Multiple-Sclerosis-Multiple-Sclerosis-The-Blood-Brain-Barrier-and-New-Treatment

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.