Jump to content

The NO-ONOO theory of oxidative stress as the cause of disease (ML Pall)


[ra...]

Recommended Posts

Ok Buddies,

 

This is part of a thread that came from the "Protracted" area, where we were discussing ideas to actively reverse the damage benzos has caused us.  This was one of the ideas, and we will move the best of the posts on that topic here.

 

If you were not part of the original thread, give us a day to move the topics.  It is now 12:30 pm Eastern US time on Tuesday Nov. 6.  Please wait until Midnight Thursday Nov 8 wherever you live to make any comments on this topic.

 

Thank you all for your cooperation.

 

Ramcon1

Your personal neuroscientist, reminding you to hang in there, and if you are going thru hell, keep going!

Link to comment
Share on other sites

  • Replies 77
  • Created
  • Last Reply

Top Posters In This Topic

  • [Aj...]

    14

  • [ra...]

    11

  • [Po...]

    8

  • [Te...]

    7

Top Posters In This Topic

My initial post regarding NO/ONOO on the protracted board.

...................................................................................

 

An NO/ONOO(−) cycle disorder is a cascading, biochemical vicious cycle. A pathophysiological mechanism that repeats and habituates after it is triggered by certain stressors. It is theorized to be the same basic, propagating cycle that causes a myriad of multisystem, chronic illnesses - fibromyalgia, dysautonomia, PTSD, chronic fatigue, multiple chemical sensitivity, etc. etc.  Common NO/ONOO(−) cycle elements include elevated peroxynitrite and the depletion of BH4, elevated activity of the NMDA receptors and excitotoxicity (sound familiar?), an inflammatory cascade, mitochondrial dysfunction which leads to lowered energy metabolism and depletion of ATP, etc.

 

This biochemical process happens at a cellular level and thus, can be focused on any location or tissue in the body. Its location determines the symptoms or diseases that manifest... All of which are different, but caused by the same issues happening in different cells or tissues. LaCorte does an incredible job of elucidating the neurophysiological process that benzos initiate and how that triggers the perpetuating NO/ONOO(−) cycle. I.e. Potentiation of calcium channels and excessive NMDA activity result in calcium influx into the cell that creates nitric oxide synthesis, which leads to high peroxynitrite formation, which results in the triggering of the aforementioned cycle....... said NO/ONOO(−) cycle is caused by and results in this central couplet of low BH4 and excessive peroxynitrite, and thus the vicious cycle.

 

There have been studies that apparently implicate certain genes as making one more susceptible to this cycle and the accompanying diseases. Which would explain why not all of benzo users fall victim to the protracted sh*t... I actually reached out and have been speaking to the team at the University of Arizona who held the Benzo Withdrawal Symposium last month. One of the speakers, Steven Wright, really likes this theory. I do too. It seems to add up and make a lot of sense. Especially since my symptoms are basically the exact ones I mentioned; fibromyalgia, dysautonomia, PTSD, chronic fatigue, multiple chemical sensitivity, yes to all.

Link to comment
Share on other sites

@[Po...]

 

 

I was very functional during tolerance, taper, and first 16 months benzo free. But something changed, I’ve gotten much worse, and vertigo has me bed bound now almost 9 months.

 

The NO OH NOO theory gives a sound explanation for what might of happened to me, and many of us, and why we don’t seem to get better. (A “trauma” or trigger or catalyst that starts the process. And once the process starts, it begins a cascade of events, and it’s hard to stop.)

 

 

I just wanted to echo this... My first 2 years off, I was *mostly* functional. I had some serious pain and nerve issues (w/d awoke a nerve condition called MALS that resulted in major surgery) but aside from that, I was pretty decent all things considered.

I had a setback at 2 years that has been way worse than acute and left me with new symptoms I never even had during acute (all of which align perfectly with NO/ONOO disorders).... major dysautonomia, pain in random places that mirrors fibromyalgia, other symptoms of fibro and dysautonomia like sensitivity to light and sound, chronic fatigue, chemical sensitivity, etc. All hallmarks of NO/ONOO, all arising after a stressor at 2 years post benzo.

Link to comment
Share on other sites

NO OH NOO

 

I was very functional during tolerance, taper, and first 16 months benzo free. But something changed, I’ve gotten much worse, and vertigo has me bed bound now almost 9 months.

 

The NO OH NOO theory gives a sound explanation for what might of happened to me, and many of us, and why we don’t seem to get better. (A “trauma” or trigger or catalyst that starts the process. And once the process starts, it begins a cascade of events, and it’s hard to stop.)

 

The very simple bio-chemical-cellular action: creation of peroxynitrite, which in turn causes a cascade of events at the cellular level, including an influx of calcium. (And your intake of calcium has no effect here).

 

That in turn leads to symptoms - symptoms which are unique to the individual, and even unique in certain parts of your body.

 

And then the symptoms that come - ones that are common for benzo, PTSD, fibromyalgia, etc., yet unique to each individual: insomnia, “anxiety”, fear, cognition, muscle tension, nerve issues, vertigo, tinnitus, etc. And what is happening in the hippocampus, amygdala, disruption to HPA axis, etc.

 

The cycle, the inflammation, what’s happening on the cellular level & calcium, need to be looked at.

 

I think the author and his theory are some of the primary references by used by S. Lacorte from BIC here https://cdn.shopify.com/s/files/1/2161/5909/files/SL.pdf

 

The author’s explanation of the ‘inflammation’, and the cascading events that happen next seem spot on.

 

Complete article here -  http://ei-resource.org/articles/chronic-fatigue-syndrome-articles/dr-palls-nitric-oxide-theory-a-treatment-options-for-chronic-fatigue-fibromyalgia-a-mcs/

 

Link to comment
Share on other sites

I have a horrible feeling that diazepam was not only helping severe muscle issues I was put on it for but has also helped the Neuro symptoms of the ME/CFS I was diagnosed with in 1996 before any meds.
Link to comment
Share on other sites

Hi friends,

 

 

A bit about NO OH NOO theory:

 

 

It has gained popularity by research and then a book by Martin Pall Ph.D.

 

The theory is that a “stress” can start the process. The stress can be just about anything - an injury, exposure to a toxin, everyday life stressors, psychological stress, a virus or bacteria, mold, medicines, exposure to something traumatic, etc. etc.

 

The actual chemical process is NO. + OO.- ———————————> ONOO-

 

It is pronounced NO OH NOO

 

NO stands for Nitric Oxide.

 

A big takeaway once the process starts - it creates too much Peroxynitrite.

 

When there is too much Peroxynitrite in a cell, it creates all kinds of problems - elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity.

 

And when those problems happen, it creates “unexplained” illnesses and symptoms like PTSD, fibromyalgia, Chemical Sensitivities, Chronic Fatigue, insomnia, “anxiety”, fear, cognition, rage, fatigue, muscle tension, nerve issues, vertigo, tinnitus, etc. In his book he goes into greater detail, including what is happening on a molecular level, and what is happening in the hippocampus, amygdala, disruption to HPA axis, etc.

 

 

An article explaining this by Martin Paul is here -  http://ei-resource.org/articles/chronic-fatigue-syndrome-articles/dr-palls-nitric-oxide-theory-a-treatment-options-for-chronic-fatigue-fibromyalgia-a-mcs/

 

 

His book, called Explaining Unexplained Illnesses is here on Amazon - https://www.amazon.com/gp/product/078902389X/ref=ppx_yo_dt_b_asin_title_o03_s00?ie=UTF8&psc=1

 

 

He does have a supplement protocol for stopping this process.

 

Vitamin C

Tocopherols/Tocotrienols

Selenium

Carotenoids

Flavonoids

Reductive stress relieving agents

Mitochondrial regeneration agents

L-Carnitine/Acetyl-L-carnitine

Hydroxocobalamin/B12

Folic acid

Vitamin B6/pyridoxal phosphate

Riboflavin

Other B vitamins

Glutathione/glutathione precursors

alpha-Lipoic acid

Magnesium

SOD minerals/zinc,manganese, copper

NMDA antagonists

Riluzole

Taurine

Inosine/uric acid

Long chain omega-3 fatty acids

Agents that lower NF-kappa B activity

Curcumin

Algal supplements

Hyperbaric oxygen

Minocycline and Other Tetracyclines

Creatine

Lowered vanilloid activity

Carnosine

TRH

Magnesium

Zinc

 

 

 

This process seems to fit what so many of us are going thru ....

 

 

 

Link to comment
Share on other sites

Here is a link to a line of over-the-counter supplements that were developed by Martin Pall himself. There are 8 of them. They combine many of the things listed above by Power. In speaking to Dr. Pall, he also recommended adding magnesium, selenium, and zinc to this stack.

 

https://www.nutricology.com/martin-pall-products/

 

In a lot of his writings, he states that the supplement stacks seem to help people considerably with symptoms, but not necessarily 'cures'. To shoot for more cures, he suggests that there be extra focus on lowering the central couplet (lower peroxynitrite and raise BH4)... Some additional things that might be beneficial to add to your regimen would therefore be:

IV of vitamin C (an important one), intranasal glutathione, sauna therapy, RNA (in the form of nutritional yeast), etc. 

 

With this supplement regimen, I think there are two other things that are very important in downregulating the cycle...

1. Avoiding stressors that will just continue to perpetuate the cycle. 2. Avoiding EMF radiation, which seems to be a key concept in Pall's ideas - also referenced in LaCorte's.

 

This is not an easy regimen to follow. Lots of supplements, all quite expensive. Avoiding stress and the normal hustle and bustle and modern lifestyle...... I feel like, best case scenario, one would retreat for a few months. Exist in nature, away from stress and technology, all the while hitting this supplemental regimen hard. I think that'd give us the best chance...... But, not sure how realistic that is for most. *shrugs*

Link to comment
Share on other sites

The more I read in Martin Pall’s book (Explaining Unexplained Illness), the more I’m convinced it’s what’s happening in our bodies in a wave, or in protracted.

 

It’s a type of “neuro inflammation”, and how it can localize in our bodies, creating symptoms that are common for us, yet unique to each of us. (Like how one person might get muscle tension in the shoulder, yet someone else gets muscle tension in the stomach. Or how one person might have nerve pain in the arms and hands, yet another person has it more prominently in the legs and feet.)

 

 

We took a drug that caused a brain injury. But now many of us have stopped. Why are we still so symptomatic, or have waves and windows? Pall’s explanation, although not specifically written about benzos, explains very well what is happening in the body, brain, and cells.

 

 

An article by Paul is here - http://ei-resource.org/articles/chronic-fatigue-syndrome-articles/dr-palls-nitric-oxide-theory-a-treatment-options-for-chronic-fatigue-fibromyalgia-a-mcs/

 

 

His book on Amazon - https://www.amazon.com/gp/product/078902389X/ref=ppx_yo_dt_b_asin_title_o03_s00?

 

 

(I know some of you have already seen this info.)

 

 

 

Link to comment
Share on other sites

This came up in response to questions Nov3 asked in the Lithium thread, but look at the bottom.  If anyone here can help us with that, please do:

 

Nov,

 

All good questions.

 

I know that lithium ions and serotonergic meds and supps work by different mechanisms, but yes they accomplish the same goal: reduction in count, firing voltage, and current flow thru glutamate receptors, particularly NMDA.  Do I know if one will work "better" than another?  I have absolutely no idea, and I SUSPECT, have no proof, that some will respond better to one than the other.  Will they be synergistic?  I SUSPECT, I really have no way to know because no one has studied this yet, that they would be additive, as in you could get some benefit from the serotonin mechanism and additional benefit from the mechanism of lithium, but not synergistic in the truest definition of the word, as in "the whole is greater than the sum of its parts, 2+2=5."

 

My theories on time frame and dosages are "educated guesses."

 

I saw a good gastro doc.  She called herself a neurological gastroenterologist, but her neurology knowledge was not that deep.  A lot of IBS comes along with something called "visceral hypersensitivity," which is a fancy way of saying you feel your colon like a normal person feels his fingertips.  I have this.  As I said, she does not know much about neurology, but she knows, "Patient has visceral hypersensitivity.  I prescribe Zoloft.  Build from 12.5 to 50 mg and in 6 months 75% of my patients are cured."

 

I dig, and find surprise surprise, visceral hypersensitivity is conclusively correlated with NMDA hyperfunction.

 

Thus the educated guess of dose and time frame.  And keep going.  Average people who benefit from SAMe benefit from between 400 and 800 mg tops.  Another educated guess.  The lithium dose was just from googling around.  Lots of psyche journals talk about the benefits of "low dose lithium" for anxiety and depression.

Here's one article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854802/

 

When they talk about low dose 150 mg, they mean 150 mg carbonate = 28 mg lithium ion, which equals 5 1/2 - 120 mg orotate supps.  My other educated guess is that anyone with health insurance will literally pay pennies a day for 150 mg lithium carbonate med, so that recommendation was purely financial.  There is no functional difference between one 150 mg carbonate med and 5 1/2 120mg orotate supps, so if it is easier/cheaper for you to use orotate the whole time, I cannot see a difference.

 

And the best for last:

 

Yes, I do think that glutamate receptor dysfunction could really be the cause of all of our misery.  BUT, that does NOT mean that the NO-ONOO mechanism does not come into play!  There are a dozen maybe dozens of different chemical reactions that control the count and function (voltage and current) of glutamate receptors, and I have absolutely if or how much the idea if NO-ONOO is important to that control.  I have only started skimming the NO-ONOO articles, and I have a few hundred pages of stuff I need to go thru first before I get to them.  But I remember seeing peroxynitrite (ONOO) NMDA and nanotubules on the same page somewhere in some article.  Nanotubules are essential for NMDA regulation and if we can tie NO-ONOO and peroxynitrite to the formulation of nanotubules, we have a strong argument that it is VERY important to NMDA.

 

But right now, I, ramcon1, do not know that.  Yet.

 

If you Nov3 or anyone who has read a lot on NO-ONOO want to post or PM me a link to the paper that says "HERE! LOOK HERE! PEROXYNITRITE NMDA NANOTUBULES IS IN THIS PAPER!" that would help me a lot.

 

Now I am back to work.  Today is a decent day, and I intend to use it.

 

Be well, and thanks for the great questions I hope will foster more discussion on all three threads.

 

Ramcon1

Link to comment
Share on other sites

Yes, I do think that glutamate receptor dysfunction could really be the cause of all of our misery.  BUT, that does NOT mean that the NO-ONOO mechanism does not come into play!  There are a dozen maybe dozens of different chemical reactions that control the count and function (voltage and current) of glutamate receptors, and I have absolutely if or how much the idea if NO-ONOO is important to that control.  I have only started skimming the NO-ONOO articles, and I have a few hundred pages of stuff I need to go thru first before I get to them.  But I remember seeing peroxynitrite (ONOO) NMDA and nanotubules on the same page somewhere in some article.  Nanotubules are essential for NMDA regulation and if we can tie NO-ONOO and peroxynitrite to the formulation of nanotubules, we have a strong argument that it is VERY important to NMDA.

 

If you Nov3 or anyone who has read a lot on NO-ONOO want to post or PM me a link to the paper that says "HERE! LOOK HERE! PEROXYNITRITE NMDA NANOTUBULES IS IN THIS PAPER!" that would help me a lot.

 

As Power said, Pall's book is a great suggestion.

I would like to add, make sure you read LaCorte's article as well. As that is the root of this whole connection to benzos.

 

https://cdn.shopify.com/s/files/1/2161/5909/files/SL.pdf

 

Elevated activity of the NMDA receptors is a hallmark element of the NO/ONOO cycle that is mentioned by both Pall and LaCorte. LaCorte acknowledges the role of these receptors in later stages of 'withdrawal', but in either his or Pall's work, I don't believe there are specific mentions of the formation of nanotubules... None that I have seen.

 

Regardless, while excessive NMDA activity is a central part of the LaCorte/Pall's NO/ONOO cycle theory, as it is with your theory, the underlying mechanism that causes both differs greatly between the two. So the proposed solutions for rectifying each issue are totally different and I can't imagine a way to tie them together in any poetic fashion.

 

Ramcon, have you reached out to the University of Arizona team that held the Benzo Withdrawal Symposium? I have spoken to a couple different members of their team. They are super cool guys; receptive to discussion and also interested in finding solutions. Maybe you could run your idea of upregulated ionotropic glutamate receptors by them. See if they have any thoughts. They might be able to provide more guidance or criticism than our non-neurochemist-minds can.

 

 

Link to comment
Share on other sites

[6f...]
[6f...]

The more I read in Martin Pall’s book (Explaining Unexplained Illness), the more I’m convinced it’s what’s happening in our bodies in a wave, or in protracted.

 

It’s a type of “neuro inflammation”, and how it can localize in our bodies, creating symptoms that are common for us, yet unique to each of us. (Like how one person might get muscle tension in the shoulder, yet someone else gets muscle tension in the stomach. Or how one person might have nerve pain in the arms and hands, yet another person has it more prominently in the legs and feet.)

 

 

We took a drug that caused a brain injury. But now many of us have stopped. Why are we still so symptomatic, or have waves and windows? Pall’s explanation, although not specifically written about benzos, explains very well what is happening in the body, brain, and cells.

 

 

An article by Paul is here - http://ei-resource.org/articles/chronic-fatigue-syndrome-articles/dr-palls-nitric-oxide-theory-a-treatment-options-for-chronic-fatigue-fibromyalgia-a-mcs/

 

 

His book on Amazon - https://www.amazon.com/gp/product/078902389X/ref=ppx_yo_dt_b_asin_title_o03_s00?

 

 

(I know some of you have already seen this info.)

 

and as it says in that article by Paul you included Nov 3

 

however  that book is rather  a heavy read for many  me included.  :)

 

excessive NMDA activity is involved leading to increased nNOS activity. It follows that no single form of nitric oxide synthase is involved, but rather the common factor is nitric oxide. I have argued that the most important consequences of this are mediated not through nitric oxide itself but rather through the action of the oxidant product of nitric oxide, peroxynitrite.

 

:thumbsup: :thumbsup:

Link to comment
Share on other sites

Just wanted to chime in real quick here. I've stopped the supplement protocol that I was trying out from some links that were orignally posted on this topic. It was said that there may be efficacy in supplementing to shift this NO cycle.... I didn't notice any positives over a two week period except for a small amount of energy in the beginning. Most of what I experienced the following days / weeks were similar but there was an added "edginess" on top of my regular symptoms. And a few days filled with feeling with feeling a little worse if that's possible. This could have been some detoxing happening... I'm not sure.

 

I may pick this up again in a week or so but for the time being, I am only taking EMP (vitamin / mineral combo), SAM-E, Lithium Orotate, Vitamin C, Vitamin D, and possibly some vit K2 (for the Vitamin D), ginger w/ black charcoal combo.

 

I was taking the following:

 

ALCAR

Alpha-Lipoic Acid

Ubiquinol (Q10)

Advnced Multi B

Beta Carotene

Vitamin E

Green Tea (Phytosome)

Glutathione

Selenium

 

 

Part of the protocol that I wasn't really taking:

 

Betaine

Zinc

Magnesium

...also missing some outlying supplements which I didn't have.

 

I'm not sure why but when I take magnesium and / or zinc, I feel worse. So I didn't take them really at all (I think I had one or two days of both). Betaine gives me a little bit of acid reflux so I don't like it but I was taking it every few days.

 

 

 

Link to comment
Share on other sites

Buddies,

 

I have thousands of pages I need to read in a hurry, I want to know more about Pall's NO-ONOO theory, especially how it pertains to NMDA and microtubules (I misspoke previously about "nanotubules, or maybe that is someone else's term for them)

 

To those of you who have read the book:

1. How many pages is it?

2. Is there information in the book beyond the available articles on PubMed, as they pertain to NMDA and microtubules?

3. If you know of an article that discussed NO-ONOO, NMDA, and Microtubules, can you post it here?

 

Thank you, in advance, for your help.

 

Ramcon1

Link to comment
Share on other sites

This terrifies me as had ME/CFS since 1996. Have horrible feeling diazepam been on since at least 2001 for spinal/muscle stuff has helped a lot of ME stuff like hyperacusis etc.

 

Glutamate and glial cells are known to be a factor in ME as is NOONO and Krebs cycle, ATP etc.

 

Before WD I had resolved a lot of it apart from spinal/muscle stuff by doing Dr Wahl diet for years.

 

 

Link to comment
Share on other sites

Power,

 

I will not be able to get to a 446 book for at least a month.  I will get there, but I have to prioritize.  If not microtubules or nanotubles, just whatever puts peroxynitrite/NO-ONOO in the same paper or section as glutamate/NMDA. 

 

I appreciate anything you can do that can get me from 446 pages to 10.

 

Thanks buddy,

 

Ramcon1

 

And Ajusta,

 

Do not be discouraged.  Be ENCOURAGED.  We are looking at things that tie together, or rather find similarities between ME/CFS to benzo wd.  The resulting conclusions and possible treatments should help both equally.

 

Ramcon1

Link to comment
Share on other sites

[6f...]

an 11 page PDF by Pall

 

on  peroxynitrite/NO-ONOO  and glutamate/NMDA.

 

https://emerge.org.au/wp-content/uploads/2015/03/Pall-M.-L.-NMDA-sensitization-and-stimulation-by-ONOO-NO-and-organic-solvents-as-the-mechanism-of-CS-in-MCS.-FASEB-J.-2002-1611-1407-1417.pdf

 

and a pdf on how it affects tinnitus by Pall for you

 

http://www.tinnitusjournal.com/articles/the-noonoo--cycle-as-the-etiological-mechanism-of-tinnitus.pdf

 

However the book has a bigger/more comprehensive broader picture re all this. :thumbsup:

 

Link to comment
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now

×
×
  • Create New...