This Is MS Multiple Sclerosis Community: Knowledge & Support

Very interesting – the discovery of a new pathway which can give rise to both the inflammatory and degenerative stages of the disease:



Public release date: 20-Sep-2007
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Contact: Tom Vasich
tmvasich@uci.edu
949-824-6455
University of California - Irvine
Cell-surface sugar defects may trigger nerve damage in multiple sclerosis patients
Study also suggests treatment for short-term and long-term damage caused by chronic disease
Irvine, Calif., Sept. 20, 2007 — Defects on cell-surface sugars may promote the short-term inflammation and long-term neurodegeneration that occurs in the central nervous system of multiple sclerosis patients, according to University of California, Irvine researchers.
The findings also suggest that a dietary supplement similar to glucosamine may be useful as an oral therapy to correct these defects and to treat both the short-term and the long-term symptoms of the disease. Study results appear on the online version of the Journal of Biological Chemistry.
“The findings raise the possibility that these may both be treated by metabolic therapy,” said Dr. Michael Demetriou, an assistant professor of neurology, and microbiology and molecular genetics. “This is particularly important, as therapies are not currently available to treat neurodegeneration in MS.”
In tests on mice, Demetriou found that genetic deficiencies in a process called protein glycosylation led to a spontaneous disease very similar to MS, including paralysis associated with inflammatory damage to the protective myelin coating on nerve cells and degeneration of axons and neurons. Protein glycosylation refers to the addition of specific sugars to proteins; virtually all cell-surface and secreted proteins have complex sugars attached to them.
MS is a two-stage disease, with initial attacks of inflammatory demyelination, which damages myelin, followed approximately 10 years later by a slow, progressive neurdegenerative phase marked by loss of axons and nerve cells.
The irreversible damage to the central nervous system induced by neurodegeneration in MS leads to long term disability, including paralysis, incoordination, dementia and pain, and is not targeted by currently available therapies.
Demetriou’s findings provide the first genetic model of MS in which both inflammatory demyelination and neurodegeneration arise from defects in a single biological pathway.
In previous studies, Demetriou found that the dietary supplement N-acetylglucosamine (GlcNAc), which is similar but more effective than the widely available glucosamine, corrected defects in protein glycosylation in cells and inhibited inflammatory demyelination in mice. The new study opens the possibility that metabolic therapy with GlcNAc may also prevent neurodegeneration. Studies in humans are required to assess the potential of this therapy in MS.
###
Sung-Uk Lee, Ani Grigorian, I-Ju Chen, Guoyan Gao and Dr. Tahseen Mozaffar of UC Irvine and Judy Pawling and Colin McKerlie of the Samuel Lunenfeld Research Institute in Toronto participated in the study, which was supported by the National Multiple Sclerosis Society, the Juvenile Diabetes Research Foundation, the Wadsworth Foundation and the National Institutes of Health.
About the University of California, Irvine: The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 25,000 undergraduate and graduate students and about 1,800 faculty members. The second-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.7 billion. For more UCI news, visit www.today.uci.edu.
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_________________
Dom

I wonder if this release is new or more information on this May 2007 story? I believe glucosamine is an amino acid and copaxone is also an amino acid maybe they are doing the same thing? I know nothing about amino acids so they could be very different? Anyway, I really like this story about Glucosamine if there turns out to be something behind it, it sure looks like it has a great deal of potential.


Glucosamine-like supplement inhibits multiple sclerosis, type 1 diabetes

Metabolic therapy shows promise for treating autoimmune diseases, UC Irvine study finds

Irvine, Calif., May 14, 2007
A glucosamine-like dietary supplement has been found to suppress the damaging autoimmune response seen in multiple sclerosis and type 1 diabetes mellitus, according to University of California, Irvine health sciences researchers.

In studies on mice, Dr. Michael Demetriou and colleagues with the UC Irvine Center for Immunology found that N-acetylglucosamine (GlcNAc), which is similar but more effective than the widely available glucosamine, inhibited the growth and function of abnormal T-cells that incorrectly direct the immune system to attack specific tissues in the body, such as brain myelin in MS and insulin-producing cells of the pancreas in diabetes. Study results appear on the online version of the Journal of Biological Chemistry.

“This finding shows the potential of using a dietary supplement to help treat autoimmune diseases,” said Demetriou, an assistant professor of neurology, and microbiology and molecular genetics. “Most importantly, we understand how this sugar-based supplement inhibits the cells that attack the body, making metabolic therapy a rational approach to prevent or treat these debilitating diseases.”

The UC Irvine study defines how metabolic therapy with the sugar GlcNAc and other related nutrients modifies the growth and autoimmune activitiy of T-cells. Virtually all proteins on the surface of cells, including T-cells, are modified with complex sugars of variable lengths and composition. Recent studies have shown that changes in these sugars are often associated with T-cell hyperactivity and autoimmune disease.

In mouse models of both MS and type 1 diabetes, Demetriou and colleages found that GlcNAc prevented this hyperactivity and autoimmune response by increasing sugar modifications to the T-cell proteins. This therapy normalized T-cell function and prevented development of paralysis in MS and high blood glucose levels in type 1 diabetes.

This study comes on the heels of others showing the potential of GlcNAc in humans. One previous clinical study reported that 8 of 12 children with treatment-resistant autoimmune inflammatory bowel disease improved significantly following two years of treatment with GlcNAc. No significant adverse side effects were noted.

“Together, these findings identify metabolic therapy using dietary supplements such as GlcNAc as potential treatments for autoimmune diseases.” Demetriou said. “Excitement for this treatment strategy stems from the novel mechanism for affecting T-cell function and autoimmunity and the availability and simplicity of its use. However, additional studies in humans will be required to assess the full potential of this therapeutic approach.”

Autoimmune diseases such as MS and type 1 diabetes mellitus result from poorly understood interactions between inherited genetic risk and environmental exposure. MS results in neurological dysfunction, while uncontrolled blood glucose in type 1 diabetes can lead to damage of multiple organs.

Ani Grigorian, Sung-Uk Lee, Wenqiang Tian, I-Ju Chen and Guoyan Gao of UC Irvine and Richard Mendelsohn and James W. Dennis of the Samuel Lunenfeld Research Institute in Toronto participated in the study, which was funded by the National Institutes of Health, the National Multiple Sclerosis Society, the Juvenile Diabetes Research Foundation, the Wadsworth Foundation and the Canadian Institutes for Health Research.

I guess it just takes things like this forever to move forward if there is no money in it for the drug companies. Two years and we are still dealing with mice.


Glucosamine may be useful in multiple sclerosis

Source: Thomas Jefferson University, 2005

Glucosamine, a product that has been touted to help with joint and cartilage problems associated with arthritis, may also provide some relief to individuals with multiple sclerosis ( MS ), a degenerative, nervous system disease with no known cure.

Using a mouse model of multiple sclerosis, researchers at Jefferson Medical College found that doses of Glucosamine similar to those taken for osteoarthritis dramatically delayed the onset of symptoms and improved the animals’ ability to move and walk.

The scientists, led by A. M. Rostami, at Jefferson Medical College of Thomas Jefferson University and the Jefferson Hospital for Neuroscience in Philadelphia, and Guang-Xian Zhang, at Jefferson Medical College, say the treatment’s anti-inflammatory effects may be useful in conjunction with more mainstream therapies such as beta-Interferon in helping patients with multiple sclerosis to delay or perhaps stave off some of the debilitating effects of the disease.

The findings are published in the The Journal of Immunology.

Rostami and his group used an animal model of multiple sclerosis called experimental autoimmune encephalomyelitis ( EAE ), which mimics the human disease, to investigate glucosamine’s potential immune system-suppressing properties. Such animals gradually develop the disease.

In the studies, some of the mice received Glucosamine, while others did not.

They gave Glucosamine to the mice three ways: orally, intraperitoneally and intravenously. They also tested the drug in one set of animals before the onset of symptoms, and in another group at the time the animals began to show symptoms.

In each case, the researchers showed they could significantly prolong the onset of disease. That is, those animals that got Glucosamine took longer to get ill and once they became ill, the disease was much less severe. It was just as effective when given early in the disease or when the animals became sick.

They examined the animals’ spinal cords and found less inflammation and “demyelination” in those that were given Glucosamine.

“ As a therapy, it might be used in combination with other proven treatments, such as beta-Interferon and Copaxone,” says Rostami.

The research team has some ideas of how Glucosamine exerts its effects.

According to Rostami, EAE and multiple sclerosis are caused by abnormal responses from the immune system’s T cells.
There are two types: TH1, which promotes inflammation, and TH2, which is anti-inflammatory. “ We’ve shown the Glucosamine modulates the immune response by producing more TH2 responses, suppressing brain inflammation,” he says. “ At the same time, it suppresses TH1 response. ”

The researchers currently are testing the effectiveness of combinations of Glucosamine and standard drugs for multiple sclerosis in the same mouse model to look for adverse effects. They are also trying to find out if Glucosamine can suppress the relapses in the relapsing/remitting form of the disease.

I started my hubby on N-Acetyl Glucosamine supplements after reading that Jefferson Un. paper from 1995 over the summer.

I purchase Jarrow formulas N-A-G 750 from Vitacost.com. 120 capules of 750mg. each tablet, one-three tablets per day.

N-A-G is the body's precursor to hyaluronic acid- part of the fluid which lubricates joints. It is produced in the intestinal tract via goblet cells, which also produce the mucosal lining.

Y'know, we're trying alot of supplements...no adverse reactions from my husband, and it's too soon into his MS journey (6 months) to know if these supplements will make a difference, but I remain ever hopeful in complementary treatments. Heck, it worked for the mice!

Best,
AC

Dom--thanks for posting this.

First one "OT" comment.
I think it's still open to question if MS is a "two stage" disease process with axonal loss 10 years later. Here's a recent abstract.

Axonal damage but no increased glial cell activity in the normal-appearing white matter of patients with clinically isolated syndromes

Cheerleader
I didn't know that, but based on this research, Hyaluronic acid prevents oligodendrocytes from repairing the damaged myelin I was of the impression people with MS may not want more hyaluronic acid. So, I think it's hard to determine if N-A-G might or might not be a good thing. Comments anyone?

Thanks

Sharon

Great information! Unfortunately, I have no faith in the current "conventional" MS drugs. I really like it when research steps outside of the box. Now...only one question: where will this go?

I have "Pooh-bah'ed" Ambrotose on this site and now I see that this stuff is in it. Sugars? Who'd have thunk? I may need to re-think this. Anyone trying this? Can I get it at supplement stores? Vitamin Shoppe? napay

is this the report?

_________________
My Starting Point
Understanding MS 101: Doctor Talk and People Talk<br /><br />

Sharon-
Thanks for the link regarding hyaluronic acid and its affect on remylenization- obviously something that an MS patient would NOT want.

N-acetyl-glucosamine in a precursor to HA, but I believe N-A-G taken as an oral supplement never gets as far as HA in the body. When this supplement is broken down in the intestine, it is the sugars that are absorbed, and that HA is not actually created. It is the cell-surface sugars which are reponsible for the immune modulating results recently reported.

I recently had HA injected as a dermal filler into my face (as Restylane). Ah, vanity. Here's a biochemist explaining why N-A-G supplements are NOT useful for creating cartilage and HA in the human body...because the human intestine breaks down N-A-G into cell-surface sugars it can use, and doesn't turn it into HA.

http://www.madsci.org/posts/archives/20 ... .Bc.r.html

But all this has made me think. I'm not a biochemist, so we'll probably back off the N-A-G supplements until there's more research.
Thanks for the input-
AC

how much would someone take each day?

Does is penetrate the BBB?

_________________
My Starting Point
Understanding MS 101: Doctor Talk and People Talk<br /><br />

AC

Thanks so much for even more info and the link. I really appreciate it.

I don't think I'll be adding N-A-G to my gig. I'm more interested in neuroprotection from angles other than immune system modulation.

Take care

Sharon

HA is produced outside the CNS and don't belong in the CNS. Of course, that's a familiar sounding idea, isn't it? The real question is whether in MS it is penetrating the BBB. I don't know the answer to that.

I'd be interested to see a study that shows that this stuff is present in the CNS of patients with MS.

Does anyone know how much to take each day? napay

_________________
My Starting Point
Understanding MS 101: Doctor Talk and People Talk<br /><br />

Hi Napay,
Hyaluronic acid is a normal component of the extracellular matrix in the CNS. I believe I'm right in saying that it's actually supposed to inhibit oligodendrocytes precursors from maturing – that's part of its job. It's part of the complicated switching on and switching off that goes on during development, but it's supposed to be down-regulated after. Two other components of the extracellular matrix also seem to play a role in active lesions: Vitronectin and Fibronectin. I'm sorry for the long extracts, but I think the ECM is starting to look very interesting:


Membrane-associated Syndecans, glypicans Cell adhesion, binding of growth factors Bernfield et al. (1992),
Fransson (2003)
Hyaluronan Cell division and motility, ECM–ECM
interactions, inhibition of the differentiation
of oligodendrocyte progenitors
Bignami et al. (1993)

Hyaluronan
A high molecular weight (HMW) form of the GAG hyaluronan accumulates in demyelinating MS lesions and in the brain tissue of experimental autoimmune encephalomyelitis mice, a widely used animal model to study MS pathology (Back et al. 2005). Back and co-workers demonstrated that the HMW form of hyaluronan inhibits remyelination in an experimental demyelination animal model. HMW hyaluronan inhibits the maturation of oligodendrocyte precursors into myelin-forming oligodendrocytes. These findings suggest that deposition of HMW hyaluronan in MS lesions may contribute to lesion progression by blocking the maturation of oligodendrocyte precursor cells.

In the CNS, vitronectin plays a role in the induction of neurite outgrowth in development (Grabham et al. 1992; Martinez-Morales et al. 1995). Vitronectin is primarily synthesized in the liver (Tomasini and Mosher 1991) and has affinity for different integrins expressed on T-cells, platelets, endothelial cells and macrophages. In normal adult CNS, vitronectin is localized to most blood vessels with the exception of capillaries, suggesting that small amounts of vitronectin are deposited in the CNS under normal conditions. In active demyelinating MS lesions vitronectin expression was strikingly enhanced in blood vessel walls, at the border of chronic active MS lesions, in demyelinated axons and on a small number of hypertrophic astrocytes (Sobel et al. 1995). The functional role of vitronectin under inflammatory conditions is still unknown, however it has been shown that vitronectin promotes neurite outgrowth (Neugebauer et al. 1991) and affects cellular migration of astrocytes (Milner et al. 1999). As vitronectin mRNAwas undetectable in normal adult brain (Gladson et al. 1995), it might be synthesized by infiltrating leukocytes or derived from plasma as a result of BBB breakdown.

Fibronectin
Fibronectin is an HMW glycoprotein that exists as an insoluble glycoprotein dimer, which serves as a linker in the ECM, and as a soluble disulfide linked dimer found in the plasma. The plasma form is synthesized by hepatocytes, while the ECM form is produced by fibroblasts, endothelial cells and macrophages (Stenman and Vaheri 1978; Tamkun and Hynes 1983). Fibronectin is involved in cellular interaction by binding to different components of the ECM and to membrane-bound fibronectin receptors on cell surfaces. In normal CNS tissue, fibronectin is expressed in the adventitia of parenchymal and leptomeningeal blood vessels and in the choroid plexus (Esiri and Morris 1991). In MS brain tissue enhanced fibronectin deposition was primarily localized to vessel walls, in particular in perivascular infiltrates, and correlated with the extent of inflammation. Fibronectin accumulation was also detected in the parenchyma of active demyelinating MS lesions suggesting that, in addition to extravasation from affected blood vessels, fibronectin may be locally produced by endothelial cells or infiltrated macrophages in the CNS (Sobel and Mitchell 1989; Esiri and Morris 1991). Recent data demonstrated that fibronectin inhibits the differentiation of oligodendrocyte progenitors and thus remyelination

Nowadays, the definition of the ECM is broadened and basically includes all secreted molecules that are immobilized outside cells. Table 1 provides an overview on the distinct ECM components of the CNS and their major functions. Generally, the ECM of the CNS is involved in various regulatory processes in the development and normal function of the CNS, provides physical support for neurons and glial cells and regulates ionic and nutritional homeostasis (Bandtlow and Zimmermann 2000; Yamaguchi 2000). The molecular composition of the ECM in the CNS influences interactions between a variety of molecules and cells, and is specifically involved in growth and regeneration of nerve fibers, but also in programmed cell death of neurons. Insulin-like growth factors (IGFs) are trophic factors in the CNS and are involved in migration and differentiation of oligodendrocyte precursor cells and remyelination of axons by stimulating myelin protein synthesis (Jones and Clemmons 1995). Modes of IGF action are regulated by IGF-binding proteins (IGFBPs), which are secreted in the extracellular space. It has been shown that several IGFBPs, including IGFBP- 2, -3 and-5 bind constituent proteins of the ECM, thereby influencing cellular growth and proliferation (Jones et al. 1993; Conover and Khosla 2003; Martin and Jambazov 2006). Interestingly, many other ECM components are involved in different aspects of oligodendrocyte biology and myelin formation (Table 2). ECM molecules interact via specific ligands, such as integrins, with cell surface receptors and thus provide cellular signals for growth, movement, proliferation, differentiation and, if needed, apoptosis. Consequently, alterations in the localization and composition of the ECM may result in different biological responses and therefore play an important role in disease development and progression. Highly specialized ECM sheets are the basement membranes (BM) that are present at the interface between epithelial and endothelial cells and their surrounding connective tissues. BM not only function as a tissue boundary on which cells are attached, but may also act as a molecular filter with selective permeability for soluble factors and form a highly specialized substrate for cellular differentiation and gene expression (Kalluri 2003). The regulation of ECM production and degradation is a tightly controlled process involving various proteins and Received April 24, 2007; revised manuscript received July 6, 2007; accepted July 9, 2007.

Address correspondence and reprint requests to Jack van Horssen,
Department of Molecular Cell Biology and Immunology, VU University
Medical Center Amsterdam, PO Box 7057, 1007 MB Amsterdam, The
Netherlands. E-mail: j.vanhorssen@vumc.nl

Abbreviations used: BBB, blood–brain barrier; BM, basement membrane,
CS-1, connecting segment-1, ECM, extracellular matrix, GAG,
glycosaminoglycan, HMW, high molecular weight, HSPG, heparan
sulfate proteoglycan, IGF, insulin-like growth factor, IGFBP, IGF-binding
proteins, MMP, matrix metalloproteinase, MS, multiple sclerosis,
PG, proteoglycan, SLRP, small leucine-rich PG.

_________________
Dom

Dom,
Any chance this stuff could initiate an exacerbation? I'd say this is our experience over the last month on NAG. Has not been good. I speculate that Kim will improve now that we have stopped taking it.
Ken

_________________
My Starting Point
Understanding MS 101: Doctor Talk and People Talk<br /><br />

As far as this NAG thing is concerned... it's another "mouse" study. So who's mouse do you trust.... If these other mice in another study were given glucosamine, then why didn't they develope NAG?

read up about mice and NAG

Further investigation revealed that the tremors were associated with the loss of myelin sheaths on nerve cells, very similar to the myelin loss associated with MS and other neurological diseases, as well as in premature infants. In addition, Sherman's lab found large amounts of hyaluronic acid (HA), a carbohydrate, in the brains of these mice. A comparison to brain tissue of deceased human MS patients also revealed heightened levels of HA, apparently caused by the increased presence of CD44 -- something which had never been noted before. It was at this point that Sherman contacted Bebo, who had been studying an MS-like disease in mice for many years, and they began a collaboration to study how HA accumulated in regions of the nervous system where myelin had been destroyed.

"These investigations revealed that oligodendrocytes, which are cells that form myelin in the brain, were prevented from repairing the damaged myelin when there were elevated levels of HA," explained Bebo. "By studying another mouse model in my lab, we made the connection between heightened levels of HA -- specifically a high-molecular weight version of HA -- and myelin loss in an MS-like disease in mice. We also identified the cells that were making the HA and determined that HA accumulation was linked to an overabundance of the CD44 protein."

In reading all of the scary stuff about HA, I did notice that in some places, it mentions HMW HA (High Molecular Weight). Is that different than regular HA? According to SOME of the stuff I read, it does sound like HA is doing what it is _supposed_ to be doing, and possible helping to repair:

"Hyaluronic Acid Hydrogels
Hyaluronic acid (HA) is a widely used biomaterial as a result of its excellent biocompatibility and its physiologic function diversity. It is abundant in the extracellular matrix (ECM) where it binds large glycosaminoglycans (GAGs) and proteoglycans through specific HA-protein interactions. HA also binds cell surface receptors such as CD44, which results in the activation of intracellular signaling cascades that regulate cell adhesion and motility and promote proliferation and differentiation [36]. HA is also known to support angiogenesis because its degradation products stimulate endothelial cell proliferation and migration. Thus, HA plays a pivotal role in maintaining the normal processes necessary for tissue survival. Unmodified HA has been used in clinical applications such as ocular surgery, wound healing, and plastic surgery [36]. HA can be crosslinked to form hydrogels. HA hydrogels that were either unmodified or modified with laminin were implanted into an adult central nervous system lesion and tested for their ability to induce neural tissue formation in a study by Hou et al.. They demonstrated the ability to support cell ingrowth and angiogenesis, in addition to inhibiting glial scar formation. Also, the HA hydrogels modified with laminin were able to promote neurite extension [36]. These results support HA gels as a promising biomaterial for a nerve guidance conduit."
From a Wikipedia article -- I know, who trusts wikipedia...
http://en.wikipedia.org/wiki/Nerve_guidance_conduit
(Originally found because I was reading about Astrocytes (NOT related to Star Trek).

I have to wonder if the association of HA and CD44 is HA binding to CD44 to remove it [CD44] or deactivate its harmful activity.

So, when it comes to NAG, my jury is still out, but based on anecdotal evidence, I think it might be useful. More from JP, I hope.

My other strong interests are in glutathione support (bio-available whey, NAC (sound familiar), N-A-Carnitine, etc.) and vitamine D3, etc.

Even if MS can't be -cured- by an orthomolecular approach, we do know that many nutrients can ease its effects. If NAG does nothing more than ease it, I think it will be enough.

This reply actually started from research for another post...
http://www.thisisms.com/ftopic-4895-0-d ... rasc-.html
... now I've got to go there and ask questions.

-M.
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