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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
The Role of Nutrition in Health
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 The Public Good has been replaced by the Private Good (i.e., industry and their profits)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
Salvador Dali: ‘Fight between San Salvador and Antoni Gaudi’
Inflammation is necessary to fight infection: but in the absence of infection inflammation is harmful
Inflammation and Veins-1
Veins need to be inflamed before immune cells can enter the brain and spinal cord tissueInflamed 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
Inflammation and Veins-2
Angioplasty causes tissue damage that in turn causes inflammation
Inflammation causes fibrosis that causes re-narrowing 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
What Can Cause Oxidative Stress?
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 flowTissue 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 (NFkB)Activated NFkB moves to the nucleus and
increases the expression of pro-inflammatory genes whose protein products drive inflammation
Pro-inflammatory Genes
Cytokines & chemokinesActivate and attract leukocytes to site of infection or
damageCell 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 NFkB
1: Decrease Probability of Forming Pro-Inflammatory Eicosanoids from COX2
Enzyme ActivityEicosanoids 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 anti-inflammatory
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 oilCanola 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 acidsHowever, 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: >1,000:1Sunflower oil - 71:1Corn oil – 57:1Solin oil - 36:1Soy oil – 7:1
Canola oil: 2:1
2: Decreasing the Probability of NFkB Activation
Decrease oxidative stress – this increases with metabolic diseases, injury as well as with ageGlutathione (GSH and associated enzymes are important in
inactivating oxidants
Increasing GSH Synthesis
Increase consumption of proteins rich in the amino acid cysteineProlonged 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)
How Nrf2 Activators WorkEither 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
Thiol-Oxidizers
A large number of compounds will oxidize thiolsMost 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
Plant Flavonoids and Nrf2
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 teaKaempferol – very high concentrations in brassica
(especially high in kale and capers)
Concluding Remarks
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?
Protectable Intellectual Property
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 GoodThis 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 angioplastyIs 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?
Which makes more economic sense?Ameliorate or prevent diseases through evidence-
based lifestyle changes
Create a few more jobs for pharmaceutical industry sales representatives while impoverishing the public and governments through increased pharmaceutical drug costs