Nitric Oxide and MS

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Nitric Oxide and MS

Postby Liberation » Tue Jan 29, 2013 10:27 am

Calabrese, V., G. Scapagnini, et al. (2003). "Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine." Neurochem Res 28(9): 1321-8.

Recent studies suggest that NO and its reactive derivative peroxynitrite are implicated in the pathogenesis of multiple sclerosis (MS). Patients dying with MS demonstrate increased astrocytic inducible nitric oxide synthase activity, as well as increased levels of iNOS mRNA. Peroxynitrite is a strong oxidant capable of damaging target tissues, particularly the brain, which is known to be endowed with poor antioxidant buffering capacity. Inducible nitric oxide synthase is upregulated in the central nervous system (CNS) of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. We have recently demonstrated in patients with active MS a significant increase of NOS activity associated with increased nitration of proteins in the cerebrospinal fluid (CSF). Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, in the present study, MS patients were treated for 6 months with acetylcarnitine and compared with untreated MS subjects or with patients noninflammatory neurological conditions, taken as controls. Western blot analysis showed in MS patients increased nitrosative stress associated with a significant decrease of reduced glutathione (GSH). Increased levels of oxidized glutathione (GSSG) and nitrosothiols were also observed. Interestingly, treatment of MS patients with acetylcarnitine resulted in decreased CSF levels of NO reactive metabolites and protein nitration, as well as increased content of GSH and GSH/GSSG ratio. Our data sustain the hypothesis that nitrosative stress is a major consequence of NO produced in MS-affected CNS and implicate a possible important role for acetylcarnitine in protecting brain against nitrosative stress, which may underlie the pathogenesis of MS.


Anyone has information on the role of nitric oxide on MS?
I saw several contradictory opinions about it. For erectile dysfunction NO is commonly used. As erectile dysfunction is a common problem with MS patients it would be worth knowing whether it helps or hurts.
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Re: Nitric Oxide and MS

Postby Anonymoose » Tue Jan 29, 2013 6:52 pm

Good question. I saw a lot of conflicting info on NO too. I never took time to figure it out though. I think this is might explain why it is bad for pwms.

The Good (in normal people)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1533368/
NO synthesis has also clearly been shown to have a beneficial role in regulating organ perfusion and mediating cytotoxicity.
There's probably a lot more good but I'm too lazy to find it all.

The Bad (in pwms)
Using triple-labeled fluorescent immunocytochemistry, we also show that Nav1.6, which is known to produce a persistent sodium current, and the Na+/Ca2+ exchanger, which can be driven by persistent sodium current to import damaging levels of calcium into axons, are colocalized with β-amyloid precursor protein, a marker of axonal injury, in acute MS lesions. Our results demonstrate the molecular identities of the sodium channels expressed along demyelinated and degenerating axons in MS and suggest that coexpression of Nav1.6 and Na+/Ca2+ exchanger is associated with axonal degeneration in MS.

http://cdn.intechopen.com/pdfs/34158/In ... e_drug.pdf
Inhibition of L-type Ca2+ channels (vascular smooth muscle, in vitro); inhibition of N-type Ca2+ channels (sympathetic neuron, in vitro)
Pharmacology
1) Cardiovascular action
Vascular relaxation (in vitro); hypotensive action (in vivo)
2) Anti-sympathetic action
Decrease of catecholamine release, tissue (kidney) norepinephrine level, (in vitro, in vivo); inhibition of sympathetic tachycardia and cold stress-induced vasoconstriction (in vivo); decrease in plasma/urinary norepinephrine, muscle sympathetic nerve activity, low frequency/high frequency ratio (LF/HF ratio), and plasma level of ß-thromboglobulin (clinical)
3) Suppression of renin- angiotensin-aldosterone system
Decrease in plasma level of angiotensin II and aldosterone (in vivo, clinical); inhibition of aldosterone production (adrenocortical cells, in vitro); inhibition of reflex aldosterone production, and angiotensin II-renin feedback (in vivo)
4) Anti-oxidation
Inhibition of NADPH oxidase-derived superoxide production (kidney, in vivo)

http://www.ingentaconnect.com/content/m ... 3/art00015
Peroxynitrite, a reactive oxidant formed by the reaction of nitric oxide with superoxide at sites of inflammation in multiple sclerosis (MS), is capable of damaging tissues and cells.

We have elevated levels of ca2 in MS. If you inhibit ca2 channels, production of superoxide is decreased...which would mean that ca2 is involved in superoxide production and likely causes increased levels of superoxide in pwms. If you add NO, superoxide can react with it creating peroxynitrite, which damages cells and tissues. Pwms have low levels of uric acid which can be attributed to it's "work" in scavenging peroxynitrite. So, I think ultimately, NO is bad for pwms...it helps make more brain eaters.
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Re: Nitric Oxide and MS

Postby Scott1 » Wed Jan 30, 2013 12:25 am

Hi,

I've been having a good look at this for some time now and I'm not really ready to go into great detail but I can tell you this much; nitric oxide occurs in two ways 1) as constitutive nitric oxide and 2) as inducible nitric oxide. The constitutive forms ( eNOS and nNOS) are fine. The problematic form is iNOS. Inducible nitric oxide occurs when the endothelial layer is damaged. The problem with iNOS is it is much longer lived than the other forms. This elevates the chance that Superoxide will combine with it to create Peroxynitrite. If you have bowel or stomach disorders or gluten intolerances the chances are your endothelial layer is damaged. The way I have dealt with this is to take a teaspoon of the non-essential amino acid L-Arginine as it helps the endothelial layer and promotes eNOS and nNOS rather than iNOS. I haven't taken Avonex for 3 months now to see what happens and I think it has helped.
The peroxynitrite in your system is adversely affecting your ability to make sufficient ATP. I found taken 450mg of Co-enzyme Q10 before bed is the right dose for me. My Superoxide is a result of my EBV infection (that's life). By taking one Valacyclovir tablet per day (I used to need more) I am controlling the production of Superoxide.
Try L-Arginine for the iNoS but you will need to boost ATP and limit Superoxide production as well.

As usual, I remain very well.

Regards
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Re: Nitric Oxide and MS

Postby cheerleader » Wed Jan 30, 2013 8:06 pm

Scott's right---nitric oxide (NO) should remain behind the blood brain barrier. A healthy cerebral endothelium, which is regulated by NO, will protect against iNOS damaging the brain-- a permeable blood brain barrier will not. Think about it like this--iron is an important component of red blood cells, but you do not want iron passing through the blood brain barrier. Iron in plasma is good---iron passing through the BBB, not good. Same with NO.
http://www.direct-ms.org/sites/default/ ... n%2003.pdf

I put together the endothelial health program to help my husband heal his vasculature, and promote a strong blood brain barrier. It involves nutrition, lifestyle, supplements. Here's the research I compiled on NO, the endothelium and MS. Note: you don't take NO as a supplement, you encourage NO production in your body.
http://www.ccsvi.org/index.php/helping- ... ial-health

Glad you're still doing well, Scott! You've really found your path. Jeff remains MS progression free, now six years. Four years since his venoplasty, his gray matter atrophy reversed and his GM now looks normal on MRI.
stay healthy!
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: Nitric Oxide and MS

Postby CureOrBust » Thu Jan 31, 2013 1:57 am

cheerleader wrote:Think about it like this--iron is an important component of red blood cells, but you do not want iron passing through the blood brain barrier. Iron in plasma is good---iron passing through the BBB, not good.
Is this an oversimplification? I thought Oxygen travels in the blood through Iron, so having absolutely no iron in the liquid making into the brain, would imply no oxygen making it to the brain. Or is iron suppose to transfer the O2 at the interface (ie the BBB) itself?
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Re: Nitric Oxide and MS

Postby cheerleader » Thu Jan 31, 2013 8:55 am

CureOrBust wrote:
cheerleader wrote:Think about it like this--iron is an important component of red blood cells, but you do not want iron passing through the blood brain barrier. Iron in plasma is good---iron passing through the BBB, not good.
Is this an oversimplification? I thought Oxygen travels in the blood through Iron, so having absolutely no iron in the liquid making into the brain, would imply no oxygen making it to the brain. Or is iron suppose to transfer the O2 at the interface (ie the BBB) itself?


yeah...that was a lousy example, Cure. I meant the insoluble iron in heme, but you're right, the brain needs iron, and gets it thru the transferrin receptor of the cerebral endothelium. I shoulda said plasma. Just trying to come up with an example of how something can be good/bad depending on which side of the BBB it resides. Because inhibiting iNOS doesn't help MS, but reducing oxidative stress does. http://www.direct-ms.org/sites/default/ ... d%20MS.pdf
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dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: Nitric Oxide and MS

Postby Liberation » Fri Feb 01, 2013 11:40 am

Scott1 wrote:Hi,

I've been having a good look at this for some time now and I'm not really ready to go into great detail but I can tell you this much; nitric oxide occurs in two ways 1) as constitutive nitric oxide and 2) as inducible nitric oxide. The constitutive forms ( eNOS and nNOS) are fine. The problematic form is iNOS. Inducible nitric oxide occurs when the endothelial layer is damaged. The problem with iNOS is it is much longer lived than the other forms. This elevates the chance that Superoxide will combine with it to create Peroxynitrite. If you have bowel or stomach disorders or gluten intolerances the chances are your endothelial layer is damaged. The way I have dealt with this is to take a teaspoon of the non-essential amino acid L-Arginine as it helps the endothelial layer and promotes eNOS and nNOS rather than iNOS. I haven't taken Avonex for 3 months now to see what happens and I think it has helped.
The peroxynitrite in your system is adversely affecting your ability to make sufficient ATP. I found taken 450mg of Co-enzyme Q10 before bed is the right dose for me. My Superoxide is a result of my EBV infection (that's life). By taking one Valacyclovir tablet per day (I used to need more) I am controlling the production of Superoxide.
Try L-Arginine for the iNoS but you will need to boost ATP and limit Superoxide production as well.

As usual, I remain very well.

Regards


Thanks Scott,
so, L-Arginine is the right stuff. Wouldn't L-Lysine do something similar as Valacyclovir?
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Re: Nitric Oxide and MS

Postby Scott1 » Fri Feb 01, 2013 1:04 pm

Hi Liberation,

Yes, it would but I don't think as potently.

Arginine is a non-essential amino acid that I was very low in when I had my Amino acid studies done so taking L-Arginine just fitted in nicely with thinking about treating the endothelial damage. It may be that taking a butyric acid supplement is even better. I haven't tried that yet as I have not quite finished triple checking that it's the correct thing to do.

The L-Arginine can only help if you don't make enough yourself. The top of the tree in my thinking is to limit superoxide production. We actually need to make some superoxide naturally but we don't want it running rampant and combining with an abundance of iNOS to make peroxynitrite. If we are making to much peroxynitrite with we absolutely be short of ATP and have no energy. By taking a big dose of Q10 I've overcome all energy issues.

Whilst I think interferon is important I'm to see it as an intermediate step and after 15 years of use I may have not the same need for it as in the past. I will go back on it if I think I need it again.

I also try to promote a more alkaline system by taking a teaspoon of bicarbonate of soda each day. I was taking it morning and night but my need has reduced after a year.

The other thing I do daily is drink a large glass of carrot juice. It's the safest way to take in a good dose of Vitamin A. It is hard to get good articles on Vitamin A deficiency but I suspect we were born either to mothers who were low in it or we were born unable to access it appropriately. I don't think we will ever find out the answer to that. The Vitamin A gives you retinoids, particularly all trans retinoic acid and 9-cis retinoic acid. The first is all round good guy and the second activates a receptor called RXR. That receptor is the master switch for the thyroid like receptors which include the option mentioned Vitamin D receptor. I'm afraid I can't see the point in D3 supplements if you don't activate RXR.

Lastly I've added Olive leaf extract to get a good dose of oleuropein. This is the magic element in the so called Mediterranean diet. Oleuropein will activate another receptor called PPAR. If you google it you will see it pretty important.

What I do each day

breakfast
a teaspoon of bicarbonate of soda in a galss of water
greek style (hopefully real) yoghurt
3 boiled eggs
I valacyclovir tablet and a swig of Olive oil extract - you space all this out over the morning. No need to slam it all down
1 large glass of carrot juice

lunch
salad and a lot of something meaty ( i do cheat a lot here)

Dinner
whatever the family eats but I try to avoid gluten

mid evening

a teaspoon of L-Arginine in a glass of water - tastes awful

Before bed

450mg of Q10

That's it

Regards
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Re: Nitric Oxide and MS

Postby Liberation » Fri Feb 01, 2013 3:33 pm

Anonymoose wrote:Good question. I saw a lot of conflicting info on NO too. I never took time to figure it out though. I think this is might explain why it is bad for pwms.

We have elevated levels of ca2 in MS. If you inhibit ca2 channels, production of superoxide is decreased...which would mean that ca2 is involved in superoxide production and likely causes increased levels of superoxide in pwms. If you add NO, superoxide can react with it creating peroxynitrite, which damages cells and tissues. Pwms have low levels of uric acid which can be attributed to it's "work" in scavenging peroxynitrite. So, I think ultimately, NO is bad for pwms...it helps make more brain eaters.


Thanks Anonymoose. I was just wondering if Viagra and Cialis aren't increasing Nitric Oxide too? Could using them be a problem for MS patients? I would have assumed that excercises increase nitic oxid as well.

Increasing testosterone level and taking Cialis would help solve sexual problems with male MS patients? As far as I know Cialis also increasing the testosterone to estrogen ratio. Is that good for MS?
I assume that the better blood flow resulted in is good.
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Re: Nitric Oxide and MS

Postby Scott1 » Fri Feb 01, 2013 4:04 pm

Hi Again,

Hopefully, this time I won't leave little words out like and make spelling mistakes like the last post I did!

In regard to Anonymoose's post about uric acid scavenging peroxynitrite,I have to say that the low uric acids does not arise because it has been consumed by the scavenging process. It is the low ATP caused by peroxynitrite that results in low uric acid. The uric acid will be insufficient to manage an excess of peroxynitrite and that in itself is a problem. You need to boost ATP production. The Valacyclovir I take is a Purine nucleotide analogue. Purine boosts Uric acid but I have to do something different to boost ATP. That's why I take Q10.

Regards
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Re: Nitric Oxide and MS

Postby Anonymoose » Fri Feb 01, 2013 4:25 pm

Liberation wrote:Thanks Anonymoose. I was just wondering if Viagra and Cialis aren't increasing Nitric Oxide too? Could using them be a problem for MS patients? I would have assumed that excercises increase nitic oxid as well.

Increasing testosterone level and taking Cialis would help solve sexual problems with male MS patients? As far as I know Cialis also increasing the testosterone to estrogen ratio. Is that good for MS?
I assume that the better blood flow resulted in is good.


Liberation,

I don't know much about viagra or cialis except weren't they used to improve blood flow in pwms? I wonder how that turned out. I think I'll leave the nitric oxide to Scott as he's obviously thought and researched more about it than I have. :)

If you have low testosterone, it could be because your high aldosterone and cortisol production is stealing all the precursors for testosterone. I'm sure it's interference with nutrient absorption doesn't help either.
Image
If you correct those levels using something that inhibits aldo/cortisol production (NOT a blocker), I imagine you will see a cascade of improvements in a lot of your bloodwork levels and in your physical health. I'm hoping to have proof of this in about 5-6 months. I can say in the meantime that I have experienced definite physical improvements and increased libido...the clonidine must be influencing my overall hormone balance (I'm a girl so I don't really know what effect it would have on ED).

Rather than taking a pill for this and a pill for that and worrying about how it will affect the numerous oddities we have with MS, why not just slap a patch on your arm and let everything else even out naturally?

Oh...and about that uric acid...
http://www.ingentaconnect.com/content/m ... 3/art00015
Quote:
Uric acid in multiple sclerosis
Authors: Koch, Marcus; De Keyser, Jacques
Source: Neurological Research, Volume 28, Number 3, April 2006 , pp. 316-319(4)
Publisher: Maney Publishing
Abstract:
Peroxynitrite, a reactive oxidant formed by the reaction of nitric oxide with superoxide at sites of inflammation in multiple sclerosis (MS), is capable of damaging tissues and cells. Uric acid, a natural scavenger of peroxynitrite, reduces inflammatory demyelination in experimental allergic encephalomyelitis. Some studies reported lower serum levels of uric acid in MS patients compared with controls, whereas other studies found no difference. A critical appraisal of these studies favors the view that reduced uric acid in MS is secondary to its peroxynitrite scavenging activity during inflammatory disease activity, rather than a primary deficiency. Serum uric acid levels could be used as a biomarker for monitoring disease activity in MS. Therapeutic strategies aimed at raising serum uric acid levels may have a glial/neuroprotective effect on MS patients.
More information about it (and aldosterone's influence on levels) here chronic-cerebrospinal-venous-insufficiency-ccsvi-f40/topic21244-60.html It's near the bottom of the page.

I think maybe Scott and I each have a piece of the uric acid puzzle. :)
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Re: Nitric Oxide and MS

Postby PointsNorth » Wed Feb 06, 2013 6:06 pm

I tried taking an NO supplement which seemed to work for me at first at which point it started to have less desirable affects. I think it was called Qivana or something like that. Scott dissuaded me from using any further.

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Calcitriol+D3 2013-
Hurry up and wait.
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Re: Nitric Oxide and MS

Postby Scott1 » Thu Feb 07, 2013 12:06 am

Hi PointsNorth,

I didn't know I had that much influence!
I just looked up Qivana, as I don't know it, and it looks like a marketing company. If I don't know what it is I generally don't touch it. That would be the situation in this case.
You could try L-Arginine but like most things it won't do much by itself. If you increase eNOS or nNos you will reduce iNOS and that is the only reason to boost Nitric Oxide that seems to stack up to me. Try to lower superoxide production and boost ATP. What works for me is detailed above. Increased Nitric Oxide is not a magic bullet.

Regards
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Re: Nitric Oxide and MS

Postby daniel » Wed Mar 27, 2013 7:55 pm

Just came across a TEDTalk by Richard Weller: "Could the sun be good for your heart?"

http://www.youtube.com/watch?v=Lh9lDWPMWrM

He is claiming it's true people with high levels of vitamin D have less heart disease/cancer, but that people given supplements don't seem to change the risk of heart disease/cancer

"Our bodies get Vitamin D from the sun, but as dermatologist Richard Weller suggests, sunlight may confer another surprising benefit too. New research by his team shows that nitric oxide, a chemical transmitter stored in huge reserves in the skin, can be released by UV light, to great benefit for blood pressure and the cardiovascular system. What does it mean? Well, it might begin to explain why Scots get sick more than Australians ..."

In the talk he says that UVA radiation also causes dilation of blood vessels for up to an hour after exposure on the skin

Edit: found one of his papers:
Journal of Investigative Dermatology (2009) 129, 834–842; doi:10.1038/jid.2008.296; published online 25 September 2008

Enzyme-Independent NO Stores in Human Skin: Quantification and Influence of UV Radiation
http://www.nature.com/jid/journal/v129/ ... 8296a.html

Dr. Richard Weller MD, FRCP (Ed)
email: r.weller@ed.ac.uk
http://www.derm.med.ed.ac.uk/Weller.html
"I have two main research interests. My most longstanding [1-14] area of study has been in the role of Nitric Oxide (NO) in human skin physiology, both in healthy homeostasis and in disease. More recently I have become interested in the role of the skin barrier function deficiencies in the development of atopic disease." -- maybe we could get him interested in CCSVI?
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