Nitric Oxide and CPn: Multiple sclerosis link

Nitric oxide has long been suspected as the possible damaging factor in multiple sclerosis. The logic goes like this: The body for some unknown reason starts attacking the brain as if it were a foreign protein (like a bacteria). The microglia (the cells in the brain which are responsible for immune responses that might be needed inside the blood brain barrier-the regular white blood cells are kept out by the BBBi)produce large amounts of nitric oxide (NO) which damage the nearby nerves and support cells. If only we could get rid of the NO then we could control MSi. An example of this kind of research can be found HERE<. Also another one HERE<. It is clear that the researchers consider the production of NO an abherrent and undesirable response and a contributor to autoimmunity. You might note that they also are very clearly believing the autoimmune model. Many physicians and researchers forget that this is just a model, not a proven fact.
Yet, as we are so abundantly aware here on this site, CPn has been implicated in the pathogenesis of MS. How might the NO angle play in to that? Jim recently found a paper which indicates NO is important to the body in it's fight against CPn. In other words, the body uses NO on purpose to fight CPn. What follows is that abstract printed from pubmed:

Can J Microbiol. 2005 Nov;51(11):941-947.

Effect of nitric oxide on the growth of Chlamydophila pneumoniae.

Carratelli CR, Rizzo A, Paolillo R, Catania MR, Catalanotti P, Rossano F.

Chlamydophila pneumoniae is an important human intracellulari pathogen; however, the pathogenesis of C. pneumoniae infection is poorly understood and the immune control mechanism versus host cells is not completely known. The role of the nitric oxide (NO) synthase pathway in inhibiting the ability of C. pneumoniae to infect macrophage J774 cells and the ability of NO to damage isolated C. pneumoniae were investigated. Exposure of infected cultures to recombinant murine gamma interferon (MurIFN-γ) resulted in increased production of NO and reduced viability. Addition of 2-(N,N-diethylamino)-diazenolase-2-oxide before infection of J774 cells or during chlamydial cultivation released NO, both resulting in a reduction in the viability of C. pneumoniae in a dose-dependent way. These results indicate that immune control of chlamydial growth in murine macrophage cells may trigger a mechanism that includes NO release with effects on the multiplication of the microorganism, thus suggesting that NO may play a role in preventing the systemic spread of Chlamydia.

PMID: 16333333 [PubMed - as supplied by publisher]

Yet another important angle is highlighted in this work. Note that the gamma interferon plays a role in the NO production just as it does in the inhibition of tryptophan which also knocks back the infectoin. Gamma interferon is an important player in the reduction of CPn stores with this dual role in the fight! But also consider this important fact: It is well known that giving people with MS gamma interferon makes them worse. Symptoms increase dramatically. Could it be that the sudden ample stores of gamma interferon result in a sudden vigorous response to CPn causing both NO bystander damage (the nerves near the area with the NO get hurt by the NO) and also an endotoxini reaction? Interesting theory.

This will be even more incredible as you read THIS< paper. It says clearly that lipopolysaccharidei (LPSi) causes demyelinationi. What is LPS? Endotoxin, the protein fragments left over when a gram negative bacteria like CPn dies.

Another smoking gun for CPn as the causitive agent in MS.

Comments

Just another article in case anyone is interested. I confirms for me I am on the right path.

Increased nitric oxide in expired air in patients with Sjogren's syndrome. BHR study group. Bronchial hyperresponsiveness
D Ludviksdottir, C Janson, M Hogman, B Gudbjornsson, E Bjornsson, S Valtysdottir, H Hedenstrom, P Venge, and G Boman


Nitric oxide has an important role in the regulation of airway function and can have pro-inflammatory effects. Bronchial hyperresponsiveness (BHR) and respiratory symptoms are common in patients with Sjogren's syndrome (SS). The aim of this study was to determine whether patients with SS have an increased amount of exhaled NO and whether this NO correlates with respiratory symptoms and BHR. Exhaled NO was measured in 18 patients with SS and 13 normal subjects on three different occasions with intervals of at least 3 days using a chemiluminescence method. Airway responsiveness was assessed with methacholine provocation. Serum levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) were measured. Exhaled NO was significantly higher in patients with SS than in controls (147+/-82 versus 88+/-52 nL x min(-1); mean+/-SD; p=0.041). Exhaled NO was correlated with age (partial r=0.52, p=0.006) and serum HNL (partial r=0.46, p=0.014). There were no significant correlations between exhaled NO and respiratory symptoms, BHR or serum MPO, ECP or EPO. Disease duration was negatively associated with serum MPO (r=-0.47, p=0.043). In patients with SS, a positive correlation was found between symptom score and serum ECP (partial r=0.65, p=0.003) and EPO (partial r=0.62, p=0.004) and a negative correlation with age (partial r=-0.60, p=0.005). In conclusion, elevated levels of exhaled nitric oxide in patients with Sjogren's syndrome were demonstrated. The mechanism underlying this increase in exhaled nitric oxide in Sjogren's syndrome is not known.

200mg doxyi daily, 500 zithromax mwf,flagyli 1000 m-fri.rifampin 2x daily,chloestryramine 2x daily

More evidence: J Interferon Cytokinei Res. 2001 Mar;21(3):137-46. Regulation by IFN-beta of inducible nitric oxide synthase and interleukin-12/p40 in murine macrophages cultured in the presence of Chlamydia pneumoniae antigens. Yao SY, Ljunggren-Rose A, Stratton CW, Mitchell WM, Sriram S. Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA. Chlamydia pneumoniae has been demonstrated in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MSi). Interferon-beta (IFN-beta) has favorable effects on the clinical course of MS. We investigated whether the beneficial effects of IFN-beta in MS may involve its role in regulating nitric oxide (NO) and interleukin-12 (IL-12) in macrophages, as these immunei modulators form part of the innate immune response to intracellulari pathogens, such as C. pneumoniae. Murine macrophages in cultures exposed to elementary body antigens or recombinant major outer membrane protein (rMOMP) of C. pneumoniae demonstrate a significant increase in NO as well as production of IL-12/p40 in culture supernatants compared with basal levels. Addition of murine IFN-beta increased NO activity in murine macrophages cultured with chlamydial antigens. Addition of neutralizing anti-IFN-beta antibody prevented the NO increase. In contrast to its effect on inducible NO synthase (iNOS), IFN-beta reduced induction of IL-12/p40 following culture with either elementary body antigens or rMOMP. Inhibition was reversed with anti-IFN-beta antibody. If C. pneumoniae infection is responsible for the inflammatory response in the pathogenesis of MS, the beneficial effects of IFN-beta in MS may be due to its enhancing intracellular NO activity while inhibiting secretion of the proinflammatory cytokine, IL-12. David
D W - [Myalgia and hypertension">i (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazolei. No medication now. Morning BP typically 110/75]
Foods that increase NO
Looking up foods that increase NO I found this article about flavanols and cocoa. Seems like tea, garlic and certain nuts also increase
NO production along with apples and berries. 
http://www.medscape.com/viewarticle/490533
Raven
 

Feeling 98% well-going for 100. Very low test for Cpni. CAPi since 8-05 for Cpn/Mycoplasma P.,Lyme, Bartonella, Mold exposure,NACi,BHRT, MethyB12 FIRi Sauna. 1-18-11 begin new treatment plan with naturopath

Chocolate's also listed in that article, though actually, cocoa drinks seem to be the major thrust of the study. How does one measure the amount of flavanols in a given food, though? 

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

Check this link, you hot pepper lovers!
http://lpi.oregonstate.edu/infocenter/phytochemicals/flavonoids/
Raven 

Feeling 98% well-going for 100. Very low test for Cpni. CAPi since 8-05 for Cpn/Mycoplasma P.,Lyme, Bartonella, Mold exposure,NACi,BHRT, MethyB12 FIRi Sauna. 1-18-11 begin new treatment plan with naturopath

Hi Mac, I didn't answer your question. Here's a link to download a chart on flavinoids
 
http://www.nal.usda.gov/fnic/foodcomp/Data/Flav/flav.html
Raven 
 

Feeling 98% well-going for 100. Very low test for Cpni. CAPi since 8-05 for Cpn/Mycoplasma P.,Lyme, Bartonella, Mold exposure,NACi,BHRT, MethyB12 FIRi Sauna. 1-18-11 begin new treatment plan with naturopath

This is some excellent work, Marie.  Isn't it funny how several common threads seem to be emerging on the site, though, garlic and hot peppers for starters, never mind flavonoids and everything else.  I guess your current craving is just your body telling you something.....Sarah
Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.

Marie- The LPSi study is mind boggling-- a real smoking gun for infectious endotoxini and demyelinationi. I hope you reference this in the Research section and maybe under Treatments/endotoxin. A great find.

 

On Wheldon/Stratton protocol for Cpni in CFSi/FMSi since December 2004.

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

Thanks! It's referenced on the physicians page...
Marie

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

If you want to eat something for this, Vitamin Di is a good candidate.  It has been found to enhance NO production in macrophages, enabling them to clear themselves of intracellulari tuberculosis bacteria.  (To be precise, it is the active form of Vitamin D, that is, 1,25-dihydroxyvitamin D3, which does this.)  See, for instance, this article:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9784538

Trytophan is contraindicated if I read the article correctly. Is that correct?

minocycline, azithromycine, metronidazolei 2007-2009, chelation for lead poisoning, muscle pain, insomnia, interstitial cystitisi (almost well), sinus, dry eyes, stiff neck, veins, hypothyroid, TMJ, hip joints (no longer hurt)

Yes, it is, but no worries, Janice, tryptophan might not be a good idea, but instead of this you can take melatonin">i, of which tryptophan is the precursor. 

http://www.davidwheldon.co.uk/supplement_rationale.html<

You can read the full piece easily by clicking here:

http://www.cpnhelp.org/?q=taking_a_break_for_a_bit#comment-923<

I take it most nights and it really works, but I wouldn't take tryptophan........Sarah

Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.
Interesting study on Vit.D Norman. The question is, how much to take? Recent news items in the US have been saying 1,000 mg per day, but in the case of infection this should probably be more. I was on a high dose once a week (6,000 mg) but I now take 2000 per day. I have to check back with Dr. Powell next week and will ask him about this.
So it not only protects against infection by increasing NO but also preserves the blood brain barrier. No wonder I became ill, I was avoiding the sun because of the skin cancer issue and not getting enough D in my diet or by suppliment!
Raven 

Feeling 98% well-going for 100. Very low test for Cpni. CAPi since 8-05 for Cpn/Mycoplasma P.,Lyme, Bartonella, Mold exposure,NACi,BHRT, MethyB12 FIRi Sauna. 1-18-11 begin new treatment plan with naturopath

I recently began taking Vit. D3.  I have been taking one 2000 i.u. capsule daily.[Super D3--AllergyResearchGroup] and have wondered whether this is enough?  It has made such a difference for me, I most certainly was deficient.

Anyone else know the recommended amt for those of us doing the protocol?

 

Wheldon Protocol for rrmsi since Oct '05.  Added LDN 4.5mg qhs Oct '07.  All supp's.  Positive IGGi's for Lyme Disease,Babesia, & Erlichiosis Sept. 2008.  Currently:  Mepron 750mg bid and Azithromycin 250mg qdi for Babesia.

Hi KK2

As I remember, the protocol lists 4000 units per day.  I take only 2400 in 2 1200 unit doses.  Whether that is the correct dose I will never really know but based on size it is probably close.  For 25 years I have used sunscreen always outside in addition to a broad-brimmed hat.  When I was a kid in West Texas I rode many hours a day (horse) and ALWAYS wore my Stetson and long sleeves.  I can thank my mother for skin that doesn't look like and old shoe.  But I undoubtedly had some skin exposed unlike the past years. My comclusion is that I really have had a deficiency building for years.

Another thing I just learned is what a "herx" really is: a regression in abilities in reaction to abxi.  I thought it was much more dramatic.  I always regress with Flagyli, but I know that after 4 0r 5 days I will be better that ever.  I don't know about when I began Rifampin and Doxyi- I was simply too mentally dim to be aware of much for the first few months.

Rica

Ignorance is voluntary bad luck.  Lauritz S.   A true Viking

If you come to a fork in the road, take it. Yogi Berra

3/9 Symptoms returning. Began 5 abxi protocol 5/9 Rifampin 600, Amox 1000, Doxyi 200, MWF Azith 250, flagyli 1000 daily. Began Sept 04 PPMSi EDSSi 6.7 Now good days EDSS 1 Mind, like parachute, work only when open. Charlie Chan  In for the duration.&am

Rica, thank you for the clarification(s).  lol!  :)  Every little bit helps me to pull together some sort of ordered understanding of all that Cpni entails.  I remain so thankful--often having to pinch myself--for this life-changing website.  Lord knows I searched the net for 4 yrs for something like this--I felt all along that my neuroi just HAD to be mistaken about the msi dxi.  I was neg for Lyme disease but I knew I got worse with every infection.  This is the best I have felt for some time now.

As for the Rifampicin, which I took for about 10 days around Thanksgiving, I know I am on the right track as I had icy cold hands and feet for awhile after stopping.  I felt positively horrid on that stuff.  Good for you that you kept on with it for so long.  Right now, doxyi/azith is about all I can handle--tho I am considering a Tinidazole pulse in the next  couple months. 

We'll see.

Thanks for the support and info-- always need both!

KK2  :)

Wheldon Protocol for rrmsi since Oct '05.  Added LDN 4.5mg qhs Oct '07.  All supp's.  Positive IGGi's for Lyme Disease,Babesia, & Erlichiosis Sept. 2008.  Currently:  Mepron 750mg bid and Azithromycin 250mg qdi for Babesia.

KK2

I still take it and have twice every single day since Sept 22, 2004!  On my daily menu also is Doxyi, and MWF Zithi and, of course, supplementsi by the ton.  Maybe I'm a masochist since I am terribly hungry much of the time but I was very bad and getting worse very fast and I had been 9 years PPMSi before I knew what was going on.   Living is my best thing and besides, it's the only thing I have ever done!

 Rica

Ignorance is voluntary bad luck.  Lauritz S.   A true Viking

If you come to a fork in the road, take it. Yogi Berra

3/9 Symptoms returning. Began 5 abxi protocol 5/9 Rifampin 600, Amox 1000, Doxyi 200, MWF Azith 250, flagyli 1000 daily. Began Sept 04 PPMSi EDSSi 6.7 Now good days EDSS 1 Mind, like parachute, work only when open. Charlie Chan  In for the duration.&am

There is a common belief that above 2000 IU/day, Vitamin Di can be toxic.  However, Reinhold Vieth, in his exhaustive study of the toxicology literature on Vitamin D (free full text at:

http://www.ajcn.org/cgi/content/full/69/5/842<


), found that this belief is utterly without foundation; the lowest level for which he found credible reports of toxicity in adults was 40,000 IU/day (and even then, only after that amount had been taken for months).  He is of the opinion that about 4000 IU/day is required to duplicate the levels at which human biochemistry evolved.

Measure your Vitamin Di-

This link http://lassesen.com/cfids/recommended_levels.htm< gives an excellent review of Vitamin D in infectionsi and in CFS/FM. It is updated regularly, and is one of the best sources I've found. Like Dr. Powell, blood levels are measured and usually a high dose at the beginning is needed to bring blood levels up, then a lower maintenance dose to maintain them. From Lassensen (please see web link for the indicated references and more detail):

What is appropriate Vitamin D level and supplementsi?

The first question is simple, what should the Vitamin D level be? Reviewing recent literature suggests the following:

  • No less than 78 nmol/l (31 ng/ml)<[15].
  • All numbers refer to Vitamin D3 (Vitamin D2 is estimated to be 20% as effective)

 It should be noted that 62.4 to 99.8 nmol/L (25 to 40 ng/mL) is cited by older reference books<[16]. The older level was based on short term disease presentation, while the newer level was based on Serum iPTH<[17].

 The author suggests that a level of 108 nmol/l (43 ng/ml) or more is desirable for CFIDS/FM patients and that lower levels may require supplementation. This is based on the observation that individual laboratories can differ by up to 38% on Vitamin D measurements<[18], thus 78 x 1.38 insures that the minimal level is reached.

From Robert P Heaney, Functional indices of vitamin D status and ramifications of vitamin D
deficiency
Am J Clin Nutr 2004;80(suppl):1706S–9S.

 What is the supplemental dosage that may be appropriate? Reviewing recent literature suggests the following:

·         In healthy persons, it is recommended that supplementsi of at least 1000 IU vitamin D per day is required to maintain a healthy concentration of vitamin D in the blood<[19].

·         For typical older individuals, supplemental oral intakes of approximately 1300 IU per day are required to reach the lower end of the optimal range

 

On Wheldon/Stratton protocol for Cpni in CFS/FMSi since December 2004.

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

Jim K - Vitamin Di...Michael McClanahan has me on 50,000 IU of Vitamin D a week.  I have yet to start it yet because I wanted to distinguish between side effects of different medications that I was starting all at once.  Anyone starting at this dosage??? Any comments???

What does 50,000 IU convert to in mg?  I am supposed to take it once a week!  I am a little confused though because I am on iron supplementation and it says DO NOT TAKE MEGA DOSES OF VITAMINSi with this medication.  I know the Dr knows what he is doing I just don't want something crazy to happy to me.

Cera, it converts to 7000 iU a day. I had read somewhere that up to 10000/day is safe. I tell people to take 5000 daily and skip Sundays during winter. You must have really low D3 level.

                                                                                              Barbara

Cured of multiple sclerosisi, stopped the Wheldon's protocol in Nov,2008. Use only LDNi.

Cera- Don't worry about the Vitamin Di Dr. Powell bases his use of Vit D on your actual blood levels of D3. If you are depleted he uses the 50,000 units once per week and then remeasures in a month, basing your next dose on what he finds. Remember, we aren't like normal folks taking Vit D. If we are severely depleted we need extra "front end loading" to make up for the deficiency, plus our body starvation for this (a kind of sub-clinical pellegra) will use up the first bunch of D very quickly, so little chance of overdose if you are starting out so low. This is true of a number of supplementsi: the normal criteria don't apply, especially if we have been sick for a while and are just starting out. Especially then, the starting state of depletion, the increased detox and immunei reactions as we start to kill Cpni, and the demands of turning on body systems which have shut down due to depletion and illness, all require more supplementation than normal doses. My example is Vitamin C. Early on I did a 'Vitamin C flush' to counter endotoxini reaction from the Flagyli pulses I was doing. This is a process of taking powdered buffered C in water, 1-2grams every 15 minutes, until you find "bowel tolerance"-- ie purging of the bowels. The idea is that your body will quickly absorb Vitamin C, and bowel tolerance is reached when your tissues become saturated. Remember that humans, unlike most other mammals, can't make our own Vit C. Reaching bowel tolerance, you then are suppossed to use the final dose you required to calculate a daily, lower, dose of Vitamin C which your body needs for the conditions you are dealing with. Imagine my shock when it took 40 grams of vitamin C to reach bowel tolerance! My tissues just sucked it up. All the endotoxin load I had been under must have created a huge need. This meant that my daily dose of C was now supposed to be 75% of bowel tolerance, or 120grams per day! Yikes! I couldn't do that much by any means, but I did periods of higher dose and now my bowel tolerance when I do a flush (third day of flagyl pulses) requires only about 25grams. I use this as an example of how different a depleted and ill state is from the standards based on the well for vitamin dose and toxicity.

On Wheldon/Stratton protocol for Cpn in CFSi/FMSi since December 2004.

 

CAPi for Cpni 11/04. Dxi: 25+yrs CFSi & FMSi. Currently: 250 aithromycin mwf, doxycycline 100mg BIDi, restarted Tinii pulses; Vit D2000 units, T4 & T3, 6mg Iodoral

The reason for testing Vitamin Di levels would be in order to not give too much.
But Vieth's study, referenced above, shows that it's hard to give too much.  The human body can easily make 10,000 IU/day from the sun, and some people have been found to make 25,000 IU/day from the sun; thus the Wheldon protocol's recommendation of 4,000 IU/day is mild and conservative.  If one is an adult, one can just take that amount, and not worry about testing.  (It might be a bit high for kids.)

The only adults to whom this does not apply are people with bad cases of diseasesi such as sarcoidosis or Crohn's diseasei.  Some of those people cannot tolerate Vitamin D at all; they convert so much of it into the active form (1,25-dihydroxy-D), for fighting disease, that the amount which leaks out into the bloodstream is dangerous: it raises blood calcium levels, which produces severe reactions, and can even stop the heart.  But less severe cases of the same diseases can probably benefit from Vitamin D.  If one has this problem, one has to stay out of the sun, for fear of one's life, and one shouldn't take Vitamin D pills at all; conversely, if one doesn't have to worry about staying out of the sun, one doesn't have to worry about eating too much Vitamin D (within reason).  This is a threshold effect, something like giving water to the starving: water is normally good and useful, yet giving too much to a starving person can kill him.

The other problem with testing is that the tests are unreliable.  Laessesen includes a 38% margin, to compensate for that, but that number is not the upper bound for unreliability that he uses it for; it was just the worst number found by one particular study, which sent eight samples to each of five laboratories.  It wasn't even the worst difference found in individual test results; it was the worst difference found in the average test result.  About half the differences in individual test results, between those two laboratories, must have been worse than 38%, for 38% to be the average difference between them.

As for the 50,000 IU pills, the thing to worry about is not whether they are excessive (that dose, weekly, is about right), nor whether they will interfere with iron absorption (50,000 IU is 1250 micrograms, not enough to interfere by mass action; and this is an oil-soluble vitamin, not a water-soluble one, so it probably wouldn't interfere anyway), but whether they consist of Vitamin D2 (aka ergocalciferol) or Vitamin D3 (aka cholecalciferol).  D3 is the one to take, as it is the one the body makes naturally; but many of the larger pills contain D2, because some MBA wanted to save a buck or two.  D3 is quite cheap enough, but D2 is even cheaper.

By the way, as regards the iron, many physicians avoid prescribing iron to people with active bacterial disease.  Iron is a key nutrient needed by bacteria; anemia, in chronic disease, can be caused not by lack of iron but by the body locking up its iron so tightly, to keep it away from bacteria, that it has difficulty making new red blood cells.

Regarding Nitric Oxide-

Are weightlifting products which supposedly increase production of NOS of any utility when treating suspected CPni infection?

I know that Inosine is now being trialed in MSi, don't know if NOS has anything to do with that, though. 

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