This Is MS Multiple Sclerosis Knowledge & Support Community

Multiple Sclerosis is an autoimmune disease that affects the brain and spinal cord, destroying tissue and cells along the way. Previous research and practices have found that therapies can help with relapses of MS, but cannot help repair the tissue and cells that have been affected.<br><br>

After MS has affected the body and caused cell damage, the brain produces new cells to repair the old ones. However, a majority of cases has shown that there are unknown factors that hinder the cells from completely repairing, thus creating a permanent loss. The brain inflammation caused by MS leads to the destruction of myelin, which is the fatty insulation for the axon nerve fibers in the brain, thus destroying brain cells. A molecule known as Endothelin-1 (ET-1) is known to inhibit the repair of the myelin..... Read More - http://www.ms-uk.org/myelin

I am going to post the following information on my Facebook page tonight. You can check my profile for the link if you would like to check the page out.


NEW MULTIPLE SCLEROSIS STUDY FINDS THAT A POTENT VASOCONSTRICTOR CALLED ENDOTHELIN-1 INHIBITS MYELIN REPAIR/IMPLICATIONS FOR FIBROMYALGIA AND OTHER AUTOIMMUNE DISEASES

The study authors stated:

"...The molecule, endothelin-1 (ET-1), is shown to inhibit repair of myelin. Myelin damage is a hallmark characteristic of MS...We demonstrate that ET-1 drastically reduces the rate of remyelination..."

So, if multiple sclerosis originates with the missing enzymes "protease and DNase 1", how would a lack of these enzymes explain this study finding?


Elevated levels of endothelin-1 would be due to increased levels of the amino acid "homocysteine". We recently posted research that confirms patients with MS have elevated levels of homocysteine due to an inability to properly metabolize vitamin B12. Homocysteine will rise in direct proportion to a lack of vitamin B12. Protease are "essential" for the proper metabolism of vitamin B12.

The following information from our soon to be released MS book explains the connection to elevated homocysteine and increased levels of endothelin-1.



ELEVATED ENDOTHELIN-1


Nitric oxide regulates a potent vasoconstrictor called endothelin-1 (ET-1). In the following study the researchers found that ET-1 was significantly elevated in patients with MS and concluded that cerebral hypoperfusion (decreased cerebral blood flow) in MS is mediated by ET-1.



Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.
D'haeseleer M, Beelen R, et al. 2013. Proc Natl Acad Sci USA. 110(14):5654-8. doi: 10.1073/pnas.1222560110. Epub 2013 Mar 18.


“Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein…These data demonstrate that reduced CBF in MS is mediated by ET-1…”







Researchers in the following study found that ET-1 levels were, on average, 224% higher in patients with MS.



Increased endothelin-1 plasma levels in patients with multiple sclerosis.
Haufschild T, Shaw SG, Kesselring J, Flammer J. 2001. J Neuroophthalmol. 21(1):37-8.

“We tested the hypothesis that the plasma level of endothelin-1 (ET-1) is increased in patients with multiple sclerosis (MS). The peptide ET-1 is one of the most potent known vasoconstrictors. An increased level of endothelin could explain some of the vascular symptoms of these patients…The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005). The mean ET-1 levels (mean +/- standard deviation [SD]) were 3.5 +/- 0.83 pg/mL (min 2.13, max 5.37 pg/mL) in patients with MS and 1.56 +/- 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in healthy volunteers. Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease...The plasma ET-1 level is markedly and significantly increased in patients with MS. Neither the cause of such an increase nor the pathogenetic role is known.”







In the following study the researchers concluded that diminished nitric oxide “bioavailability” results in "unmitigated" ET-1 actions which lead to vasoconstriction and eventually to vascular dysfunction.

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives.
Bourque SL, Davidge ST, Adams MA. 2011. Am J Physiol Regul Integr Comp Physiol. 300(6):R1288-95. doi: 10.1152/ajpregu.00397.2010. Epub 2011 Mar 2.

“Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease…we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.”





In our next study the researchers concluded that homocysteine decreases “bioavailable” nitric oxide.


Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase.
Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J. 1997. J Biol Chem. 272(27):17012-7.

“Hyperhomocysteinemia is believed to injure endothelial cells in vivo through a number of mechanisms…Hcy affects the bioavailability of NO…”


Elevated homocysteine is part of the underlying disease pathway that all autoimmune and fibromyalgia patients share, so we should find evidence of elevated endothelin-1 in fibromyalgia and other autoimmune diseases as well.

ELEVATED LEVELS OF ENDOTHELIN-1 IN FIBROMYALGIA
http://rheumatology.oxfordjournals.org/content/42/3/493

ELEVATED LEVELS OF ENDOTHELIN-1 IN LUPUS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1004476/

ELEVATED LEVELS OF ENDOTHELIN-1 IN RHEUMATOID ARTHRITIS
http://www.ncbi.nlm.nih.gov/pubmed/12218941

ELEVATED LEVELS OF ENDOTHELIN-1 IN BEHCET'S DISEASE
http://www.ncbi.nlm.nih.gov/pubmed/7801056

ELEVATED LEVELS OF ENDOTHELIN-1 IN DIABETES
http://www.ncbi.nlm.nih.gov/pubmed/12441216


Take home message

An inability to properly metabolize vitamin B12, due to a lack of protease, leads to elevated levels of homocysteine. Homocysteine interferes with nitric oxide bioavailability. Nitric oxide inhibits endothelin-1 and its absence results in "unmitigated" endothelin-1 actions.

Annesse,

Can our inability to metabolize B12 be present even though our serum levels are shown to be very high? I'm in hospital at present. Is there any way I can supplement with something containing protease and or DNase here besides a digestive enzyme I have on hand that contains protease I believe?

Thx, PN

Annesse wrote:I am going to post the following information on my Facebook page tonight. You can check my profile for the link if you would like to check the page out.


NEW MULTIPLE SCLEROSIS STUDY FINDS THAT A POTENT VASOCONSTRICTOR CALLED ENDOTHELIN-1 INHIBITS MYELIN REPAIR/IMPLICATIONS FOR FIBROMYALGIA AND OTHER AUTOIMMUNE DISEASES

The study authors stated:

"...The molecule, endothelin-1 (ET-1), is shown to inhibit repair of myelin. Myelin damage is a hallmark characteristic of MS...We demonstrate that ET-1 drastically reduces the rate of remyelination..."

So, if multiple sclerosis originates with the missing enzymes "protease and DNase 1", how would a lack of these enzymes explain this study finding?


Elevated levels of endothelin-1 would be due to increased levels of the amino acid "homocysteine". We recently posted research that confirms patients with MS have elevated levels of homocysteine due to an inability to properly metabolize vitamin B12. Homocysteine will rise in direct proportion to a lack of vitamin B12. Protease are "essential" for the proper metabolism of vitamin B12.

The following information from our soon to be released MS book explains the connection to elevated homocysteine and increased levels of endothelin-1.



ELEVATED ENDOTHELIN-1


Nitric oxide regulates a potent vasoconstrictor called endothelin-1 (ET-1). In the following study the researchers found that ET-1 was significantly elevated in patients with MS and concluded that cerebral hypoperfusion (decreased cerebral blood flow) in MS is mediated by ET-1.



Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.
D'haeseleer M, Beelen R, et al. 2013. Proc Natl Acad Sci USA. 110(14):5654-8. doi: 10.1073/pnas.1222560110. Epub 2013 Mar 18.


“Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein…These data demonstrate that reduced CBF in MS is mediated by ET-1…”







Researchers in the following study found that ET-1 levels were, on average, 224% higher in patients with MS.



Increased endothelin-1 plasma levels in patients with multiple sclerosis.
Haufschild T, Shaw SG, Kesselring J, Flammer J. 2001. J Neuroophthalmol. 21(1):37-8.

“We tested the hypothesis that the plasma level of endothelin-1 (ET-1) is increased in patients with multiple sclerosis (MS). The peptide ET-1 is one of the most potent known vasoconstrictors. An increased level of endothelin could explain some of the vascular symptoms of these patients…The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005). The mean ET-1 levels (mean +/- standard deviation [SD]) were 3.5 +/- 0.83 pg/mL (min 2.13, max 5.37 pg/mL) in patients with MS and 1.56 +/- 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in healthy volunteers. Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease...The plasma ET-1 level is markedly and significantly increased in patients with MS. Neither the cause of such an increase nor the pathogenetic role is known.”







In the following study the researchers concluded that diminished nitric oxide “bioavailability” results in "unmitigated" ET-1 actions which lead to vasoconstriction and eventually to vascular dysfunction.

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives.
Bourque SL, Davidge ST, Adams MA. 2011. Am J Physiol Regul Integr Comp Physiol. 300(6):R1288-95. doi: 10.1152/ajpregu.00397.2010. Epub 2011 Mar 2.

“Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease…we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.”





In our next study the researchers concluded that homocysteine decreases “bioavailable” nitric oxide.


Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase.
Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J. 1997. J Biol Chem. 272(27):17012-7.

“Hyperhomocysteinemia is believed to injure endothelial cells in vivo through a number of mechanisms…Hcy affects the bioavailability of NO…”


Elevated homocysteine is part of the underlying disease pathway that all autoimmune and fibromyalgia patients share, so we should find evidence of elevated endothelin-1 in fibromyalgia and other autoimmune diseases as well.

ELEVATED LEVELS OF ENDOTHELIN-1 IN FIBROMYALGIA
http://rheumatology.oxfordjournals.org/content/42/3/493

ELEVATED LEVELS OF ENDOTHELIN-1 IN LUPUS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1004476/

ELEVATED LEVELS OF ENDOTHELIN-1 IN RHEUMATOID ARTHRITIS
http://www.ncbi.nlm.nih.gov/pubmed/12218941

ELEVATED LEVELS OF ENDOTHELIN-1 IN BEHCET'S DISEASE
http://www.ncbi.nlm.nih.gov/pubmed/7801056

ELEVATED LEVELS OF ENDOTHELIN-1 IN DIABETES
http://www.ncbi.nlm.nih.gov/pubmed/12441216


Take home message

An inability to properly metabolize vitamin B12, due to a lack of protease, leads to elevated levels of homocysteine. Homocysteine interferes with nitric oxide bioavailability. Nitric oxide inhibits endothelin-1 and its absence results in "unmitigated" endothelin-1 actions.

I would argue, in order to pinpoint the cause of elevated et-1 in chronic inflammatory disease, we needn't go so far from the obvious. Monocytes/macrophages are involved in the cascade and cause elevated et-1 (in mice anyway).
http://www.ncbi.nlm.nih.gov/m/pubmed/23670300/
I'm sure other cascade components likely contribute to the problem as well.

Do you have any evidence yet that your protease ideas have helped someone with ms?

Hi PN~

So sorry you are in the hospital. Yes, you can have elevated serum levels of B12 and low cellular levels if you are supplementing. There really isn't anything you could take in a supplement form that would restore your protease and DNase 1 safely and effectively. It will take some time to heal your GI tract and to restore the function of the pancreas. Let me think about what we could do though and I will PM you.

The common denominator that all of the diseases I listed share that would increase endothelin-1 is elevated homocysteine. Homocysteine also activates monocytes and macrophages. Following is some information I posted previously on this.



Homocysteine increases the expression of the pro-inflammatory chemokines interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1). MCP-1 and IL-8 are key chemokines that regulate migration and infiltration of monocytes. In the following study the researchers stated, “In particular, monocyte chemoattractant protein 1 (MCP-1) has been implicated in diseases characterized by monocyte-rich infiltrates, including atherosclerosis, rheumatoid arthritis and multiple sclerosis.”





Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease.
Rollins BJ. 1996. Mol Med Today. 2(5):198-204.


“The appearance of specific types of leukocytes in inflammatory infiltrates may be governed by cell-specific chemoattractants called chemokines. In particular, monocyte chemoattractant protein 1 (MCP-1) has been implicated in diseases characterized by monocyte-rich infiltrates, including atherosclerosis, rheumatoid arthritis and multiple sclerosis…”


In the following study the researchers found that patients with MS had significantly higher levels of IL-8.

Increased CXCL8 (IL-8) expression in multiple sclerosis.
Lund BT, Ashikian N, et al. 2004. J Neuroimmunol. 155(1-2):161-71.



“Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS which is characterized by large mononuclear cell infiltration and significant demyelination. CXCL8 is a chemo-attractant for both neutrophils and monocytes and triggers their firm adhesion to endothelium. In this study, we demonstrate that serum CXCL8 and CXCL8 secretion from PBMCs are significantly higher in untreated MS patients compared to controls and are significantly reduced in MS patients receiving interferon-beta1a therapy. We suggest that CXCL8 may serve as a marker of monocyte activity in MS and may play a role in monocyte recruitment to the CNS.”


In the next study the researchers found that homocysteine increased the secretion and expression as well as activity of MCP-1 and IL-8 in monocytes.

Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes.
Zeng X, Dai J, Remick DG, Wang X. 2003. Circ Res. 93(4):311-20. Epub 2003 Jul 24.


“Homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) are major chemokines for leukocyte trafficking and have been identified in atheromatous plaques. MCP-1 and IL-8 have been found to express mainly by macrophages in human lesion. We undertook this study to determine whether Hcy could induce the secretion of chemokines from human monocytes and, if so, to explore the mediating mechanism. We found that clinically relevant levels of Hcy (10 to 1000 micromol/L) increased the protein secretion and mRNA expression as well as activity of MCP-1 and IL-8 in cultured primary human monocytes. These effects of Hcy were primarily mediated by reactive oxygen species (ROS) through NAD(P)H oxidase, because Hcy could upregulate the production of ROS and the inhibitors of protein kinase C, calmodulin, free radical scavengers, or NAD(P)H oxidase abolished Hcy-induced ROS production and MCP-1 and IL-8 secretion in these cells…”



In the next study published in Molecular and Cellular Biochemistry the researchers found that the secretion of MCP-1 was increased 195% in cells treated with homocysteine.

Homocysteine stimulates the expression of monocyte chemoattractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis.
Sung FL, Slow YL, Wang G, Lynn EG, O K. 2001. Mol Cell Biochem. 216(1-2):121-8.


“Hyperhomocysteinemia has been identified as an independent risk factor for atherosclerosis. The infiltration of monocytes into the arterial wall is one of the key events during atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall. The mechanism by which increased monocyte infiltration occurs in atherosclerotic lesions in patients with hyperhomocysteinemia has not been delineated. The objective of the present study was to investigate the effect of homocysteine on MCP-1 production in endothelial cells. Cells were incubated with homocysteine. The secretion of MCP-1 protein was significantly increased (195% as compared to the control) in cells treated with pathological concentrations of homocysteine. Such effect was accompanied by an increased expression of MCP-1 mRNA (176% as compared to the control) in endothelial cells which resulted in enhanced monocyte chemotaxis. The p38 MAP kinase as well as other members of the p38 MAP kinase pathway, including MKK3, MKK6, ATF-2 and Elk-1, were activated in homocysteine-treated cells…In conclusion, our results indicate that homocysteine stimulates MCP-1 expression in endothelial cells leading to enhanced monocyte chemotaxis.”


In the next study the researchers found that homocysteine promoted “proliferation and activation” of microglia (the resident macrophages of the brain). The researchers concluded, “Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.”

Homocysteine promotes proliferation and activation of microglia.
Zou CG, Zhao YS, Gao SY, Li SD, Cao XZ, Zhang M, Zhang KQ. 2010. Neurobiol Aging. 31(12):2069-79. doi: 10.1016/j.neurobiolaging.2008.11.007. Epub 2009 Jan 7.


“Epidemiological and experimental studies have correlated hyperhomocysteinemia to a range of neurodegenerative conditions, including Alzheimer's disease, stroke, and Parkinson's disease. Although homocysteine-induced apoptosis in neurons has been extensively studied, little information is available regarding the effect of homocysteine on microglia. In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation). Consistent with our in vitro results, a significant increase in the number of CD11b-positive microglia was also observed in brain sections of mice with hyperhomocysteinemia. Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. Up-regulation of NAD(P)H oxidase activity by homocysteine appears to be due to its ability to induce the phosphorylation of p47phox through the p38 MAPK pathway…Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.”

Hey PN--
So sorry you're in the hospital!!! What's going on? Please keep us posted---sending healing thoughts.

You're right--there are many reasons for elevated ET-1, which is a marker of endothelial dysfunction.
But the first cause that researchers point to is ischemia, or low oxygen--which is why ET-1 levels are so high in ischemic stroke.

Homocysteine and low B12 are implicated, as well....but endothelial dysfunction is not created by one molecule or one cause. There are a myriad of reasons. Which is why you can have normal B12 levels, and still have endothelial dysfunction. For some people, it's created by stress hormones. In others it's smoking, or eating Big Macs and fries. Others, it's no physical activity. For some, it's a trip to high altitude. Saying all endothelial dysfunction comes from the same root cause is just not right. Scientists don't do it....neither should laypeople on forums.

I know my opinion doesn't hold much weight--that's why I go to medical conferences, and talk to actual researchers. Because they know what's up. And the two world-reknowned endothelial researchers at the ISNVD conference discussed the many ways the endothelium can be damaged, and begin this cascade. Included in their presentations were slowed venous return and lack of shear stress affecting NO, iNOS being created and breaking the blood brain barrier, the miscommunication of endothelial cells in the angiogenesis process and environmental factors like exercise and nutrition. Not one researcher said, I know! It's blah, blah, blah....They all agree, there are many factors. It's worth listening to them and considering the bigger picture. http://ccsviinms.blogspot.com/2014/02/i ... cture.html
cheer

I am not sure I even mentioned endothelial cells in my post, but I agree that endothelial cells can be damaged in various ways. In MS though, the research shows they are being damaged and the blood-brain barrier breakdown is occurring in a "specific" manner. For instance, in the following study the researchers investigated the “anatomical route” of the blood-brain barrier (BBB) breakdown in MS. The researchers explored the possible involvement of interendothelial tight junctions (TJ) by examining the expression of the TJ proteins, occludin and ZO-1, in the blood vessels of patients with MS.

Tight junctions are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. The downregulation of the tight junction proteins, occludin and ZO-1, leads to breaks in the tight junctions between endothelial cells in the veins, which leads to leakage of toxic blood components into CNS tissue.

The study authors discovered that patients with MS had endothelial tight junctional pathology and concluded that BBB, due to disruption to tight junctional pathology, should be regarded as a significant form of tissue injury in MS, alongside demyelination and axonopathy.

Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis.
Plumb J, McQuaid S, Mirakhur M, Kirk J. 2002. Brain Pathol. 12(2):154-69.

“Blood-brain barrier (BBB) breakdown, demonstrable in vivo by enhanced MRI is characteristic of new and expanding inflammatory lesions in relapsing-remitting and chronic progressive multiple sclerosis (MS). Subtle leakage may also occur in primary progressive MS. However, the anatomical route(s) of BBB leakage have not been demonstrated. We investigated the possible involvement of interendothelial tight junctions (TJ) by examining the expression of TJ proteins (occludin and ZO-1 ) in blood vessels in active MS lesions from 8 cases of MS and in normal-appearing white (NAWM) matter from 6 cases…TJ abnormalities manifested as beading, interruption, absence or diffuse cytoplasmic localization of fluorescence, or separation of junctions (putative opening) were frequent (affecting 40% of vessels)… Putatively "open" junctions were seen in vessels in active lesions and in microscopically inflamed vessels in NAWM. Dual fluorescence revealed abnormal TJs in vessels with pre-mortem serum protein leakage. Abnormal or open TJs, associated with inflammation may contribute to BBB leakage in enhancing MRI lesions and may also be involved in subtle leakage in non-enhancing focal and diffuse lesions in NAWM. BBB disruption due to tight junctional pathology should be regarded as a significant form of tissue injury in MS, alongside demyelination and axonopathy.”






In the following study the researchers stated that elevated homocysteine causes blood brain barrier dysfunction. In addition, the researchers explored the “mechanism” by which elevated homocysteine leads to blood-brain barrier dysfunction and concluded that homocysteine causes downregulation of the endothelial tight junction proteins occludin and ZO-1.

Homocysteine attenuates blood brain barrier function by inducing oxidative stress and the junctional proteins.
Tyagi N, Kumar M, Pushpakumar SB, Lominadze D, Moshal KS, Sen U, Vacek TP, Tyagi SC. 2008. FASEB J. (Meeting Abstract Supplement) 734.7


“Hyperhomocysteinmia (HHcy) is associated with neurological disorders and causes blood brain barrier (BBB) dysfunction. However, the mechanism of BBB dysfunction is unclear. We hypothesize that Hcy induces oxidative stress, activates inter-endothelial junctional (TJ) proteins leading to BBB dysfunction... Our results show that Hcy induces oxidative stress, which causes downregulation of the inter-endothelial junctional proteins (ZO-1, caludin, occludin)…In conclusion, Hcy-induced oxidative stress leads to BBB dysfunction, in part by, activating TJ proteins.”

In our next study the researchers found that homocysteine induced a dose-dependent decrease in endothelial tight junction integrity. The researchers concluded that homocysteine induces oxidative stress, which causes downregulation of the endothelial tight junction proteins occludin and ZO-1.

Homocysteine induces alternations of tight junction proteins in brain endothelial cells.
Tyagi N, Qipshidze N, Givvimani S, Mishra PK, Lominadze D, Tyag SC. 2012. Stroke 43: A3754

“Hyperhomocysteinmia (HHcy) is associated with neurological disorders (Stroke, Alzheimer, Parkinson etc.) and causes blood brain barrier (BBB) dysfunction. We previously showed that an elevated level of homocysteine (Hcy) increased formation of filamentous actin and enhanced endothelial layer permeability. In the present work we tested the hypothesis that Hcy induces oxidative stress and binding to endothelial cells (ECs) alters expression of endothelial tight junction proteins (TJP)…Hcy induced a dose-dependent decrease in EC junction integrity…Our results show that high dose of Hcy induces oxidative stress, which cause downregulation of the TJPs contents occludin, zona occluden-1 (ZO-1)…”


The point I was trying to make in responding to the post was that endothelin-1 is not just elevated in MS, but in all autoimmune diseases, and the common denominator is elevated levels of homocysteine. Homocysteine interferes with the bioavailability of nitric oxide. The lack of bioavailable nitric oxide was shown to result in "unmitigated" endothelin-1. Patients with MS had levels of endothelin-1 that were 224% higher than normal.