MS as a vascular disease

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dignan
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MS as a vascular disease

Post by dignan »

I haven't heard of anyone looking at MS this way before...



Multiple sclerosis as a vascular disease.

Neurol Res. 2006 Apr;28(3):230-5.
Minagar A, Jy W, Jimenez JJ, Alexander JS.
Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.

Multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated disease with principal emphasis on the role of activated inflammatory cells, oligodendrocytes and astrocytes in its pathogenesis. Abnormalities of cerebral endothelial cells (CECs) is an under explored facet of MS pathogenesis and vascular abnormalities play a crucial role in formation of the MS lesions and disease progress, at least in the initial stages of disease.

This review will focus on MS as a central nervous system (CNS) disease with a strong vascular constituent and examines abnormalities within CECs in MS and their role in the loss of blood-brain barrier and transendothelial migration of activated leukocytes into the CNS. One goal of this paper is to persuade and promote research on the endothelial abnormalities in pathogenesis of MS and to exploit existing knowledge on endothelial injury.

A deeper understanding of endothelial pathophysiology in MS may help develop effective treatments through stabilization of endothelial function, translating into delay or arrest of MS disease onset and disability in MS patients.

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lyndacarol
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Vascular component

Post by lyndacarol »

I am glad to see that some researchers have the courage to look at this disease in a novel way.

Beyond the CNS and lesions, I think many of our symptoms can be chalked up to vascular abnormalities. (And, of course, you know what I think causes damage there--insulin!)

Maybe our tingling sensation (paresthesia) in the extremities occurs because of damage in the blood vessels. When I put pressure on my hands (like sitting on them or, when lying down on my side, putting the top hand under my lower arm), I feel a pulsation (which seems to have more a "circulatory" connection). Also, I have always thought my fingertip pads were a slightly deeper color. I have ridges in my fingernails. I attribute all this to circulation problems....Then there are my cold feet and hands....
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Post by viper498 »

Agreed. Very good find. That is really an interesting angle. It could be entirely possible that MS for some, is a vascular disease/syndrome.

@ LyndaCarol,

I would think the tingling would still be caused by lack of blood flow to a very specific part of the brain rather than an overall vascular issue. Although, I too get the pulsing feeling in my fingertips and hand. I can especially feel it when I make a fist, or hold something tightly. I thought that might becaused by high blood pressure, but mine isn't too terrible high (130 / 90 ), its not very good either.
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lyndacarol
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Post by lyndacarol »

Viper, the cause of tingling could certainly be as you say. But maybe these researchers will find some definitive answers.

I don't see how your blood pressure could be responsible for the pulsing feeling; it's not really "high." It can't be the culprit at all in my case; mine is always lower. I'm still voting with "damage to the blood vessels"...circulation.
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HarryZ
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Re: MS as a vascular disease

Post by HarryZ »

Dignan,

Go back to the late 40's and early 50's and look at Dr. Hinton Jonez's work with MS patients. He had a similar theory about MS and treated thousands of patients with IV histamine. He got some pretty amazing results at his MS Clinic and of course was at odds with the established MS medical world at the time.

Too bad Dr. Jonez died suddenly in 1952. The clinic closed and despite all the positive results he got, his research disappeared from the face of the earth. Only when Prokarin surfaced in 1999 did the use of histamine start to make its way back.

Harry
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Post by viper498 »

And for what reason were histamines abandoned if they seemed to have some effect?? Why would this die with Dr. Jonez after he had results? What about the people it did help? Wouldn't they continue lobbying for continued research in this field? Is there any other research in relation to MS & histamines?

Brock
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Post by HarryZ »

Hi Brock,
viper498 wrote:And for what reason were histamines abandoned if they seemed to have some effect?? Why would this die with Dr. Jonez after he had results? What about the people it did help? Wouldn't they continue lobbying for continued research in this field? Is there any other research in relation to MS & histamines?

Brock
You've asked a question that nobody has ever been able to answer! On one of the other MS forums a few years ago, a very talented PHd participant looked into a number of articles that were published about histamine way back then. He wrote several commentary messages on the board outlining all the success that Dr. Jonez had but couldn't find any reason as to why nobody ever continued with the work.

Had there been the kind of communication channels available back then that we have now, I'm sure Jonez's work would have been continued.

Of course today, histamine is a none patentable drug and no major drug company would put out the kind of money required to perform the proper research. The person who developed Prokarin ( in essence histamine) didn't even know Jonez existed until she went to get a patent on Prokarin and discovered his work.

Unless a drug is part of the mainstream MS world and is supported by a big pharma, there is no chance at all of anything else catching on in a big way. Just look at what has happened to LDN in the past few years.

Harry
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Post by dignan »

I had to check out histamines and MS a little. There does appear to be some current research related to this:



Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1867-72. Epub 2003 Feb 7.

Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination.

Pedotti R, DeVoss JJ, Youssef S, Mitchell D, Wedemeyer J, Madanat R, Garren H, Fontoura P, Tsai M, Galli SJ, Sobel RA, Steinman L.
Department of Neurology and Neurological Science, Stanford University Medical Center, Stanford, CA 94305, USA.

Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc epsilon receptor 1 (Fc epsilon RI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig Fc gamma RIII or both Fc gamma RIII and Fc epsilon RI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and "allergic" responses.

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Int J Immunopathol Pharmacol. 2005 Oct-Dec;18(4):771-8.

A pilot, open label, clinical trial using hydroxyzine in multiple sclerosis.

Logothetis L, Mylonas IA, Baloyannis S, Pashalidou M, Orologas A, Zafeiropoulos A, Kosta V, Theoharides TC.
Department of Neurology, Aristotle University, AHEPA Hospital, Thessaloniki, Greece.

Multiple sclerosis (MS) is an autoimmune disorder of myelin destruction. Blood-brain-barrier (BBB) disruption precedes pathological or clinical findings and could involve mediators from perivascular brain mast cells, such as histamine and vascular endothelial growth factor (VEGF). Mast cells could be activated by many triggers, including acute stress that has been correlated with MS exacerbations. We considered that the histamine-1 (H1) receptor antagonist hydroxyzine, which also partially inhibits brain mast cells and has anxiolytic properties, may reduce MS symptoms. This open label, pilot, clinical trial investigated the effect on MS of an oral solution of hydroxyzine (100 mg per day), together with caffeine (200 mg per day) to reduce sedation. Twenty patients (8 males; 12 females) with relapsing-remitting or relapsing-progressive MS completed the study (12 +/- 1 months) and were evaluated using disability scales. Most patients on hydroxyzine (75%) remained stable or improved neurologically and all but one showed improved mood. Hydroxyzine could be used as an adjuvant in MS, but the small number of patients enrolled and the short duration of the study precludes any definitive conclusions. A double-blind, placebo-controlled study is warranted.

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J Immunol. 2006 Jan 1;176(1):17-26.

A key regulatory role for histamine in experimental autoimmune encephalomyelitis: disease exacerbation in histidine decarboxylase-deficient mice.

Musio S, Gallo B, Scabeni S, Lapilla M, Poliani PL, Matarese G, Ohtsu H, Galli SJ, Mantegazza R, Steinman L, Pedotti R.
Immunology and Muscular Pathology Unit, National Neurological Institute "C. Besta," Milan, Italy.

Histamine can modulate the cytokine network and influence Th1 and Th2 balance and Ab-isotype switching. Thus, pharmacological blockade or genetic deletion of specific histamine receptors has been shown to reduce the severity of experimental autoimmune encephalomyelitis (EAE), a prototypic Th1-mediated disease with similarities to human multiple sclerosis. To study the comprehensive contribution of endogenous histamine to the expression of EAE, we attempted to induce EAE in histidine decarboxylase-deficient mice, which are genetically unable to make histamine. In this study, we show that EAE is significantly more severe in HDC-/-, histamine-deficient mice, with diffuse inflammatory infiltrates, including a prevalent granulocytic component, in the brain and cerebellum. Unlike splenocytes from wild-type mice, splenocytes from HDC-/- mice do not produce histamine in response to the myelin Ag, whereas production of IFN-gamma, TNF, and leptin are increased in HDC-/- splenocytes in comparison to those from wild-type mice. Endogenous histamine thus appears to regulate importantly the autoimmune response against myelin and the expression of EAE, in this model, and to limit immune damage to the CNS. Understanding which receptor(s) for histamine is/are involved in regulating autoimmunity against the CNS might help in the development of new strategies of treatment for EAE and multiple sclerosis.

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Neurology. 2006 Feb 28;66(4):572-5.

Allergy, histamine 1 receptor blockers, and the risk of multiple sclerosis.

Alonso A, Jick SS, Hernan MA.
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. aalogut@alumni.unav.es

BACKGROUND: It is unclear whether allergic diseases are associated with multiple sclerosis (MS), but histamine 1 receptor blockers, used in the treatment of allergic conditions, decreased the severity of experimental autoimmune encephalomyelitis (an animal model of MS).

OBJECTIVE: To assess the association of allergy history and use of histamine 1 receptor blockers with the risk of MS.

METHODS: Using a case-control study nested in the United Kingdom-based General Practice Research Database cohort, the authors identified 163 incident cases of MS with at least 3 years of follow-up before their first symptoms (index date). Up to 10 controls matched to the cases by age, sex, general practice, and time in the cohort were selected. Previous history of allergic disease and use of histamine 1 receptor blockers in the 3 years before the index date were assessed through computerized medical records.

RESULTS: History of any allergic condition in the 3 years before the index date was not associated with MS risk (adjusted odds ratio [OR] 1.2, 95% CI 0.8 to 1.8 ). However, use of sedating histamine 1 receptor blockers was associated with decreased MS risk (adjusted OR 0.2, 95% CI 0.1 to 0.8 ).

CONCLUSION: These results do not support a strong link between allergic conditions and multiple sclerosis (MS) risk but suggest a possible beneficial effect of antihistamines on the onset of MS.

<shortened url>
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Post by HarryZ »

Dignan,

Elaine Delack, the inventor of Prokarin, has done a lot of research involving histamine (mostly the role of the H2 receptor). That is the basis of her theory as to why histamine and the subsequent creation of the H2 neuro receptors help relieve a lot of MS symptoms. Note that it is the H2 not the H1 receptor that is important here.

If you go to www.edmsllc.com and read the Professional explanation of her work, you'll see what I mean.

But Elaine is neither a doctor nor scientist (as is often commented, only a nurse) and getting anyone to acknowledge her work is all but impossible.

Harry
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Repeating Copaxone forum posting on Vascular connection

Post by lyndacarol »

Although the following was first posted on the Copaxone forum in response to Shayk's contribution, I think this is more appropriate here with dignan's posting of the LSU researchers' work, one of the items I reference and VERY important, I think:

"First, there was the General Discussion posting from Lyon on October 30, 2006, of the History of MS brochure by the NMSS which said,
Quote:
Because most MS damage occurs around blood vessels, it seemed reasonable that a toxin circulating in the bloodstream leaked out into the brain, even though no researcher could find a trace of it.


Then, I read the Paul Le Gac papers from the Wheldon site which stated,
Quote:
In point of fact, thanks to the work of Dejerine [1], we know that multiple sclerosis is a chronic, diffuse, and interstitial myelitis, in which the irritative process begins with the vascular element. The vessels are the seat of periarteritis and of endoarteritis. Their wall thickens and their lumen is constricted until, in the region of the capillaries, it is almost completely closed. Dejerine himself actually wondered whether these vascular infiltrations, which constitute the most significant manifestations of medullar involvement, might be the only histo-pathological lesions that can explain the genesis of multiple sclerosis.


Then, I read the abstract by researchers at Louisiana State University that proposed that MS is a vascular disease.

Now, in the Boston Cure interview with Daniel Pelletier that Shayk posted here I found this paragraph VERY interesting:
Quote:
Well, recently we've seen with MRI studies that there are blood perfusion abnormalities in active, acute MS plaques. Specifically, blood flow is increased in these areas. The idea that MS has something to do with the blood vessels and blood flow is new to me, and I'm not sure what it means.


I certainly hope that more researchers are looking in the direction of the blood vessels! By the way, I believe I've read that insulin thickens smooth muscles; aren't they around the blood vessels?

And just now I read bromley's posting of an abstract from the MS Society in the UK which stated:
Quote:
MS results in intense inflammation within the brain and spinal cord, and there is increasing evidence that this can directly cause conduction and neurological deficits. This PhD project explores the hypothesis that the deficits arise because the nerve fibres passing through inflammatory lesions are relatively starved of oxygen and glucose. The hypothesis is strongly supported by historical evidence, currently largely forgotten, that drugs that open blood vessels (e.g. amyl nitrite) can restore function in MS within an hour. This study proposes to explore the mechanisms underlying such phenomena using several different experimental inflammatory and/or demyelinating models, focusing on the oxygen concentration within the lesions.


Again, I found the sentence, "The hypothesis is strongly supported by historical evidence, currently largely forgotten, that drugs that open blood vessels (e. g., amyl nitrite) can restore function in MS within an hour." VERY interesting!!! Maybe this work will lead researchers to start looking in the right 'box of keys.'"
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Re: Repeating Copaxone forum posting on Vascular connection

Post by Lyon »

lyndacarol wrote:And just now I read bromley's posting of an abstract from the MS Society in the UK which stated:
Quote:
MS results in intense inflammation within the brain and spinal cord, and there is increasing evidence that this can directly cause conduction and neurological deficits. This PhD project explores the hypothesis that the deficits arise because the nerve fibres passing through inflammatory lesions are relatively starved of oxygen and glucose. The hypothesis is strongly supported by historical evidence, currently largely forgotten, that drugs that open blood vessels (e.g. amyl nitrite) can restore function in MS within an hour. This study proposes to explore the mechanisms underlying such phenomena using several different experimental inflammatory and/or demyelinating models, focusing on the oxygen concentration within the lesions.
I'm responding to Lynda's post but this isn't necessarily directed at Lynda,
What my mind goes to is these researchers are speculating on the effect increased vascular circulation has on lesions, which for all intents and purposes are scar tissue, damaged areas.

I've come to the conclusion, but I want to see if it's the conclusion others have come to, that this vascular circulation thing isn't purported to be directly related to the disease process but holds the hope of lessening the noticed physical effect from the damage that MS has caused.(?)

That in itself isn't necessarily a bad thing except I've also read speculation that efforts to increase vascular circulation might also tend to increase permeability of the bbb which might be akin to creating a vicious circle....increasing performance in damaged areas but further opening the floodgates and creating more damage.

While I appreciate the abundance of information the researchers have presented us with over the last....more than a century of research, it puts us now in the unenviable position of having to determine which of this plethora of things which "seem" to show a positive effect are actually related to the disease process, which are caused by secondary elements and which are nothing more than completely unrelated but inconclusive results.

I'll admit that MS is complicated but NOTHING is this damned complicated.

If we're ever going to understand this thing in my lifetime researchers have somehow GOT to find a way to better separate the wheat from the chaft.

Bob
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Post by CureOrBust »

Be careful with amyl nitrate. I *THINK* I tried it a number of years ago, and from memory it caused temporary partial blindness! I dont think my MS has ever caused me ON in itself. Maybe I overdid it. I have also read that some stuff purported to be amyl nitrate is actually something else including isobutyl nitrite, butyl nitrite, and amyl nitrite.

I forgot this thread, it kinda supports my recent thread regarding the BBB, as the BBB is basically all the vessels controlling exchange between the peripheral blood and the CNS.
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Post by TwistedHelix »

I found this thread on a discussion forum about Parkinson's disease, (PD), and I was absolutely staggered at the similarities with some of the discussions here about the blood brain barrier, and also some of the things which strengthen or weaken it.
Circumin, stress, nitric oxide, carbon monoxide, hypertension, iron levels, berries and Anthocyanins, inflammation, bacterial infection, (interesting that H pylori can cause both intestinal AND BBB permeability -- antibiotics, anyone?), there is even a bit of bickering between posters... sound familiar?

As I hypothesised in the thread about amyl nitrite, and Lyon wondered here, it does seem to me that vasodilation may provide a short-term boost to starving nerve cells but it does stretch open the tight joins between endothelial cells, and therefore compromise the blood brain barrier.

http://neurotalk.psychcentral.com/showthread.php?t=190


Dom.

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Post by Lyon »

Thanks for the link Dom, and also there were some other interesting links once I got there.

While you are admittedly on the homely side, you aren't nearly as homely as I am so I have to admit a little jealousy in regards to your picture.

I've been thinking about using Brock's picture as my avatar. While the poor thing is every bit as homely as I am, he's a heckuva lot younger!
Bob
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Post by TwistedHelix »

Hi Bob,

Until I stumbled across the "Parkinson's" thread, I don't think I ever really considered other neurological diseases as a source of relevant information for MS, (although I have read a bit about Huntington's disease because my brother and niece have it).
The mention of H pylori really made my ears prick up because it can cause leaky gut AND leaky BBB: two things which have cropped up on this site several times before and, of course, would be something which would respond to an antibiotic regime.
Infection with H pylori has some other effects which could be relevant to us -- it has been shown to cause secretion of Matrix Metalloproteinase - 9, (MMP-9), by human macrophages, (FEMS Immunol Med Microbiol. 2005 Aug 1;45:159-69 16051068), and it has been shown that MMP - 8 and MMP - 9 play an important role in EAE, (Clin Exp Immunol. 2002 May ;128 (2):245-54 11985514).

The mention of organophosphates was also intriguing. Some time ago I looked at Mark Purdey's website, (www.markpurdey.com)... which was mainly focused on BSE, CJD, and other spongiform diseases but he had quite a long essay about MS. I have to say, some of his ideas were pretty leftfield and he was shunned by the establishment, but I would say parts of it were very convincing and warranted further investigation -- he believed organophosphates used in pesticides on farm animals, particularly to eradicate warble fly infestation, were responsible for some of these diseases... they are, after all, derived from nerve agents. He also seemed to show that imbalances in environmental or dietary intake of metals could compromise the nervous system -- as I understand it copper, in balance with other metals, is crucial for the maintenance of the BBB.

Sadly Mr Purdey died in November 2006, and his website appears to have been substantially altered since then.

So, that's one bacterial and two environmental conditions which can affect the BBB. I bet there's dozens more which could probably explain all the "subsets" of MS.

Food for thought, anyway.

Dom.

PS by the way Bob, obviously my photo has been heavily Photoshopped, in reality I'm devastatingly handsome.
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