Transcript Disk 1-1 JUURLINK – ENGLISH

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 The Public Good has been replaced by the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
 Inflammation is necessary to fight infection: but in the
absence of infection inflammation is harmful
Salvador Dali: ‘Fight between San Salvador and Antoni Gaudi’
Inflammation and Veins-1
 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
Veins and Immune Cell Trafficking
Inflammation and Veins-2
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
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 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 (NFkB)
Activated NFkB moves to the nucleus and
increases the expression of pro-inflammatory
genes whose protein products drive inflammation
Nuclear Factor Kappa B (NFkB)
Pro-inflammatory Genes
 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
NFkB
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 NFkB
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
Increasing GSH Synthesis
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 GSHDependent 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 Work
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
Thiol-Oxidizers
 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
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 tea
Kaempferol – 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 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?
Finally
‘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
Je vous remercie de votre attention
‘Persistence of Memory’ by Salvador Dali