Nitric Oxide Cycle Theory: Will It Explain CFS, FM, and Other ‘Unexplained’ Illn

[Guest guest]

Nitric Oxide Cycle Theory: Will It Explain CFS, FM, and Other ‘Unexplained’

Illnesses? - Q & A with Martin L. Pall, PhD

 

_http://www.immunesupport.com/library/showarticle.cfm?id=8071 & T=CFIDS_FM_

(http://www.immunesupport.com/library/showarticle.cfm?id=8071 & T=CFIDS_FM)

by Monika Quinlan

ImmuneSupport.com

06-11-2007

Martin L. Pall, PhD, is generating excitement in scientific communities

worldwide with his theory that a " stressor-initiated " biochemical mechanism -

the

nitric oxide/peroxynitrite (NO/ONOO-) cycle - may be responsible for CFS,

FM, and other syndromes.

The attention began with publication of his new book, _Explaining

'Unexplained Illnesses': Disease Paradigm for Chronic Fatigue Syndrome,

Multiple

Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War

Syndrome and Others_

(http://www.amazon.com/Explaining-Unexplained-Illnesses-Fibromyalgia-Post-Trauma\

tic/dp/078902389X/ref=sr_1_1/103-6953908-9698264?ie=UTF8 & s=bo

oks & qid=1181681200 & sr=8-1) .*

 

In the following Q & A, Dr. Pall, Professor of Biochemistry and Basic Medical

Sciences at Washington State University, explains his theory in lay terms.

Simply put, Dr. Pall proposes that the complex NO/ONOO- cycle he describes may

result in high levels of oxidants, which affect different tissues in

different individuals, accounting for a “stunning†variety of symptoms. Dr.

Pall

also believes a regimen of antioxidant supplementation may help the body “

downregulate†the NO/ONOO- cycle biochemistry.

___________________________

Q: Dr. Pall, you suggest that cases of chronic fatigue syndrome (CFS),

fibromyalgia (FM), multiple chemical sensitivity (MCS) and post-traumatic

stress

disorder (PTSD) may all get started (get “initiatedâ€) by similar

mechanisms.

What led you to that conclusion?

Dr. Pall: Cases of each of these are initiated by certain short-term

stressors. These include both bacterial and viral infections in CFS and FM,

exposure

to three types of pesticides or to organic solvents, in MCS, to physical

trauma in FM or PTSD, or to severe psychological stress for PTSD or any of

these

others. There are others, totaling 12 or 13 such stressors.

Each of these diverse stressors can increase levels of a chemical compound

called nitric oxide in the body. So I proposed that nitric oxide is likely to

have a role in the initiation of chronic illness.

* * * *

Q: So how can nitric oxide act to initiate chronic illness?

Dr. Pall: That is a very important question. I proposed that nitric oxide,

acting via its product peroxynitrite, a potent oxidant, acts to initiate a

biochemical vicious cycle which is the cause of illness.

This cycle, which we now call the NO/ONOO- (pronounced no, oh no!) after the

structure of nitric oxide (NO) and peroxynitrite (ONOO-) is based on many

well documented biochemical mechanisms, and the combination of such mechanisms

is a complex vicious cycle which can propagate itself over time, producing

chronic illness.

So for each of these cases of illness, we have an initial cause, one or more

stressors, and an ongoing cause, the NO/ONOO- cycle mechanism. The

pronunciation no, oh no reflects both the role of these two chemicals and the

way

people who suffer from these illnesses feel.

* * * *

Q: What else can you explain about these illnesses?

Dr. Pall: Almost everything:

· How many of the symptoms are generated,

· Why these symptoms are variable from one individual to another,

· Why these illnesses often occur together in the same individuals,

· Why they also often occur with such diseases as asthma, migraine

headache, tinnitus, lupus or rheumatoid arthritis,

· And how they should be treated.

* * * *

Q: You have described five principles that summarize the NO/ONOO- cycle

mechanism as a model of disease. Please describe these.

Dr. Pall:

n The first principle, which we have discussed, is that NO/ONOO- cycle

illnesses are initiated by stressors that can raise levels of nitric oxide or

other cycle elements.

n The second principle is that the chronic illness is caused by the NO/ONOO-

cycle and that ill people will, therefore, have raised levels of various

cycle elements.

n The third is that the symptoms and signs of illness must be generated by

the elements of the cycle.

n The fourth is that the basic mechanism is local. This local nature is

caused by the fact that the three chemicals that have central role in the

NO/ONOO- cycle, nitric oxide, peroxynitrite, and a third chemical –

superoxide –

all have relatively short half lives in biological tissues, so that they

don’t

travel very far from where they are produced to where they are destroyed. And

the mechanisms of the cycle act at the level of individual cells of the

body.

The consequences of these are that one person may have certain tissues of

their body impacted by this local NO/ONOO- cycle biochemistry, but others may

have different tissues impacted, leading, in turn, to much variation in

symptoms and signs from one individual to another.

This variation in symptoms and signs of illness has been one of the greatest

puzzles of this group of illnesses, and this can be explained easily with

the current model.

n The fifth principle, the one that most sufferers as well as most

physicians should find of the most interest, is how to treat these illnesses.

We should treat these by lowering (down-regulating) the NO/ONOO- cycle

biochemistry. In other words we need to treat the cause of illness, not just

the

symptoms.

* * * *

Q: We’ll get back to therapy shortly. You suggest that the complexity of the

cycle is the most difficult aspect in the effective treatment of these

illnesses. Why is that?

Dr. Pall: The cycle involves at least 22 different mechanisms, by which one

element of the cycle leads to an increase in another element of the cycle.

It is the combination of these mechanisms, diagrammed by arrows in Figure 1 on

my website and in my book.

 

 

The cycle involves many such mechanisms, as stated here, and also such

variables as the activity of a “transciption factor†called NF-kappa B,

which

turns on the inflammatory cytokine genes and a gene that encodes the inducible

nitric oxide synthase (iNOS), the levels of superoxide, the levels of calcium

in the cytoplasm of cells, and the levels of two receptor systems that act

mainly in the nervous system, the vanilloid receptors and the NMDA receptors.

The cycle also involves decreased ability to make energy in the form of ATP,

due to the attacks of peroxynitrite on proteins and other components in the

mitochondria.

* * * *

Q: So how does this explain what we need to do for effective therapy?

Dr. Pall: It is the complexity of the cycle that makes treatment such a

challenge.

I discuss many “agents†that are predicted to lower the NO/ONOO- cycle

biochemistry in the chapter of my book on therapy (the longest chapter in the

book). Twelve or 13 classes of such agents that have been reported to produce

significant improvement in CFS, FM, or MCS in clinical trial studies and others

may also be useful, albeit with less evidence.

However, individual agents produce only modest improvements.

Five physicians have produced complex treatment protocols having 14 or more

agents predicted to down-regulate the NO/ONOO- cycle biochemistry, and these

complex protocols appear to be much more effective than are the individual

agents. It is these complex combinations of agents that have the most promise

in the treatment of these illnesses. Most of these agents are nutritional, but

some are conventional pharmaceuticals and some are “herbals.†[Dr. Pall

refers to protocols developed by Dr. Paul Cheney, Dr. Garth Nicolson, Dr.

Noboysa (Nash) Petrovic, and Dr. Jacob Teitelbaum, as well as Dr. Grace Ziem -

with

whom Dr. Pall has cooperated in his own efforts to evolve a protocol.]

* * * *

Q: This treatment approach seems to the almost the opposite of that usually

used in modern medicine. Is that so?

Dr. Pall: You are quite right – this approach is opposite to the predominant

current approach to treatment. That predominant approach dates from the

development of wide spectrum antibiotics in the 1940’s and 1950’s. That

“magic

bullet†approach is still very effective in the treatment of many acute

bacterial infections. But it has been a failure with most chronic diseases,

which

are rarely cured; and often one cannot even greatly slow their progression.

The evidence of these five physicians suggests that we may be able to get a

good clinical response with our group of four illnesses. Our goal should, in

my view, be to get a substantial number of cures and it is my hope that by

improving this approach, we will be able to do so.

* * * *

Q: We understand you have designed a protocol that is available

over-the-counter, is that right?

Dr. Pall: Yes, I have designed...an approach to down-regulating the NO/ONOO-

cycle biochemistry that involves only over-the-counter supplements.

 

[see _ " Antioxidant Suggestions for Down-Regulation of the NO/ONOO- Cycle from

Dr. Martin Pall, PhD " _

(http://www.immunesupport.com/library/showarticle.cfm?id=8075 & T=CFIDS_FM)

_http://www.immunesupport.com/library/showarticle.cfm?id=8075 & T=CFIDS_FM_

(http://www.immunesupport.com/library/showarticle.cfm?id=8075 & T=CFIDS_FM) ]

Let me just caution that I am a PhD, not an MD, and none of this should be

viewed as medical advice, and that the supplements included in the protocol

are not sold as a treatment or cure for any disease.

* * * *

Q: You argue, we take it from the title of the book, that these four

illnesses are true diseases and that the NO/ONOO- cycle is a disease mechanism.

Dr. Pall: Exactly. I propose that the NO/ONOO- cycle is the tenth paradigm

of human disease, adding it to the nine well-accepted disease paradigms

described in Chapter 14 of my book.

It is unusual, however, primarily because the local nature of the cycle

leads to much variation of symptoms of illness, depending on which tissues are

impacted by the cycle and how severely they are impacted. What we are dealing

with here with CFS, MCS, FM and PTSD is a huge spectrum of disease, with

stunning variations in different individuals.

* * * *

Q: Are there any other important breakthroughs proposed in your book?

Dr. Pall: One very important breakthrough is that there are other diseases

that are good candidates for NO/ONOO- cycle diseases. I suggest 14 additional

diseases/illnesses that appear to be good candidates for NO/ONOO- cycle

diseases, including such diseases as multiple sclerosis, tinnitus,

Alzheimer’s,

Parkinson’s, amyotrophic lateral sclerosis, and asthma.

Each of these six has the apparent involvement of the NO/ONOO- cycle in

different tissues. Another disease that is a candidate as a NO/ONOO- cycle

disease is autism, where the early onset and the impact of the cycle on the

developing brain may produce the characteristic properties of autism. Autism

also

has a huge spectrum of disease, the autistic spectrum disorders.

The criteria for other diseases/illnesses being candidates for inclusion

under the NO/ONOO- cycle paradigm are their fit with the five principles we

discussed earlier.

The possibility that this single mechanism may explain many different

diseases is truly stunning. But it should not be completely surprising. There

are

dozens of diseases that are chronic inflammatory diseases, and the NO/ONOO-

cycle involves inflammatory biochemistry, much the same biochemistry that

occurs in inflammation. Thus the NO/ONOO- cycle may explain many of the

diseases

that are so predominant in medicine.

* * * *

Q: What response has the scientific community given to your theory?

Dr. Pall: The response has been truly amazing. I have just returned from

giving five talks in Europe, two in Britain, and three in Spain. And the

response at each of these talks has been extraordinary. I have already been

invited

back to both countries to give more talks. I am scheduled to give a talk in

Mexico and five others in the U.S. this year. My book sold out within a week,

with a second printing scheduled. I have had nine radio interviews to date

and still more will occur fairly shortly.

I have to say that I am amazed at how positive the responses have been to

date, especially when you consider how conservative science tends to be and how

difficult it usually is to get acceptance of new scientific paradigms.

* * * *

Thank you very much, Professor Pall, for your responses to our questions,

and we hope to hear more about your ongoing work in the future.

For More Information

If you are interested in reading a more detailed synopsis of Dr. Pall’s

NO/ONOO- cycle concept - including a chart detailing “plausible mechanismsâ€

for

the different signs and symptoms associated with multisystem illnesses, from

fatigue and memory dysfunction to chronic pain and IBS - visit Dr. Pall’s

website at _http://molecular.biosciences.wsu.edu/Faculty/pall/pall_main.htm_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_main.htm)

This Q & A is reproduced with kind permission of the Chemical Injury

Information Network, PO Box 301, White Sulphur Springs, MT 59645: 406/547-2255;

_chemicalinjury_ (chemicalinjury) ;

_http://www.ciin.org_

(http://www.ciin.org/) CIIN is a charitable nonprofit support and advocacy

organization dealing with Multiple Chemical Sensitivities.

___

* Dr. Pall's book, Explaining 'Unexplained Illnesses': Disease Paradigm for

Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia,

Posttraumatic Stress Disorder, Gulf War Syndrome and Others (Haworth Press,

2007)

is available through _Amazon.com_

(http://www.amazon.com/Explaining-Unexplained-Illnesses-Fibromyalgia-Post-Trauma\

tic/dp/078902389X) and may be ordered at

your local bookstore.