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NO/ONOO- cycle diseases:
Martin L. Pall
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Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
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In Chapter 14 of my book (1), I argue two important things. Firstly that the NO/ONOO- cycle is a major new paradigm of human disease, the tenth paradigm following the nine well accepted paradigms described there and on my main web page. Secondly, that there may be many other chronic inflammatory diseases that may be NO/ONOO- cycle diseases. I listed 14 of these, 12 in Chapter 14 of my book and one each in Chapter 7 (asthma) and in Chapter 3 (irritable bowel syndrome). Many of these 14 show comorbidity with some of the multisystem illnesses. The 14 are:
2. Post-radiation syndrome
3. Multiple sclerosis
5. Irritable bowel syndrome
7. Overtraining syndrome
8. Silicone implant-associated syndrome
9. Sudeckís atrophy
10. Postherpetic neuralgia
11. Chronic whiplash associated disorder
12. Amyotrophic lateral sclerosis
13. Parkinsonís disease
14. Alzheimerís disease
Most of these (nos. 1,3,4,5,10,11,12,13,14) may be argued to differ from one another and from the multisystem illnesses mainly in what tissues are impacted and thus can be explained as examples of the local NO/ONOO- cycle impact on various regions of the body. Clearly the basically local nature of the cycle means that multiple diseases may be caused by the NO/ONOO- cycle simply by the cycle being localized to various tissues. Others may differ mainly by what initiators are involved. For example, post-radiation syndrome can be argued to be CFS or a CFS-like disease that is initiated by ionizing radiation exposure (2, Chapter 14 in ref 1). Autism can be viewed as being very similar to the four multisystem illnesses described elsewhere on this web site, except that it is initiated around the time of birth and therefore its impact on the developing nervous system makes it distinct from the multisystem illnesses.
The criteria for deciding whether these are good candidates to be NO/ONOO- cycle diseases are the same five principles that are discussed elsewhere on this web site and in my book. For many of these, there is extensive evidence for a good fit to the five principles, but for others, there is very limited evidence, but that evidence is supportive. Still, it may be argued that the even where there is very limited evidence, the NO/ONOO- cycle mechanism may still be the best available explanatory model for these illnesses. I must add that the case for a NO/ONOO- cycle etiology presented in my book for each of these 14 is relatively superficial. I clearly did not have either the time or the space to write a tome on each of these.
I have only published on two of these to date in the scientific literature and those are tinnitus (3) and post-radiation syndrome (2). The tinnitus paper provides much more extensive evidence for a NO/ONOO- cycle etiology than does Chapter 14 in my book (1), and has created a considerable amount of interest. The notion in that paper is that when tinnitus impacts the cochlea in the inner ear, it can cause tinnitus, but when it is located elsewhere, it causes other diseases.
The 14 diseases/illnesses listed above a possible NO/ONOO- cycle diseases are not the only ones for which I think one can make a case. They were chosen because I thought I could make the case for them relatively economically, not requiring a long a detailed discussion. I would not at all be surprised if readers of this web page may not be able to come up with their own candidates not considered here.
Iíd like to discuss one of these diseases, Alzheimerís because it demonstrates an interesting challenge and an interesting lesson. The documentation for this discussion is provided in Chapter 14 (1) and is not duplicated here. If one goes through each of the five principles underlying the NO/ONOO- cycle, one finds that there is a good fit for Alzheimerís for each of them. However, if you argue to someone who knows a lot about Alzheimerís that it may be a NO/ONOO- cycle disease, you are likely to get the following response: No it canít be! Why not?? Well, because you are arguing that the NO/ONOO- cycle is causal but we have good evidence that the amyloid beta protein is causal and these are incompatible with each other. This is a strong argument, there is strong genetic and other evidence for a causal role for the amyloid beta protein, so how do I respond to this argument?
There is evidence that the beta-secretase, the rate limiting enzyme in the production of the amyloid beta protein is synthesized at much higher levels under conditions of oxidative stress and therefore will be synthesized at higher levels due to the action of the cycle in the cycle in the cerebral tissues mainly impacted by Alzheimerís disease. Furthermore, there are a series of studies of the impact of the amyloid beta protein on neuronal cells in culture that have shown that a whole series of cycle elements are elevated by the action of this protein. It follows that in the regions of the brain impacted by Alzheimerís disease, the amyloid beta protein may be predicted to be elevated as a consequence of the cycle and to act in turn to stimulate the cycle. In other words, it may be part of the cycle and therefore there is no conflict between the notion that the NO/ONOO- cycle is causal and the notion that the amyloid beta protein is causal. This argument does not prove that Alzheimerís is a NO/ONOO- cycle disease but it does argue that there is a consistent case to be made for this and that what appeared to conflict with this case, when considered more carefully, does not in fact conflict.
Clearly, one of the take home lessons from this discussion is that there may well be tissue-specific elements of the NO/ONOO- cycle that may have substantial roles in particular diseases.
Is the NO/ONOO- Cycle a Generic Model of Chronic Inflammatory Disease?
There are many dozens of chronic inflammatory diseases which according to the conventional wisdom, can be collectively considered to the the number one problem in modern medicine. And yet with one exception, there has not been any generic models of chronic inflammatory disease. Somewhat strangely, these chronic inflammatory diseases are often most studied for how they differ from one another rather than how they may be similar.
The one exception, here is autoimmune disease. And many proposed autoimmune diseases have been argued about for decades as to whether they really are autoimmune or at least, strictly autoimmune in nature. A good example of that is multiple sclerosis, where an autoimmune etiology to this day is questioned and which I suggested here and in Chapter 14 (1) may actually be a NO/ONOO- cycle disease.
So the question raised here is whether the NO/ONOO- cycle may be a generic model for chronic inflammatory disease?
There is another question that i raised in my book. Are these delusions of grandeur??
There are three answers to this. The first (the one I gave in my book) is that what one needs to do is to examine, one disease at a time, how good the fit is to the five principles and that, in turn will tell you how broadly applicable this model appears to be. No delusions necessary, let the science tell us the answers, to the extent that the data currently exists or can be generated in the future.
There is a second answer and one that goes most directly to two other clearly closely related questions. Why has no one else come up with the NO/ONOO- cycle mechanism previously, if it is so widely applicable? After all, many of the 14 diseases listed above have been extensively studied, with such research having been very well funded. Isnít it implausible that if the NO/ONOO- cycle is fundamentally correct, that others have not come up with it?
Those are all important questions. I raise several points in response:
Based on these four considerations, I donít think it is at all surprising that this model has not been developed previously.
But I do want to encourage others to jump in here. We obviously need much work on the model and how it may apply to specific diseases. As far as I can determine, the only other person working along similar lines with excellent competance to deal with these complexities is Dr. Bodo Kuklinski in Germany and unfortunately since his book (4) is in German, I have very limited capability to understand his contributions.
What Should a Generic Model of Chronic Inflammatory Disease Look Like?
One question that should be asked is the following: From first principles, what should a generic model of chronic inflammatory disease look like? I am not going to try to document the following argument but I think that those of you who have a deep familiarity with chronic inflammatory diseases will see its merits.
I argue that it should first of all be a vicious cycle mechanism, otherwise how can so many short term stressors apparently lead to chronic illness. And it should basically be local in nature, localized to certain regions of the body in each case, but not to other regions. Otherwise how can one explain why there are so many different chronic inflammatory diseases?
It should include, obviously, elevated inflammatory cytokines and other inflammatory markers and oxidative stress and often increased nitric oxide levels, all common aspects of inflammatory biochemistry. It should also include mitochondrial dysfunction, since this is also reported to occur in many different chronic inflammatory diseases. Because excitotoxicity including excessive NMDA activity is essentially universally found in chronic inflammatory diseases that impact the central nervous system, this may well be another aspect of the mechanism; while such excessive NMDA activity has been much less studied in peripheral chronic inflammatory diseases, this may have a role there, as well, albeit one that needs much more study. Tetrahydrobiopterin (BH4) depletion is much less studied than are most of these other NO/ONOO- cycle elements, but is increasingly being reported in various chronic inflammatory conditions and so may also be argued to be a part of such a generic mechanism. After all, it is reported that BH4 depletion has roles in such diseases as Parkinsonís disease, Alzheimerís disease, ALS, heart failure, schizophrenia, mast cell activation, chronic renal failure, hypertension, and pulmonary hypertension.
So it may be argued that from first principles, a generic model of chronic inflammatory disease will look very much like the NO/ONOO- cycle mechanism!
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