What Can Hippocrates Teach Us?
Or, Inflammation & Multiple
Sclerosis
Bernhard H.J. Juurlink, PhD
Professor emeritus, Department of
Anatomy & Cell Biology, College of
Medicine, University of Saskatchewan

 Health Canada has recently approved Tecfidera
(BG12 or dimethyl fumarate) as a treatment for multiple sclerosis. Tecfidera is an Nrf2 activator.

The therapeutic effects of Tecfidera can be as readily obtained through dietary Nrf2 activators and with fewer side-effects

Hippocrates stated: ‘Let food be your medicine and medicine your food’

BUT - there are few funders for nutritional clinical trials. The health care and health research agencies have abdicated their responsibilities for the Public
Good. The Public Good has been replaced by the
Private Good (i.e., industry and their profits)

Let Us First Consider The Roles of
Inflammation in Multiple Sclerosis

Inflammation is necessary to fight infection: but in the absence of infection inflammation is harmful
Salvador Dali: ‘Fight between San Salvador and Antoni Gaudi’


Veins need to be inflamed before immune cells can enter the brain and spinal cord tissue

Inflamed endothelium is leaky (blood-brain barrier breakdown)

Inflamed endothelium releases cytokines & chemokines that activate and attract lymphocytes

Only inflamed endothelium can interact with lymphocytes allowing their entry into brain and spinal cord tissue

Without endothelial inflammation there can be no immune attack on myelin and oligodendrocytes


Angioplasty causes tissue damage that in turn causes inflammation

Inflammation causes fibrosis that causes renarrowing of the veins

Decreasing the likelihood or extent of inflammation decreases the probability
(and severity of relapses) and the probability of re-narrowing of veins

What Can Cause Inflammation In the
Absence of Infection*?

Essentially oxidative stress drives inflammation
(oxidative stress is essentially ‘rusting’ of our cellular molecules)

Our bodies normally produce oxidants and when we are young can readily inactivate the oxidants

Note: We need inflammation to fight an infection – compromising the ability of the immune system to fight an infection is dangerous, as is seen with Tysabri


Wear and tear on our metabolic machinery as we age. Aging is associated with an increase in generalized inflammation

Hypoxia (curiously) – that is, low blood flow

Tissue damage
 Angioplasty causes tissue damage that results in inflammation. This inflammation can cause fibrosis and this fibrosis can result in the re-narrowing of the vein(s)

Hypoxia, itself, will cause tissue damage

How Does Oxidative Stress Cause
Inflammation?

A major means is to activate a protein complex known as nuclear factor kappa B (NF k
B)

Activated NF k
B moves to the nucleus and increases the expression of pro-inflammatory genes whose protein products drive inflammation

k

 Cytokines & chemokines

Activate and attract leukocytes to site of infection or damage

Cell adhesion molecules

Necessary for leukocytes to move from blood to tissues such as brain and spinal cord

Cyclo-oxygenase-2 (COX2)

Initiates process that produces eicosanoids that further promote inflammation. Aspirin and other NSAIDs inhibit COX2 activity and steroids such as prednisone completely stop this inflammatory pathway

Etc

Decreasing Non-Infectious
Inflammation Will:

Decrease the probability of blood-brain barrier breakdown and associated immune-mediated attack on white matter

Decrease the probability of restenosis of
‘ballooned’ veins

But likely will not address the underlying cause of MS

How To Decrease The Probability of
Non-Infectious Inflammation

1. Decrease the probability of formation of pro-inflammatory eicosanoids that form due to
COX2 enzymatic activity

2. Decrease the probability of activation of
NF k
B

1: Decrease Probability of Forming Pro-
Inflammatory Eicosanoids from COX2 Enzyme
Activity

Eicosanoids that are produced from omega-6 fatty acid are mainly pro-inflammatory while eicosanoids produced from omega-3 fatty acids are mainly non-inflammatory or even antiinflammatory

The ideal ratio of dietary omega-6 to omega-3 fatty acids is ~2:1

The typical Western diet has an omega-6 to omega-3 fatty acid ratio of ~15:1; hence, it is a pro-inflammatory diet

Attaining a Healthy Omega-6 to
Omega-3 Fatty Acid Ratio

All commonly used vegetable oils are very high in omega-6 fatty acid except for canola oil

Canola oil has a ratio of omega-6 to omega-3 of 2:1

Dark green vegetables have the desired omega-6 to omega-3 ratios
 Fatty fish is high in omega-3 fatty acids

However, consuming fish omega-3s while consuming high levels of omega-6 fatty acids probably accounts for the conflicting research results on the benefits or lack thereof of fish oil

Typical Omega-6 to Omega-3 Ratios in
Commonly Used Oils

Peanut oil: >1,000:1

Sunflower oil - 71:1

Corn oil – 57:1

Solin oil - 36:1

Soy oil – 7:1

Canola oil: 2:1

2: Decreasing the Probability of NF k
B
Activation
 Decrease oxidative stress – this increases with metabolic diseases, injury as well as with age

Glutathione (GSH and associated enzymes are important in inactivating oxidants

Glutathione (GSH) and GSH-Dependent Enzymes
Play a Central Role in Inactivating Oxidants


Increase consumption of proteins rich in the amino acid cysteine

Prolonged heating (cooking) can destroy a significant fraction of cysteine. Hence, eating minimally-heated proteins increases cysteine intake

Whey proteins are rich in cysteine and many whey protein preparations are minimally heated during processing

Increasing Gene Expression of GSH-
Dependent Enzymes

Increase consumption of dietary Nrf2 activators that are present in:

Brassicas: cabbage, broccoli, Brussel’s sprouts, kale, arugula, mustards, horse radish, capers, etc (certain glucosinolates and flavonoids)

Small berries: blue berries/cranberries, raspberry/blackberry, strawberries (certain flavonoids)

Onion family (allyl sulfides and certain flavonoids)

Beets (betalains plus certain beet molecules also promote blood flow)

Ground flax meal (the lignan SDG)

Soya meal (genistein)

The spice turmeric (curcumin)

Cold-pressed olive oil (contains oleocanthal)


Either by oxidizing thiols (-SH groups) in a protein known as Keap1 that then releases
Nrf2 allowing it to move to the nucleus where it turns on Nrf2-activatable genes

Or by influencing MAP kinase enzymes that also regulate Nrf2 movement to the nucleus


A large number of compounds will oxidize thiols

Most dietary Nrf2 activators have the molecular shape and charge distribution that will allow them to oxidize Keap1 thiols at very low concentrations, e.g., sulforaphane has a QD of 0.1 micromolar

Tecfidera is a thiol oxidizer that has a QD of 5.0 micromolar - this means that Tecfidera will do 50 times more damage to cells than sulforaphane to achieve the same therapeutic Nrf2 activation effect


Many flavonoids will also activate Nrf2 through modulating MAP kinase enzyme activities - they do not oxidize thiols. These flavonoids usually require concentrations of around 5.0 micromolar. The flavonoids include:

Quercetin – high concentrations in onions, brassica family, apples and black tea

Kaempferol – very high concentrations in brassica
(especially high in kale and capers)


Tecfidera or diet? Which route should one go?

Clinical trials have enabled us to know the minimal concentration of Tecfidera that is therapeutic

There are no clinical trials to determine which concentrations of dietary Nrf2 activators are therapeutic – why is that?


Driven by government policy is that research ought to yield intellectual property that can be licensed to industry
 Gone are the days when governments funded research for the general Public Good

This is how many strains of wheat, potatoes, the original canolas, etc were developed

Even private funding agencies such as the
Multiple Sclerosis Society of Canada promote research that can result in Intellectual Property

Chronic Cerebrospinal Venous
Insufficiency

There is no intellectual property in angioplasty

Is this the subliminal motive underlying the disdain exhibited by the majority of health researchers and health care providers to towards the idea that venous return problems contribute to the symptoms of multiple sclerosis?

‘Bond of Union’ by M.C. Escher


Which makes more economic sense?

Ameliorate or prevent diseases through evidencebased lifestyle changes

Create a few more jobs for pharmaceutical industry sales representatives while impoverishing the public and governments through increased pharmaceutical drug costs

‘Persistence of Memory’ by Salvador Dali