Multiple-Sclerosis-Multiple-Sclerosis-The-Blood-Brain-Barrier-and-New-Treatment3

"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.