Martin Pall's NO/ONOO Hypothesis for Chronic Fatigue Syndrome (ME/CFS) - Summary

Martin Pall's NO/ONOO Hypothesis for Chronic Fatigue Syndrome (ME/CFS) - Summary

(Posted by Martin Pall on the CFSFMResearch chat group at on March 27th, 2006)

Palls hypothesis provides a basis for some of Dr. Shungu's work in ME/CFS which posits that neuroinflammation and oxidative stress are behind the emphasis on anaerobic energy production (instead of aerobic energy production) in ME/CFS and perhaps fibromyalgia.

“This is going to be a long post. It contains the most important information on the cause of CFS, FM, MCS and related illnesses and how to effectively treat them.

I have been working to the cause of these illnesses for almost 8 years and will have a book coming out on this and many related topics from Haworth Medical Press that will provide much more information than is in this post.

Cases of each of these illnesses are initiated by short term stressors, but instead of recovering after exposure, people become ill with one or more these chronic illnesses. The stressors implicated include viral, bacterial and in a few cases, protozoan infections, physical trauma (most commonly to the head and neck but also including physical trauma to other regions of the body), chemical exposure to such chemicals a volatile organic solvents or such pesticides as organophosphorus/carbamates, organochlorine pesticides or pyrethroid pesticides, carbon monoxide exposure, severe psychological stress, certain mold toxins or ciguatoxin exposure.

Each of these diverse stressors can initiate a process leading to increased nitric oxide levels. In some cases (infection) the iNOS form of nitric oxide synthase is involved but in most others, 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. Peroxynitrite synthesis NO. + OO.- ——-> ONOO- nitric superoxide peroxynitrite oxide

How does this initiate these chronic illnesses? They act by initiating a biochemical vicious cycle which is responsible for these chronic illnesses:

These arrows represent 22 distinct biochemical mechanisms whereby one of the parameters listed stimulate the next parameter connected by an arrow. Of these 19 are very well documented in the biochemical literature and the remaining three appear to be correct but are less well documented. This vicious cycle, which we are now calling the NO/ONOO- cycle (based on the structures of nitric oxide and peroxynitrite (but pronounced, no, oh no!) is responsible for the chronic nature of these illnesses.

The NO/ONOO- cycle is based on five distinct principles, two of which I have already described. These principles are as follows: The NO/ONOO- cycle mechanism, can be summarized in five different principles:

  1. Short-term stressors that initiate cases of multisystem illnesses act by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of nitric oxide and its oxidant product peroxynitrite.
  2. Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of nitric oxide and peroxynitrite is produced and maintained.
  3. Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity.
  4. Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because most of the mechanisms involved in maintaining the NO/ONOO- cycle act at the level of individual cells, the fundamental mechanisms are local.

The consequence of this is that one tissue may be impacted by this underlying biochemistry while an adjacent tissue may be largely unaffected. The tissue distribution may be propagated indefinitely over time by these local vicious cycle mechanisms. This can lead to many differences in symptoms, depending on the tissue distribution variation, from one case to another.

This is such an important principle that I have devoted an entire chapter to it (Chapter 4). 5. Therapy should focus on down-regulating elements of the NO/ONOO- cycle, rather than on just on providing symptomatic relief.

Let me comment on principles 4 and 5. The local nature of the NO/ONOO- cycle means that impact of the cycle on different tissues may be largely independent of each other. Because of this, the symptoms and signs shown by different sufferers of these illnesses are highly variable, depending on which tissues are impacted in which individuals. This variation has been a source of much concern in trying to understand these illnesses but is easily understood as being a consequence of the NO/ONOO- cycle mechanism.

Principle 5 states that therapy should focus on down-regulating NO/ONOO- cycle biochemistry, rather than on symptomatic therapy. The difficulty in doing so can be seen from the complexity of the cycle (Figure 1). Because the cycle has such high level complexity and because scavengers for peroxynitrite, the most central compound in the cycle are inefficient, the approach that may have the most traction is to use multiple agents, particularly well-tolerated nutritional agents, to down-regulate NO/ONOO- cycle biochemistry. This is likely to be the most promising approach to such therapy.

In Chapter 15 of my book, the longest chapter in the book, I discuss 30 different agents or classes of agents that are available today and are predicted to down-regulate NO/ONOO- cycle biochemistry. These are summarized in the table below. I follow with descriptions of treatment protocols independently developed by five different physicians, each of whom use from 14 to 18 agents or classes of agents predicted to down-regulate this biochemistry. While some of these use additional agents, not linked or less obviously linked to NO/ONOO- cvcle biochemistry, I would argue that this pattern is not coincidental.

In other words, I argue that:

  1. These protocols are largely effective because so many agents in them down-regulate NO/ONOO- cycle biochemistry.
  2. The NO/ONOO_ cycle makes useful predictions in terms of therapy and this helps confirm its role as the central cause of these chronic illnesses.

Check out Pall's Treatment Recommendations here.
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