Topics from: http://www.concentric.net/~Debwalt/gsx/
Multiple Sclerosis, The Blood Brain Barrier, and New Treatment
by Timothy R. Stout
Abstract: Survey of Journal articles shows preponderance of evidence that Multiple Sclerosis
attacks occur during breakdowns of the blood-brain barrier. Other articles show that flavonoids
including those found in blueberries and grape seeds amongst others can inhibit blood-brain barrier
breakdown in rats under conditions which normally lead to such breakdown. The same flavonoids
can also be effective in reducing inflammation, which might thus have value in treating the symptoms
of an exacerbation. Suggested experiments are proposed to evaluate whether flavonoids may offer
effective treatment for multiple sclerosis.
This article is highly technical, being intended for those with a background in biology or medicine.
For a simpler version written for the lay person: Enter
Posted on the internet at http://spider.lloyd.com/~tstout/articles/multiple-sclerosis.html on June 14,
1996. This is a rewrite of earlier versions posted June 2, 1996 and May 23, 1996 .
_______________________________________________________________
For a long time multiple sclerosis has been a puzzling disease. Recent experimental studies have
clarified many of the problems associated with the disease.
Historically, it has been known that MS is caused by certain white blood cells attacking the myelin
surrounding the nerve cells of a person's own central nervous system. This was looked at as a
defect in the immune system and much work was concentrated in trying to explain MS simply as an
autoimmune disease. However, the disease was much too erratic to fit the autoimmune models with
any satisfaction.
Overlooked during these studies was a more fundamental question, "How did the white blood cells
get to the myelin in order to attack it to begin with?" Under normal conditions the blood-brain
barrier (BBB) provides an effective separation between the blood cells and the myelin, such that it
would be irrelevant whether or not some of the white cells were programmed incorrectly. Hence,
the question presents itself as to whether or not there is evidence of BBB malfunction during MS
attacks.
Indeed, that is the case. On June 1, 1996 I did a computerized journal search at the University of
California at Davis Health Sciences Library with their biosis search engine. The search revealed 214
journal articles that responded to keyword searches for both Multiple Sclerosis and Blood-Brain
Barrier.
An article published in March of 1996 demonstrates this new direction in which MS research is
heading:
"Serial brain MRI at monthly intervals has provided valuable insights into the natural history of
multiple sclerosis, and is now often used to monitor the efficacy of experimental treatments.
Scanning at this interval often shows asymptomatic new lesions in relapsing-remitting or secondary
progressive multiple sclerosis, on average five to 10 times more often than clinical relapse. About
80% of new lesions... show gadolinium enhancement..., indicating a breach of the blood-brain
barrier.
"On weekly scanning, every new lesion on long TR images showed an initial phase of gadolinium
enhancement.... Although we have only studied three patients, the consistency of this finding
suggests that breakdown of the blood-brain barrier is an invariable and perhaps obligatory event in
the development of new lesions in relapsing-remitting or secondary progressive multiple sclerosis."
(Ref 1)
The body of the article discusses how that these three patients had 38 new lesions appear on MRI
scans during the course of the study, and how that EVERY SINGLE new lesion was associated
with a breakdown in the blood-brain barrier at the early stage. Thirty-eight instances without an
exception is the consistency of which they spoke.
Although many other articles could be quoted tying together MS attacks and BBB breakdown, the
above article expresses the matter quite clearly and for our purposes we will assume that further
research will serve only to confirm and refine these findings and conclusions.
The true value of a good theory for the cause of a disease such as multiple sclerosis is the possibility
of an effective treatment proceeding from the theory. In the light of the above discussion, a simple
potential treatment presents itself: strengthen the BBB to the extent that no further breakdowns
occur.
There are three related chemicals which have been found effective in strengthening the blood-brain
barrier in animals. These are the anthocyanosides, proanthocyanidins, and procyanidolic oligomers
(PCOs). All three of these are variants of a common class of chemicals called "flavonoids."
Anthocyanosides are the chemicals which give blueberries, cherries, and blackberries their color.
Proanthocyanidins and their oligomers (PCOs) are found in purple grape skins and grape seeds and
the bark and needles of certain pine trees. At the University of California at Davis Health Sciences
Library, there were two articles discussing the effect of anthocyanosides on the blood-brain barrier:
In one set of experiments the blood brain barrier was "opened" in test rats by placing various
chemicals in the blood stream, such as proteases or DMSO. Then anthocyanosides were injected
into the blood stream of some but not all of the rats. Some of the comments of the authors are "With
all the four permeability increasing agents (proteases and DMSO) used in these experiments the
O.D. of the dye extracted from the brains was lower in the anthocyanoside-treated groups than in
the control groups. The permeability increasing effect of DMSO was nearly completely abolished.
... These results indicate that the anthocyanoside treatment diminished the permeability increase of
BBB induced by proteases or DMSO." ... "As shown above, treatment with anthocyanosides
diminished the permeability of the BBB to trypan blue after intraventricular injection of a high dose
of collagenase." ... "Animals treated with the anthocyanosides recovered their normal BBB
permeability in less than 24 hours in contrast to untreated controls who recovered only after about
72 hours." ... "Our results indicate clearly that anthocyanosides are able to act on the permeability of
brain capillaries. The mechanism of this action deserves further attention." (Ref 2)
In an another set of experiments, rats were induced with experimental hypertension using an
established procedure. One of the by-products of the procedure was an increase in the permeability
of the BBB. During the experiments, some of the rats were treated with anthocyanosides. The
experimenters' conclusions were: "Anthocyanoside treatment decreased the permeability of the
(blood) vessel walls to the tracer in all our experiments... In experimental hypertension, the greatest
reduction of permeability increase was observed in the cerebral vessels where the permeability was
completely normalized by the drug." (Ref 3)
Discussion
In both of these experiments anthocyanosides were able to strengthen the BBB in rats. The question
becomes whether or not such strengthening would be effective for human patients suffering MS
lesions. The target goal for the MS patient would be to keep the BBB strong enough such that no
future lesions would occur. If this can be realized, the goal of much MS research may finally be
reached. It should be noted that these concepts are "leading edge"; it was only three months ago
that the above journal article by Lei et al was printed (ref 1), in which evidence was given that in all
38 new lesions the researchers observed they also found evidence of BBB deficiency. The reason
for this deficiency is unknown. Just because anthocyanoside treatment is effective in rats for the
various mechanisms used to weaken the integrity of the BBB, this does not mean that it would
necessarily be effective for MS. However, there were five different mechanisms used to degrade the
BBB in the two articles we quoted and anthocyanosides were effective in strengthening the BBB in
all five. So, because there were a number of different mechanisms used to degrade the BBB and
since the anthocyanoside treatment was so general in effectiveness it may be anticipated that there
would be a carry over from the rat to the human.
Another study on the permeability of blood vessels in general (not just the BBB) using rats showed
"that previous treatment of animals with procyanidolic oligomers prevented the permeability increase
produced by collagenase injection." ref 4 abstract "In animals pretreated with OPC the collagenase
induced permeability increase is abolished. OPC protects the microvasuclar wall against the
proteolytic attack." ref 4 fig. 1 caption This is important, because this is the very effect we want to
achieve in our proposed treatment. I.e., by keeping the blood-brain barrier supplied with
appropriate flavonoids, it is hoped that when something comes along that would normally have
caused a breach and subsequent lesion, that instead the flavonoids will prevent damage from
occurring. (Incidentally, OPC is the French equivalent of PCO).
Before discussing the manner in which flavonoids may potentially assert their effectiveness, we will
first review some fundamentals. The BBB is a barrier which is caused by the capillary cells within
the central nervous system (CNS) being bound together much more tightly than they are in the rest
of the body. Because of the tightness, most substances are prevented from passing out of the
capillary and into the CNS tissue proper. An extracellular matrix consisting of a number of proteins
such as collagen and fibrin make up the matrix and function as a glue to hold the cells together.
Certain cells in the immune system produce enzymes which can dissolve the extracellular matrix. For
most parts of the body this is useful in allowing white blood cells greater access to an area of
infection. However, when these cells release their chemicals in the capillaries within the CNS, there
is a resulting breakdown of the BBB, leading to an MS lesion, at least in certain individuals. One
example of this process is with matrix metalloproteinases (MMPs), which, depending on their
specific kind, can act on collagen, gelatin, fibronectin, and other components of the extracellular
matrix. Of particular significance as we shall discuss shortly is that MMPs are not active in the form
in which they are released, but must be converted to an active form by other enzymes. ref 5
There is another process at work which also has the potential to attack BBB integrity. During
phagocytosis of target cells by phagocytes, free radicals are released. These free radicals are
extremely active and can destroy many of the tissues they contact. This can be a useful feature when
a phagocyte is trying to destroy an invading organism: "The superoxide ion and the derived oxygen
free radicals are highly reactive and capable of destroying a variety of molecules. Their liberation
during phagocytosis as potent bactericidal agents as well as their action in inflammatory events have
been clearly demonstrated." ref 6 So, the generation of super oxides and free radicals are useful
against infections. However, when the process takes place at the blood-brain barrier, such as takes
place at the beginning of an MS lesion, it can be just one more attack on the integrity of the barrier.
I would now like to discuss three proposed mechanisms by which flavonoids might be effective in
MS treatment.
1). Flavonoids have a tremendous affinity for joining themselves to enzymes. Thus, if they were to
join themselves to either the MMPs or their activators, they might be able to block this process.
This would then be a specific mechanism by which the BBB would be preserved and an impending
MS lesion thwarted.
The following excerpts from an article on the flavonoids are relevant: "More recent studies indicate
that certain flavonoids have rather extraordinary capacities to affect the activity of many enzyme
systems.... It is also obvious that some of the enzyme systems affected by flavonoids are important
in the regulation of secretory, contractile and motility processes, such as the release of inflammatory
chemical mediators from mast cells, basophils, neutrophils, and macrophages." ref 7 In this article
the author states that studies have clearly shown that certain flavonoids have an extraordinary
capacity to affect the activity of the enzyme systems related to the ones we want to inhibit. The test
results quoted above in ref 2 and ref 3 demonstrate these ideas on a practical basis. The mechanism
we envision here is that when MMPs are released as discussed earlier, that the flavonoids would
"disable" them before they joined with their activator enzyme. Thus, they would be rendered
ineffective.
2) Flavonoids tend to become part of the cellular matrix, or at least adhere to it. This is particularly
true of the PCOs. While in the matrix, they have receptor sites exposed which tend to grab onto the
enzymes which would otherwise attack the matrix. Thus, they become "sacrificial lambs" so to
speak in maintaining the integrity of the matrix. In an experiment it was "conclusively evidenced that
PCOs bind to skin elastic fibres when injected intradermally into young rabbits. As a result, these
elastic fibres were found more resistant to the hydrolytic action of porcine pancreatic elastase when
injected to the same site. These in vivo studies further emphasized the potential effect of these
compounds in preventing elastin degradation by elastase(s) as occurred in inflammatory processes."
In the same article an in vito experiment is discussed where elastin is pretreated with PCO and as a
result elastin becomes completely inhibited from dissolving the elastin: "The inhibitory effect of
procyanidolic oligomers is even more pronounced with human leukocyte elastase. Pretreatment of
elastin with this flavonoid completely inhibits the action of 10 micrograms of purified enzyme." "In
the present work, we evidenced that flavonoids could efficiently and selectively bind to elastic
fibres....Our results indicated that procyanidolic compounds bound on to insoluble elastin increased
the non-productive binding sites of elastases(s)" ref 8 Although the medium here was elastin and not
collagen or any of the other components of the BBB matrix, it is reasonable to anticipate that the
effects would have been similar if collagen had been tested instead. Indeed, that is what was done in
an experiment studied in the next paragraph.
3) Flavonoids are potent anti-oxidants. Free flavonoids (i.e., those not bound in the matrix) will
rapidly destroy free radicals before the radicals do their damage. Although this is only a secondary
issue, it could still be significant. In one experiment collagen taken from calf skin was exposed to
super oxidants. It was found that the oxidants readily split the collagen into peptides of a relatively
small size: "by use of a system generating oxygen free radicals in vitro, we were able to cleave
fibrillar preparations of acid-soluble collagen into peptides of a relatively small size... We find here
that the action of superoxide is even more complete and drastic than expected." ref 6 Thus, once
inflammation starts in the blood brain barrier, any oxygen free radicals produced may be assumed to
compound the attack on the BBB matrix, reinforcing the breakdown process. However, the authors
showed that if the collagen were first soaked in anthocyanosides, allowing them to bind with the
collagen, and next the collagen were rinsed so that there were no free anthocyanosides available,
that the oxygen free radicals still had decreased ability to dissolve the collagen: "It was found that
the anthocyanoside-treated fibrils do not contain any more free anthocyanoside and that the bound
anthocyanosides do not exert a scavenging effect.... When the collagen fibrils have been pretreated
by anthocyanosides prior to the exposure of the superoxide ion, the amount of solubilized peptides
decreases..." Table 3 of the article discloses the degree of protection offered by various
anthocyanosides and in various concentrations. Thus, the protection offered the collagen by
pretreatment was due to action by anthocyanosides which had become bound to the matrix and
were not simply floating freely. This confirms the process in step 2 above as well as showing the
importance of anti-oxidants such as the flavonoids in bolstering the integrity of the collagen before it
was attacked. Again, this is what we would like to accomplish in our efforts to prevent or reduce
the number of new MS lesions by flavonoid treatment. It should also be pointed out that efforts to
test the effects of super-oxide ions on the collagen but in the presence of free anthocyanosides were
fruitless. The anthocyanosides neutralized the free radicals so quickly that the radicals never had any
effect on the collagen: "It was not worthwhile to incubate collagen directly with both the superoxide
ion generating system and the anthocyanoside preparations because the latter alone were found to
directly inhibit the super-oxide forming system (Table 4)."
An extremely interesting experiment was performed with mice. Although MS does not naturally
occur except with human beings, there is a disease called Experimental Autoimmune
Encephalomyelitus (EAE) which behaves like MS. This diseased is induced experimentally in an
animal such as a rat, mouse, or rabbit by artificially sensitizing the animal to proteins such as are
found in its central nervous system. Once sensitized, the disease will progress in a fashion very
similar to the naturally occurring human disease MS. In the experiment of interest, EAE was induced
in mice. The progress of the disease was stopped by treating the mice with a particular drug. The
following quotes are taken from the journal article recounting the experiment:
"Gelatinases, belonging to the matrix metalloproteases, contribute to tissue destruction in
inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. We
used experimental autoimmune encephalomyelitus (EAE) as an animal model to evaluate the effect
of a hydroxamate matrix metalloprotease inhibitor (GM 6001) in inflammatory demyelination.
...results indicate that matrix metalloprotease inhibition can reverse ongoing EAE. This effect
appears to be mediated mainly through restoration of the damaged blood-brain barrier in the
inflammatory phase of the disease... ref 9
Notice that this experiment exactly parallels what we are trying to accomplish with our treatment of
MS using flavonoids, except that GM 6001 is protein based and not a flavonoid. However, from
the examples of the experimental results quoted above in ref 2 and ref 3 where blood-brain barrier
integrity was restored or maintained by the use of anthocyanosides makes it appear that the results
of this experiment might have been similar if appropriate anthocyanosides or PCOs had been used
in place of GM 6001. Let's continue with a few more quotes from the same article:
"Since MMPs appear to play an important role in lesion development in inflammatory demyelinating
diseases such as MS, inhibition of the activity of these enzymes might offer a new therapeutic
approach in these disorders." Indeed, this is exactly what we are proposing, using flavonoids to
inhibit the activity of the enzymes causing BBB breakdown.
"...the blood-brain barrier, which was significantly impaired in vehicle-treated animals, was restored
in animals treated with the MMP inhibitor." The "vehicle-treated" animals are simply those in the
control group who had similar injections to the test ones but without the GM 6001. So, effectively,
the progress of EAE, an experimental equivalent of MS, was halted by use of a drug which inhibited
MMP breakdown of the BBB. Again, this is exactly what we are proposing to do except by using
flavonoids instead of protein-based inhibitors.
If we can indeed get the same results in MS using flavonoids as the experimenters did here in EAE
using GM 6001, we will have a new, simple, cost-effective treatment for MS.
Reducing Inflammation: A Potential Side Benefit
In addition to strengthening the integrity of cell walls in general, including those of the blood-brain
barrier, flavonoids have yet another potential value for the MS patient. Specifically, certain
flavonoids have the potential ability to reduce inflammation. Since much of the damage caused to the
nerve cells during an MS exacerbation is due to the inflammation, this would give hope that the
treatment we will recommend to prevent or reduce the number of exacerbations might have as a
possible side benefit that of reducing the severity of an exacerbation as well.
"The developing plaque of MS contains large numbers of macrophages (scavenger cells), which
appear to destroy myelin by digesting its proteins and lipids. Inhibitors of the enzymes responsible
for this digestion might reduce the myelin destruction or even interfere with movement of the
macrophages into and through the tissues." "Improvements in MS are often dramatic. Much of the
improvement is thought to be due to a subsidence of swelling and inflammation." "The principle
drugs used to treat acute exacerbations are those having major antiinflamatory properties." "All of
the above-mentioned drugs (i.e. certain drugs used to reduce inflammation) have possible serious
side effects and should only be used under the supervision of a physician." ref 10 So, inflammation is
a serious feature of an exacerbation and treatment of an acute attack typically centers on reducing
inflammation with various drugs. Unfortunately, all of the drugs traditionally used have serious side
effects.
"Anthocyanosides of natural origin have double-pharmacological action: (1) antidegenerative action
... (2) antiinflammatory action, which can be a direct reduction of capillary permeability or reduction
of generation of inflammatory mediators. These common properties are considered to be due to
their common chemical composition, having all of them a cumarin nucleus, while cell or tissue
specificity of anthocyanosides comes from their variable side groups. The dual antidegenerative and
antiinflammatory action promises wide use of anthocyanosides and related drugs..." ref 11 abstract
Thus, even though our primary goal was to strengthen the blood-brain barrier, we have the added
bonus of inadvertently, simultaneously reducing inflammation as well. Furthermore, we anticipate our
proposed treatment to be WITHOUT side effects.
"Outstanding inflammatory effects are displayed by myricetin and delphindin, which contain vicinal
hydroxy groups in ring B. The results confirm the importance of hydroxy group substitution in ring
B." ("Delphindin" is an anthocyanidin.) ref 12 abstract Thus, anthocyanidins have "outstanding"
antiinflammatory effects. (Note that an anthocyanoside is simply a compound whereby two sugar
molecules are connected to an anthocyanidin).
Proposed Clinical Tests
In this section we shall derive a suggested treatment.
Fortunately, a person may significantly increase his anthocyanoside and/or proanthocyanidin intake
quite inexpensively, typically less than one hundred dollars per month even doses at the therapeutic
level. Everything needed to administer the test is readily available in a large supermarket or
drugstore. Hence, the cost to clinically test the concepts of this paper would be minimal.
The International Federation of Multiple Sclerosis Societies published a book in which the following
philosophy of treatment trial was expressed: "Another way of judging treatment efficacy in MS is to
ask: Can this method prevent worsening? A completely effective treatment would prevent
worsening in all cases, and probably produce improvements in most patients, and would be easy to
recognize. A controlled trial of therapy would not be necessary. Unfortunately, no such agent has
been discovered." ref 10 The least expensive clinical trial would be to test to see if certain
flavonoids might indeed be this yet "undiscovered agent."
Anthocyanosides, procyanidins, and procyanidolic oligomers are all families of flavonoids. "There
are over 500 varieties of flavonoids...with at least 20,760,000 members of the flavonoid class." ref
13 In a study using three different flavonoids to study their comparative abilities to protect against
the degradation of calf skin under certain circumstances, it was confirmed that the three gave
differing results. ref 6 Thus, we read that "It is essential to test a number of flavonoids of different
chemical classes in various pharmacological screens of activity before a determination of activity, or
lack thereof, can be made" ref 7
So, in considering a test of the effectiveness of flavonoids, we need to recognize that there are
many, many different kinds of them and that they have differing effects on mammalian tissue.
Furthermore, this is not a very well studied area. Thus, it is rational that our first attempts at clinical
testing should simply supply a broad range of flavonoids from those classes whose history would
lead us to anticipate favorable results. This is in opposition to an approach where one or two
specific flavonoids would be used in a tightly controlled test, which might be appropriate once the
initial basic information is available.
Furthermore, very little is known of proper dosage. However, it has been asserted that "no serious
side effects have been observed with the use of flavonoids at moderate doses (<1 g/day/adult
patient)." ref 13 Although flavonoids are quite widespread amongst vegetables and fruits and nuts,
and we have no way of anticipating what a person's total flavonoid intake might be, we will propose
a treatment based upon two principles. One is that we want to have as large a dose of the test
flavonoids as possible, to make sure that their concentration is sufficient to be effective, and 2) if we
set the limit of test flavonoid dosage to between 500 mg and 1,000 mg we will probably not have
any significant side effects.
PCOs tend to be better anti-oxidants than anthocyanosides. ref 6 tables 3 and 4 On the other hand,
anthocyanosides tend to be better antiinflammatory agents than PCOs. ref 12 For the time being we
will simply suggest that treatment consist of both PCOs and anthocyanoside.
Blueberries tend to be between 0.1 and 0.2 percent anthocyanoside. ref 14 Using 0.15 % as an
average computes to 720 mg in one pound of blueberries. Thus, fresh or frozen blueberries in an
amount between one-half pound and one pound should be adequate for anthocyanoside intake. It is
next recommended a PCO intake of 300 to 500 mg. total per day. The body disposes of excess
flavonoids rather quickly, so the consumption of the above nutrients should be spread out
reasonably evenly throughout one's waking hours.
As an intuitive starting point for lack of anything better, it would seem appropriate to initially start
with an intake of closer to 1 gram per day of combined anthocyanosides and PCOs and then after a
week or two tapering down to 500 grams per day. During an exacerbation for which symptom
relief is desired, the intake would go back up to 1 gram per day with an emphasis on the
anthocyanosides.
Anthocyanosides are also found in blackberries, cherries and other fruits. However, I have no
information on the specific anthocyanosidic content of these fruits. In general, though, it would seem
that a person would prefer the variety from mixing his intake of these three. Instead of fresh or
frozen blueberries, one might want to take bilberry extract. Bilberry is simply European blueberry.
The choice between fresh/frozen fruit versus an extract is probably mostly a matter of personal
preference.
I found in a local health food store a PCO/Anthocyanoside source called Grape Complete(TM),
manufactured by C****** L***. Each capsule contains 50 mg of PCOs and 100 mg of
anthocyanosides. 60 capsules came in a bottle for $23.00. Thus, 7 capsules a day would give us
our 1 gram daily total target. With this product the fresh or frozen berries would not be needed. The
monthly cost for this would be about $84.00. Even with vitamin C supplements added (see
discussion below) the cost is less than one hundred dollars per month during the intensive portion
and would probably be closer to fifty or sixty dollars a month during normal situations. I do not
know the relative quality of this or any other brand; therefore I cannot make any meaningful product
recommendations.
I would like to see two different groups of tests be performed to determine the general effectiveness
of flavonoids in the treatment of multiple sclerosis.
The first group of tests would be with those who have rapidly advancing MS. This would be a small
group, perhaps six to twelve in number. The test would last three to six months. Three MRI scans
of all participating members would be taken. The first would be at the outset of the test, the second
after one month so that a reference would be provided after the anthocyanosides would have had
opportunity to stabilize the development of new lesions, and then the third at the end of the test
period. At the conclusion of tests the second and third scans would be compared to see how
effective the anthocyanosides were in dealing with the disease.
A second group of tests would be made with patients having the more traditional remission-relapse
form of the disease. This group would need to be much larger, probably at least fifty if not more.
This is because two-thirds of patients having recent exacerbations will show subsequent
improvement, albeit ultimately only temporary, even without treatment. Hence, for anthocyanoside
to be considered effective in this group the size of the group must be large enough that statistical
fluctuations will not color the results. With a group of fifty patients, we would expect there to be
only sixteen or so who did not improve even without taking any kind of treatment. If, in a group of
fifty patients there were improvements in all but five or six patients, this would be considered
significant. If the group size were much less than fifty, it would be difficult to assess the significance
of the results.
In evaluating the results of the tests one should bear in mind that the flavonoids have a possible dual
role, that of reducing the number and frequency of exacerbations and also that of alleviating some of
the symptoms during an exacerbation. Those making evaluations need to keep this perspective in
view.
Vitamin C seems to work cooperatively with anthocyanosides, ref 15 p. 367 Therefore, I would
also recommend that a 100 mg vitamin C tablet be taken three times a day, simultaneously with the
other nutrients.
Depending on the results of these tests, future test plans can be established. The advantages of the
proposed treatment in this article are 1) they are consistent with the concepts behind the latest
theories of MS 2) they are relatively inexpensive and readily available 3) they are potentially good
for a person's health in general, independent of their effectiveness with MS (unlike many of the
immuno-suppression and antiinflammatory approaches used historically and currently).
Please note that these recommendations are merely suggestions for clinical tests administered by
qualified researchers. They are not intended for self-treatment by an individual apart from the
direction and supervision of his personal physician.
Note added 3/21/97: Over the past nine months anecdotal results of people trying some of these
ideas have accumulated. A representative sample is posted at
http://www.innercite.com/~tstout/ms/anec.shtml.
Ref 1
M Lai, et al, "A preliminary study into the sensitivity of disease activity detection by serial weekly
magnetic resonance imaging in multiple sclerosis." Journal of Neurology, Neurosurgery, &
Psychiatry. (1996) 60 n. 3: 339-341.
Ref 2
A. M. Robert et al. "Action of anthocyanosides of Vaccinium Myrtillis on the Permeability of the
Blood Brain Barrier." Journal of Medicine. (1977) 8 n. 5: 321-332.
Ref 3
Z. Detre et al. "Studies on Vascular Permeability in Hypertension: Action of Anthocyanosides."
Clin. Physiol. Biochem. (1986) N.4: 143-149
Ref 4
L. Robert, et al, "Action Des Oligomeres Procyanidoliques Sur La Permeabilite De La Paroi
Vasculaire. Etude Par Morphologie Qunatitative." Path Biol, (1990), 38, no.6: 608-616.
Ref 5
A. Maeda et al. "Matrix Metalloproteinases in the normal Human Central Nervous System,
Microglial Nodules, and Multiple Sclerosis Lesions." Journal of Neuropathology and Experimental
Neurology, (1996), 55 n. 3: 300-309
Ref 6
Jean Claude Monboisse, et al. "Non-Enzymatic Degradation of Acid-Soluble Calf-Skin Collagen
by Superoxide Ion: Protective Effect of Flavonoids". Biocemical Pharmacology, (1983), 32 n. 1:
53-58.
Ref 7
Elliot Middleton, Jr., "The Flavonoids", Trends in Pharmacological Sciences. (August 1984), 5:
335-338
Ref 8
J.M. Tixier, et al. "Evidence By In Vivo and In Vitro Studies That Binding of Pycnogenols to Elastin
Affects its Rate of Degradation by Elastases. Biochemical Pharmacology (1984), 33, N. 24:
3933-3939
Ref 9
K. Gijbels et al. "Reversal of Experimental Autoimmune Encephalomyelitius with a Hydroxamate
Inhibitor of Matrix Metalloproteases." The Journal of Clinical Investigation, (1994), 94: 2177-2182.
Ref 10
W.A. Sibley and the Therapeutic Claims Committee of the International Federation of Multiple
Sclerosis Societies, Therapeutic Claims in Multiple Sclerosis, 3rd Edition. 1992.
Ref 11
J.M. Feher et al. "Chorioretinal Myopic Degeneration: Treatment with Anthacyanosides." Bolletino
di Oculistica. (1990), 69 n. 5: 909-922
Ref 12
M. Gabor et al. "Effect of Benzopyrone Derivatives on Simultaneously Induced Croton Oil Ear
Oedema And Canageenan Paw Oedema in Rats." Acta Physiologica Hungarica. (1991), 77, n.3-4:
197-208
Ref 13
B. Havsteen. "Commentary. Flavonoids, A Class of natural Products of High Pharmacological
Potency". Biochemical Pharmacology. (1983), 32 n. 7: 1141-1148.
Ref 14
W. Lenartowicz et al, "The Quality of Highbush Blueberry Fruit: PI. Fresh Fruit Quality of Six
Highbush Blueberry Cultivars and Their Suitability For Freezing." Fruit Science Reports
(Skierniewice). (1990), 17 n.2: 77-86
Ref 15
M. Gabor. "Pharmacologic Effects of Flavonoids on Blood Vessels. Angiologica, (1972), 9:
355-374 (223-242)
© 1996 by Timothy R. Stout
This article may be copied and distributed freely for non-commercial uses provided credit is given
to the author and the contents are not changed.
Timothy R. Stout
P.O. Box 7
Rescue, CA 95672
The author, Timothy R. Stout, may be contacted via E-mail at tstout@spider.lloyd.com.
To go to Tim Stout's Multiple Sclerosis Page: Enter
For personal information on Tim Stout: Enter
You may contact the author of this document at: tstout@innercite.com