CCSVI & Dr. Bernie Juurlink's Thoughts On Anti-Inflammatory Diets

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CCSVI Circular *Inaugural Issue* Dr. Bernie Juurlink's Thoughts On

Anti-Inflammatory Diets

The National CCSVI Society is pleased to launch a series of essays written

on issues of particular interest to MS and CCSVI patients, caregivers,

health care practitioners by experts in the field. With our first issue, we

present Dr. Bernard Juurlink’s thoughts on anti-inflammatory diets. Dr.

Juurlink is a Board member with the National CCSVI Society. His professional

biography is found on our website:

http://www.nationalccsvisociety.org/our-board

*CCSVI Circular*

*Volume 1: Issue 1*

*Thoughts On Anti-Inflammatory Diets*

Bernhard H.J. Juurlink

Professor of Anatomy & Cell Biology

To understand the role of glutathione and dietary compounds in health

requires a bit of background on cellular metabolism and signaling. I shall

try to keep this background simple.

*Oxidation and Reduction Reactions:* The chemical reactions that sustain

life involve the transfer of electrons from one molecule to another. Loss

of an electron is known as oxidation and gain of an electron is known as

reduction; therefore, such reactions are known reduction-oxidation reactions

or redox reactions. Molecules that are electron deficient are oxidized (or

rusted in the same manner that iron rusts). Normally in metabolism when

molecules are oxidized (lose an electron) at some point that molecule or

product of that molecule will gain an electron (reduced) to maintain

electron balance. Sometimes this does not happen and the cells of the body

accumulate oxidized molecules that will affect the function of the

molecules. Increase in oxidized molecules is known as oxidative stress.

*Cellular Signaling and Inflammation:* The cells in our body must

communicate with each other. They do this via hormones and hormone-like

molecules. These molecules act on receptors present on or in the cells.

Activation of a receptor by the binding of a hormone results in a signaling

cascade of events that changes the metabolism of the cell as well as changes

gene expression. The signaling cascade molecules are mostly proteins. The

end result of many of these signaling pathways is a change in gene

expression. Of particular interest to those with MS is that several of

these signaling pathways result in expression of pro-inflammatory genes that

cause inflammation to ensue: the symptoms of MS are clearly inflammatory

driven. I will focus of how oxidative stress can drive inflammatory

reactions.

Most signaling processes in a cell involve the addition of a phosphate

chemical group to a downstream protein usually activating this protein. The

enzyme that adds the phosphate is known as a kinase – there are many

different kinases. One very important signaling cascade that promotes

pro-inflammatory gene expression is the NF kappa B cascade. There are also

MAP kinase cascades that can promote pro-inflammatory gene expression.

One cannot have a permanent state of activation: once the signaling protein

is activated it must become inactivated for normal functioning of the cell.

This is done by removal of the phosphate chemical group previously added.

The enzymes that remove the phosphate group are known as phosphatases.

Phosphatases are easily oxidized and their enzyme activity is lost; thus,

one consequence of oxidative stress is overstimulation of the NF kappaB

pathway and the MAP kinase pathways with the consequence being increased

pro-inflammatory gene expression and subsequent inflammation. Decreasing

oxidative stress allows a more normal phosphatase activity thereby allowing

more normal signaling to occur in cells with a consequence that there is

less of an inflammatory environment. If one has MS, then a less

inflammatory environment decreases the probability of exacerbations.

Glutathione plays a very central role in decreasing oxidative stress.

*Glutathione: *Glutathione is a three-amino acid peptide that is an

electron donor and donates electrons to oxidized molecules, normalizing the

function of the molecules. For example, glutathione can donate electrons to

oxidized phosphatases allowing them function normally and limits the extent

of activation of NF kappa B and MAP kinases. Glutathione is oxidized in

this reaction but cells have exquisite cellular machinery to reduce the

oxidized-glutathione back to glutathione.

Lower than normal glutathione levels promote oxidative stress and, thereby,

inflammation. Glutathione is comprised of the following three amino acids:

glutamate, cysteine and glycine. As we get older our cellular glutathione

levels become lower. Those who age the most gracefully have better

maintenance of cellular and tissue glutathione levels. The question becomes

how to optimize our cellular glutathione. Pharmaceutical injections of

glutathione are of little value since the amount that can be administered is

only a small fraction of total body glutathione and thus injections have no

measurable effects on the body’s function, except perhaps for the very

localized region of injection. Consuming glutathione is also not effective

since our intestines will break the glutathione down into its constituent

amino acids and you need to consume an awful lot of glutathione to take in

adequate levels of cysteine. Fortunately, there are several simple dietary

ways of increasing our cellular glutathione levels.

There are two essential aspects of glutathione synthesis that are

rate-limiting: availability of the amino acid cysteine and the activity of

the rate-limiting enzyme gamma-glutamyl-cysteine ligase (GCL).

*Cysteine*: Cysteine is one of the rarer amino acids found in proteins and,

hence, in our diet. One can increase tissue glutathione by ensuring that

there are adequate cysteine levels in our diet. A very rich source of

cysteine is whey protein. Whey protein can be found in health food stores.

*GCL and other phase 2 proteins:* The rate-limiting enzyme for glutathione

synthesis (GCL) belongs to a large group of proteins known as phase 2

proteins. Phase 2 proteins either decrease the probability of oxidant

formation (e.g., sequestering iron thus preventing iron-mediated damage) or

the increases the ability of our cells to reduce (i.e., inactivate

oxidants). GCL does this by being a critical component in the synthesis of

glutathione. What is interesting as well about phase 2 proteins is that

their gene expression is coordinately by activation of a protein known as

the Nrf2. Activated Nrf2 increases the expression of all phase 2 protein

genes. Of relevance to this article is that there are a number of

phytochemicals found in foods we eat that activate Nrf2. Some of these

chemicals are very potent activators of Nrf2 while others are less potent.

Very potent activators include sulforaphane found in the cabbage family

plants such as Brussels’ sprouts and broccoli. Sulforaphane is found in

very high amounts in sprouts of certain varieties of broccoli. Other potent

activators are diallyl disulfide found in onions and garlic, the isoflavone

genistein found in soya products and isoflavone kaempferol found in high

amounts in kale. The principal lignan (SDG) in flax seed is converted to

potent Nrf2 activator enterolactone by our gut bacteria: enterolactone is

then taken up by our intestine. There are still yet-to-be identified

flavonoids that activate Nrf2 in the blue berry-cranberry family.

The isoflavones genistein and enterolactone are also phytoestrogens and can

interact with estrogen receptors. In the past there has been some fear that

phytoestrogens may promote estrogen-sensitive breast cancer development.

There is no evidence for this; indeed, in the presence of estrogen,

phytoestrogens appear to counter the effect of estrogen, i.e., they

antagonize estrogen.

Other phytochemicals such as ellagitannins found in strawberries and

raspberries/blackberries, flavonoids such as found in green tea as well as

flavonoids such as quercetin (found in many food products such as black tea,

many vegetables and fruits (e.g., apples) and especially high levels in

onions also can activate Nrf2 but much higher concentrations are required.

A major advantage of increasing the consumption of dietary Nrf2 activators

is that dozens of different genes are upregulated whose protein products in

one way or another decrease oxidative stress.

*A note of caution:* Sulforaphane is derived from a precursor glucosinolate

molecule known as sulforaphane glucosinolate (or glucoraphanin). The

cabbage family can contain many different types of glucosinolates, some of

which give rise to compounds that interfere with iodine metabolism resulting

in thyroid problems. On the market there is only one variety of broccoli

sprouts that is known to be very high in sulforaphane glucosinolate and low

in the other glucosinolates: this BroccosproutsTM. I am not sure whether

Broccosprouts is available in Canada. This is not a plug for Broccosprouts

but a warning that consuming large amounts of broccoli sprouts where the

glucosinolate profile is not known may result in thyroid problems.

*MAP Kinase Inhibition:* Inflammation is characterized by over-activation

of several of the MAP kinase signaling pathways. A number of phytochemicals

in our diet have some ability to inhibit MAP kinase activity when tissues

are inflamed. The best characterized of these is the flavonoid quercetin.

There is a great deal of experimental animal evidence that increasing levels

of quercetin in our blood is therapeutic for many problems with an

underlying inflammatory component. So there is a medicinal chemistry basis

for the thinking that consuming tea (whether green or black), apples and/or

onions will keep the doctor away.

*The Therapeutic Effects of Omega-3 Fatty Acids:* One of the

pro-inflammatory genes is cyclo-oxygenase II (COX II). COX II oxidizes

arachidonic acid initiating a series of reactions that result in the

production of prostaglandins and thromboxane (collectively known as

eicosanoids), most of which promote inflammatory responses in white blood

cells and blood vessels. Aspirin and other non-steroidal

anti-inflammatories inhibit COX II activity, thus, inhibiting the formation

of eicosanoids. Arachidonic acid is found in cell membranes and must be

released from cell membranes by an enzyme known as phospholipase A2. One of

the major anti-inflammatory effects of glucocorticosteroids is the

inhibition of the activity of phospholipase A2 preventing the release of

arachidonic acid and, thus, not allowing the formation of eicosanoids. Many

MS patients have experienced how powerful in action a glucocorticoid

administration has – this is an indication of how very important role that

pro-inflammatory eicosanoids have in inflammation.

Arachidonic acid is an omega-6 fatty acid. The site that arachidonic acid

occupies in the membrane can also be occupied by omega-3 fatty acids such as

eicosadecanoic acid (EPA) or Docosahexanoic acid (DHA). If omega-3 fatty

acids are in the membrane, then phospholipase A2 will release omega-3 fatty

acids. COX II does not “care” if it is an omega-6 or an omega-3 fatty acid

that it oxidizes. Eicosanoids produced from omega-3 fatty acids tend to be

non-inflammatory while the eicosanoids from omega-6 fatty acids tend to be

pro-inflammatory. The proportion of omega-6 to omega-3 in our cell

membranes is directly dependent upon the proportions of these fatty acids in

our diet. The typical Western diet is rich in omega-6 fatty acids and poor

in omega-3 fatty acids.

Good sources of the EPA and DHA omega-3 fatty acids are fatty fish. There

are no plant sources for EPA and DHA but flax seed is rich in

alpha-linolenic acid (ALA) as are most nuts. Our bodies can convert about

5% of the ALA consumed in EPA or DHA.

*The Anti-Inflammatory Diet:* This diet should contain a good source of

cysteine. About the best protein source is whey protein. *(Dr Juurlink:

I’ll do some searching for recommended daily amounts – should somewhere

between 10 and 40 g – and update when I can).* The diet should be rich in

omega-3 fatty acids. This can be via eating fatty fish, capsules containing

defined amounts of EPA and DHA or consuming ground flax meal. Ground flax

meal will also increase the levels of the Nrf2 activator enterolactone in

the blood.

*A note of caution:* The problem with flax meal is that it is very rich in

soluble fibres and may give rise to excessive gas and/or diarrhea in certain

individuals. There is a great individual-to-individual tolerance to the

flax soluble fibres. Note also, that eating flax seeds is of little use

since they will pass through of intestine undigested: the flax must be

ground. Since flax meal is rich in alpha-linolenic acid (ALA) that can

easily oxidize in air, the flax seeds should be ground freshly to avoid

oxidation of (ALA).

The diet should be rich in Nrf2 activators that can be obtained from the

cabbage family, onions/garlic, kale, flax meal, soya products, small berries

especially blue berries and cranberries and their family members. Kale is

interesting since it is high in the Nrf2 activator kaempferol as well as in

the MAP kinase inhibitor quercetin. Onions are also interesting since not

only are they high in quercetin but also high in Nrf2 activating sulfur

compounds such as diallyl disulfide. Drinking tea, whether green or black

as well as apples is to be recommended.

With the plant phytochemicals there are almost no studies to indicate how

much of a given food should one eat to decrease the probability of

inflammation. I do know that if the average person eats a medium sized

onion, then the blood quercetin level is about 1 micromolar. My animal

studies have shown that strong therapeutic effects are seen in spinal cord

injured rats with about 5 micromolar quercetin. This suggests a

medium-sized onion daily with its quercetin content and sulfur compounds

might have some impact on inflammation.

*A note of caution:* If you have not eaten any of the above foods you may

wish to be a little careful at first in case you may have allergies. I know

some people have allergies to strawberries.

*Can An Anti-Inflammatory Diet Have An Effect On MS Progression?* We do not

know since we need clinical trials in humans but what pharmaceutical company

is interested in dietary clinical trials and the traditional funding

agencies will not fund such trials. Nine years my colleagues and I have

demonstrated in a rat model of experimental allergenic encephalomyelitis

(EAE) that administration of an Nrf2 activator greatly decreased the

severity of the lesions in the rat model of EAE. EAE is not really a

model of MS but it is the most widely used animal model of

inflammatory-mediated demyelination.

Of interest is that there is now a human clinical trial with dimethyl

fumarate. Dimethyl fumarate has been shown to have therapeutic effects in

psoriasis, another disease thought to be autoimmune in nature. Because MS

is thought to be primarily an autoimmune disease clinical trials with

dimethyl fumrate were initiated. The results to date are comparable to more

“standard” therapies such as beta-seron. Dimethyl fumarate has been known

for more than two decades to be a very potent activator of Nrf2. This

suggests that a diet rich in Nrf2 activators may well have some therapeutic

effect in MS.

*Final Thoughts:* To have an MS lesion one needs to have inflamed blood

vessels. Immune cells essentially require inflamed post-capillary veins to

enter the brain and spinal cord. An anti-inflammatory diet in principle

should decrease the probability of blood vessels being inflamed and, thus,

should in principle decrease the probability of an exacerbation. The

highest levels of the phytochemicals will be in the blood indicating the

most potent anti-inflammatory activities of phytochemicals may well be the

endothelial cell lining of blood vessels.