NOS Partial Uncoupling as a Key Switching Mechanism for the NO/ONOO- Cycle

[Guest guest]

Shan's Comment: Several urls to related articles on MCS, FMS, CFS/ME, & PTSD

at the bottom.I wonder if this works on GWS too? After all, it seems to

work for MCS, etc.

 

 

NOS Partial Uncoupling as a Key Switching Mechanism for the NO/ONOO- Cycle

_http://dfwcfids.net/index.php?option=com_content & task=view & id=501 & Itemid=1379

_

(http://dfwcfids.net/index.php?option=com_content & task=view & id=501 & Itemid=1379)

Dr Martin Pall

 

 

 

Definitions:

 

BH4: tetrahydrobiopterin

 

NO: nitric oxide

NOS: nitric oxide synthase

 

Peroxynitrite: a nitric oxide product

Superoxide: the other precursor of peroxynitrite

 

Synthase: Any of various enzymes that modify, especially to increase, the

rate of -- a chemical reaction -- by catalysis, the synthesis of a substance

without the use of a high-energy source such as cleavage of a phosphate bond in

ATP.

 

 

__

Short-term stressors, capable of increasing nitric oxide levels, act to

initiate cases of illnesses including chronic fatigue syndrome, multiple

chemical

sensitivity, fibromyalgia and posttraumatic stress disorder. These

stressors, acting primarily through the nitric oxide product, peroxynitrite,

are

thought to initiate a complex vicious cycle mechanism, known as the NO/ONOO-

cycle

that is responsible for chronic illness.

The complexity of the NO/ONOO- cycle raises the question as to whether the

mechanism that switches on this cycle is this complex cycle itself or whether

a simpler mechanism is the primary switch.

It is proposed here that the switch involves a combination of two variable

switches, the increase of nitric oxide synthase (NOS) activity and the partial

uncoupling of the NOS activity, with uncoupling caused by a

tetrahydrobiopterin (BH4) deficiency. NOS uncoupling causes the NOS enzymes to

produce

superoxide, the other precursor of peroxynitrite, in place of nitric oxide.

Thus partial uncoupling will cause NOS proteins to act like peroxynitrite

synthases, leading, in turn to increased NF-kappaB activity. Peroxynitrite is

known to oxidize BH4, and consequently partial uncoupling may initiate a

vicious cycle, propagating the partial uncoupling over time.

The combination of high NOS activity and BH4 depletion will lead to a

potential vicious cycle that may be expected to switch on the larger NO/ONOO-

cycle, thus producing the symptoms and signs of chronic illness.

The role of peroxynitrite in the NO/ONOO- cycle also implies that such

uncoupling is part of the chronic phase cycle mechanism such that agents that

lower uncoupling will be useful in treatment.

Source: Nitric oxide synthase partial uncoupling as a key switching

mechanism for the NO/ONOO- cycle. Journal: Med Hypotheses. 2007 Apr 18; [Epub

ahead

of print]

Author: Pall ML

Affiliation: School of Molecular Biosciences, Washington State University,

Pullman, WA 99164-4234, USA.

 

Related Articles:

 

Novel Disease Paradigm Produces Explanations for a Whole Group of Illnesses

A Common Causal (Etiologic) Mechanism for Chronic Fatigue Syndrome, Multiple

Chemical Sensitivity, Fibromyalgia and Posttraumatic Stress Disorder .

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

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

 

 

The NO! OH NOO! Theory and Suggestions For Treatment by Martin Pall Ph.D

" contains the most important information on the cause of CFS, FM, MCS &

related illnesses & how to effectively treat them. " " 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 & in a few cases, protozoan

infections, physical trauma (most commonly to the head & 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. "

_http://phoenix-cfs.org/NO%20ONOO%20Theory%20Treatment%20Pall%2006.htm_

(http://phoenix-cfs.org/NO%20ONOO%20Theory%20Treatment%20Pall%2006.htm)

_http://www.ei-resource.org/articles/chronic-fatigue-syndrome-articles/the-no!

-oh-noo!-theory-and-suggestions-for-treatment/_

(http://www.ei-resource.org/articles/chronic-fatigue-syndrome-articles/the-no!-o\

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s-for-treatment/)

 

Multiple Chemical Sensitivity (MCS)

Neural Sensitization and the NO/ONOO- Cycle. The nitric oxide response

predicts that this mode of action is consistent with a NO/ONOO- cycle

mechanism.

Pesticide and Solvent Action in MCS.Certain additional types of chemicals may

also act via this common mechanism, including certain oxidants such as

chlorine gas and certain mold toxins, both of which may act via vanilloid

receptor

stimulation to increase NMDA activity. MCS is the most complex of these

illnesses and has been

the most challenging of them to explain. Among its most puzzling features is

the following:

_http://molecular.biosciences.wsu.edu/Faculty/pall/pall_mcs.htm_

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

 

Multiple Chemical Sensitivity - The End of Controversy

Elevated Nitric Oxide/Peroxynitrite/NMDA Model of MCS..The combination of

all four of these mechanisms, each acting at a different level and therefore

expected to act synergistically with each other, that produces the exquisite

chemical sensitivity reported in MCS.

_http://mcs-america.org/pall.pdf_ (http://mcs-america.org/pall.pdf)

_http://www.ei-resource.org/articles/multiple-chemical-sensitivity-articles/mu

ltiple-chemical-sensitivity-%11-the-end-of-controversy/_

(http://www.ei-resource.org/articles/multiple-chemical-sensitivity-articles/mult\

iple-chemical-sensi

tivity--the-end-of-controversy/)

 

Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity:

central role of N-methyl-D-aspartate receptors in the sensitivity mechanism.

_http://www.ei-resource.org/research/multiple-chemical-sensitivity-research/el

evated-nitric-oxide-and-peroxynitrite-theory-of-multiple-chemical-sensitivity/

_

(http://www.ei-resource.org/research/multiple-chemical-sensitivity-research/elev\

ated-nitric-oxide-and-peroxynitrite-theory-of-multiple-chemical-sensitivit

y/)

 

Chronic Fatigue Syndrome as a NO/ONOO- Cycle Disease

Chronic fatigue syndrome (CFS) was the first of these multisystem illnesses

to be proposed to be caused by a vicious cycle (1-8) that has recently been

named the NO/ONOO- (no, oh no!) cycle (8) and is still one where an

increasingly strong case for this etiology can be made. CFS appears to have the

largest

group of initiating short-term stressors described in the literature of all

the multisystem illnesses, stressors where each may be expected to act to

increase nitric oxide levels. The initiating stressors implicated in CFS cases

are as follows:

_http://molecular.biosciences.wsu.edu/Faculty/pall/pall_cfs.htm_

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

 

Novel Chronic Fatigue Syndrome (CFS) Theory Finally Produces Detailed

Explanations For Many CFS Observations

A novel theory of the cause of CFS has been published which is supported by

diverse biochemical and physiological observations of CFS, while providing

explanations for five of most difficult puzzles about this medical condition.

_http://www.ei-resource.org/articles/chronic-fatigue-syndrome-articles/novel-c

hronic-fatigue-syndrome-(cfs)-theory-finally-produces-explanations-for-many-cf

s-observations/_

(http://www.ei-resource.org/articles/chronic-fatigue-syndrome-articles/novel-chr\

onic-fatigue-syndrome-(cfs)-theory-finally-produces-explana

tions-for-many-cfs-observations/)

 

Fibromyalgia

Many properties of the NO/ONOO- cycle fit quite well with the properties of

fibromyalgia (FM). Cases of FM are initiated by stressors including viral

infections, physical trauma (especially head & neck trauma), bacterial

infections, severe psychological stress & autoimmune diseases (especially lupus

&

rheumatoid arthritis). Each of these can initiate sequences that increase nitric

oxide, either through iNOS induction (infection) or through NMDA stimulation

followed by nNOS (and possibly eNOS) activation (psychological stress,

physical trauma) (1,2). Thus 2 or 3 distinct nitric oxide synthases may have

apparent roles in initiation of illness. Many of the elements of the NO/ONOO-

cycle have been studied in FM & each of these have been reported to be

elevated.

_http://molecular.biosciences.wsu.edu/Faculty/pall/pall_fibro.htm_

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

 

Fibromyalgia, Excessive Nitric Oxide/Peroxynitrite and Excessive NMDA

Activity

The human data suggests a mechanism centered on excessive levels of nitric

oxide and its oxidant product, peroxynitrite, as well as excessive activity of

a neurotransmitter system called the NMDA system. It is known that when NMDA

receptors are hyperactive they produce excessive nitric oxide and

peroxynitrite (1).

_http://www.ei-resource.org/articles/fibromyalgia-articles/fibromyalgia,-exces

sive-nitric-oxide%10peroxynitrite-and-excessive-nmda-activity/_

(http://www.ei-resource.org/articles/fibromyalgia-articles/fibromyalgia,-excessi\

ve-nitric-ox

ideperoxynitrite-and-excessive-nmda-activity/)

 

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)

_http://www.immunesupport.com/library/showarticle.cfm?id=8071_

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

 

Neural Sensitization by Dr M Pall

Neural sensitization occurs by activation of brain and nerve cell

N-methyl-D-aspartate(NMDA), which then increases brain nitric oxide (NO).1,2,3

Several

vicious biochemical cycles are then set in motion. Nitric oxide forms a

tissue damaging free radical known as peroxynitrite.2,4,5,6 Peroxynitrite

depletes energy TP,7,8 which then further increases the sensitization of NMDA.

9,10

_http://www.mcsbeaconofhope.com/neural_sensitization_by_dr_marti.htm_

(http://www.mcsbeaconofhope.com/neural_sensitization_by_dr_marti.htm)

 

REACTION FACT SHEET / Dr. Pall

Recent research indicates that biochemical changes in the brain (neural

sensitization) perpetuate/increase symptoms with chemical exposure, often

called

“reactionsâ€. Nitric oxide is increased, which converts to peroxynitrite, a

tissue damaging free radical. By several pathways, peroxynitrite is again

converted to more nitric oxide, creating a vicious cycle.

_http://www.mcsbeaconofhope.com/reaction_fact_sheet.htm_

(http://www.mcsbeaconofhope.com/reaction_fact_sheet.htm)