people with DS respond really well to Melatonin. I guess you could get two birds with one stone with this - help with sleep and help reduce oxidative stress.

J Pediatr Endocrinol Metab. 2010 Mar;23(3):277-82.
Melatonin and elimination of kynurenines in children with Down's syndrome.
Uberos J, Romero J, Molina-Carballo A, Muñoz-Hoyos A.
Source

Departamento de Pediatría, Facultad de Medicina, Universidad Granada, Granada, Spain. uberosfernandez@terra.es

Abstract

BACKGROUND:
Heightened activity of superoxide dimutase is an effect derived from the gene dose in the trisomy of Down's syndrome (DS), and has been related to the increased production of hydrogen peroxide and with greater lipid peroxidation. Many of the degenerative changes observed in patients with DS have been associated with the pathological effects of free radicals, and for this reason it is of interest to determine the levels present in these patients of powerful antioxidant molecules such as melatonin, and of metabolites with important neuroprotector and neurotoxic consequences such as those derived from the kynurenine pathway.

PATIENTS AND METHODS:
A study was made of 15 children with DS, together with a control group of 15 non-DS children, matched for age and sex, examined at the Hospital Costa del Sol, Marbella, Spain. Serum melatonin and serotonin were analyzed by RIA; urinary tryptophan metabolites (kynurenine pathway) were determined during periods of light and darkness (09.00-21.00 h and 21.00-9.00 h) by thin-layer chromatography.

RESULTS:
The mean values of serotonin and melatonin were found to be lower in the patients with DS, although the level of nocturnal secretion of melatonin was higher. Urinary excretion of kynurenine was lower in the patients with DS, although greater quantities of kynurenic acid and anthranilic acid were excreted.

CONCLUSIONS:
Patients with DS present levels of plasma melatonin and urinary kynurenine that are lower than the corresponding levels in the control population, together with higher values of kynurenic acid and anthranilic acid. These circumstances constitute an added risk to these patients of damage by free radicals.



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31 for 21: Glutathione

Side note: There was a mis-link on the post from yesterday regarding the Down Syndrome awareness shirts. The correct link is on that post, but you can also order the shirts from here.

There was some recent discussion on the Einstein Syndrome list (I know I mention this list frequently, but it's such a beneficial list!) about Glutathione (GSH) and if it's beneficial or not.

Bottom line: Yes, it's very beneficial!

But, I'll get to more detailed information here :).

L-Glutathione is an amino acid, which is a tripeptide (made up from 3 other amino acids). It's also a potent antioxidant and helps with many different functions in the body.

One of the best articles I have ever read on Glutathione and it's many mechanisms is Glutathione: Systemic Protection Against Oxidative & Free Radical Damage, which you can view as a full text here.

Glutathione is essential in the body's antioxidant system. As one quote from the above study says,

Antioxidants are the body's premier resource for protection against the diverse free radical and other oxidative stressors to which it invariably becomes exposed. the antioxidant defense system is sophisticated and adaptive, and GSH is a central constituent of this system

 Another interesting quote,

The consequences of sustained GSH depletion are grim. As cellular GSH is depleted, first individual cells die in those areas most affected [my note: we have lots of cell death already going on in DS]. Then zones of tissue damage begin to appear; those tissues with the highest content of polyunsaturated lipids and/or the most meager antioxidant defenses are generally the most vulnerable. Localized free-radical damage [my note: which is an issue in DS, due to low antioxidant levels & high oxidative stress] spreads across the tissue in an ever-widening, self-propagating wave. If this spreading wave of tissue degeneration is to be halted, the antioxidant defenses must be augmented.

Because Glutathione is low in people with DS and because it plays such a vital role in the immune system, it's important for us to try to help raise the levels of Glutathione in the body. Nutrivene-D does have Glutathione in it.

But, there is one tricky thing with GSH.

It's not very easily absorbed, although it can be absorbed. The best form of GSH is Reduced L-Glutathione. There are also some other forms of GSH called Lipsomal GSH, sublingual GSH and I believe there is also a Glutathione patch that people in the Autism community use. All of the above forms are supposed to be absorbed pretty well.

Methylcobalamin B12 also has been shown to help raise Glutathione levels in a study done by Jill James.

Someone may wonder about using N-Acetyl-Cysteine (NAC) to raise Glutathione levels. If you do much research, you will see this mentioned when talking about ways to raise Glutathione. From the research I have done, NAC should not be used in Down Syndrome. It has been shown to increase oxidative stress in people with DS and it also appears that it can cause leaky gut. Neither of which are needed in anyone, let alone someone with DS who is already struggling with increased oxidative stress and possibly gut issues.

Finally, one more interesting note about Glutathione from the above study,

Many pharmaceutical products are oxidants capable of depleting GSH [my note: Glutathione] from the liver, kidneys, heart, and other tissues. The popular over-the-counter drug acetaminophen [my note: active ingredient in Tylenol] is a potent oxidant. It depletes GSH from the cells of the liver [my note: which is where GSH is made & stored], and by so doing renders the liver more vulnerable to toxic damage.

Some may say it doesn't really matter if a drug such as Tylenol is used, if it's used in moderation. If you are comfortable giving your child Tylenol at various times, that's fine. It may be necessary at some times. We do not give Tylenol to O because of the concern that it would deplete already low Glutathione levels. There's more info on GSH and the Acetaminophen issue here.

*Don't forget to enter the book giveaway, which ends on November 2nd!*

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Full text available

I received the full text of the study done by Franz on the Brain's good and bad iron. If anyone is interested in it, feel free to email me (qf@gotdowsyndrome.net) and I will send it to you :).