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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. The theory
has been published by Dr. Martin L. Pall (Professor of
Biochemistry and Basic Medical Sciences, Washington State
University) in several publications (1-4,9). The theory starts with
the observation that infections that precede and may therefore
induce CFS and related conditions act to induce excessive
production of inflammatory cytokines that induce, in turn, the
inducible nitric oxide synthase (iNOS). This enzyme, in turn,
synthesizes excessive amounts of nitric oxide which reacts with
another compound (superoxide) to produce the potent oxidant
peroxynitrite (see Fig. 1). Peroxynitrite acts via six known
biochemical mechanisms to increase the levels of both nitric
oxide and superoxide which react to produce more peroxynitrite
(Fig. 1 - [JvR: not reproducible] ). In this way, once peroxynitrite
levels are elevated, they may act to continue the elevation, thus
producing a self-sustaining vicious cycle (ref.1). It is this cycle,
according to the theory, that maintains the chronic symptoms of
CFS and it is this cycle, therefore, that must be interrupted to
effectively treat this condition.



Twelve different observations on chronic fatigue syndrome and
its symptoms provide support for this theory:

1. The levels of neopterin, a marker for the induction of the
inducible nitric oxide synthase are reported to be elevated in
CFS (1).

2. Mitochondria are reported to be dysfunctional in CFS and
mitochondria are known to be attacked by peroxynitrite and
also by nitric oxide (1).

3. Both cis-aconitate and succinate levels are reported to be
elevated in CFS and the enzymes that metabolize these two
compounds are known to be inactivated by peroxynitrite (1).

4. The four inflammatory cytokines implicated have been
reported to been reported to be elevated in 10 different
studies of CFS (1,2).

5. These same inflammatory cytokines have been reported to
induce fatigue when injected into humans (1).

6. An animal (mouse) model of CFS has "fatigue" induced by a
bacterial extract that can induce both the inflammatory
cytokines and also the inducible nitric oxide synthase.

7. Polyunsaturated fatty acid pools are reported to be depleted
in CFS and such polyunsaturated fatty acids are known to be
oxidized by oxidants such as peroxynitrite.

8. Anecdotal evidence has suggested that antioxidants such as
coenzyme Q-10, flavonoids and glutathione precursors may
be useful in CFS treatment, consistent with a role for an
oxidant such as peroxynitrite.

9. Women are reported to produce more nitric oxide than men,
possibly explaining the gender bias seen in CFS. A similar
gender bias is seen in autoimmune diseases characterized
by excessive peroxynitrite (i.e. lupus, rheumatoid arthritis).

10. Cases of CFS are associated with high levels of deleted
mitochondria DNA, suggesting but not proving that
mitochondrial dysfunction can produce the symptoms of
CFS (1).

11. Biochemical similarities "depletion of glutamine and cystine
pools" have been reported in CFS and several diseases
characterized by elevated peroxynitrite levels, suggesting a
similar biochemical basis for all of these conditions (1).

12. Because peroxynitrite is a potent oxidant, this theory
predicts that oxidative stress will be elevated in CFS. There
was no direct evidence for this when the theory was
published but three subsequent papers have reported
substantial evidence for such oxidative stress in CFS
(5-7A). These results, may therefore, be considered to
confirm important predictions of the theory, although the
authors were unaware of this theory when they initiated
these studies.



CFS puzzles explained by the elevated nitric oxide/peroxynitrite
theory:

There are five different puzzles of CFS that are explained by this
theory. The first of these, the chronic nature of CFS, is explained
by the self-sustaining vicious cycle that is central to this theory.
The second is how infection and other stress which often
precede CFS may produce CFS. This theory predicts that each
of these can lead into this mechanism by inducing excessive
nitric oxide. Infection is not the only stress that may be involved in
this way: both physical trauma and severe psychological trauma
can produce excessive nitric oxide synthesis (2). In addition,
tissue hypoxia may induce this cycle by increasing levels of
superoxide (the other precursor of peroxynitrite) (2).

A third puzzle about CFS is how it leads to the many
biochemical/physiological correlates reported to occur in CFS.
This is discussed with the list of 12 such correlates described
above.

A fourth puzzle about CFS is how the diverse symptoms of this
condition may be generated. It turns out that a variety of factors,
including nitric oxide, superoxide, oxidative stress and
mitochondrial/energy metabolism dysfunction may have
important roles (2). For example, nitric oxide is known to
stimulate the nociceptors that initiate the perception of pain, and
therefore excessive nitric oxide may cause the multi-organ pain
associated with CFS (2). Nitric oxide has a central role in
learning and memory and so its elevation may also provide a
partial explanation for the cognitive dysfunction characteristic of
CFS (2). Other symptoms explained by this theory include
orthostatic intolerance, immune dysfunction, fatigue and
post-exertional malaise (2). The immune dysfunction reported in
CFS, may allow for opportunistic infections to develop, such as
mycoplasma or HHV6 infections, which may exacerbate the
basic CFS mechanism by increasing inflammatory cytokine
synthesis.

What about multiple chemical sensitivity, posttraumatic stress
disorder and fibromylagia?

A fifth puzzle regarding CFS is its variable symptoms and, most
importantly, its association with three other conditions of equally
puzzling etiology, multiple chemical sensitivity (MCS),
posttraumatic stress disorder (PTSD) and fibromylagia (FM).
The theory explains the variable symptoms, from one case to
another, in part, by a somewhat variable tissue distribution of the
elevated nitric oxide/peroxynitrite.

A common etiology (cause) for CFS with MCS, PTSD and FM
has been suggested by others (discussed in refs. 4,9). A
common causal mechanism for these four conditions is
suggested not only by the association among these different
conditions (many people are afflicted by more than one) but also
by the overlapping symptoms typically found in these four
conditions (see refs. 4 and 9 for discussion). These overlaps
raise the question about whether MCS, FM and PTSD may be
caused by excessive nitric oxide and peroxynitrite. Each of
these four conditions is reported to be often preceded by and
possibly induced by exposure to a relatively short-term stress
that can induce excessive nitric oxide synthesis.

Pall and Satterlee (4) present a substantial case for an
excessive nitric oxide/peroxynitrite cause for multiple chemical
sensitivity (MCS), including the following:

* Organic solvents and pesticides whose exposure is reported
to precede and presumably induce multiple chemical sensitivity,
are also reported to induce excessive nitric oxide synthesis.
Such chemicals are also reported to induce increased synthesis
of inflammatory cytokines, which induce, in turn, the inducible
nitric oxide synthase (leading to increased synthesis of nitric
oxide).

* Neopterin, a marker of induction of the inducible nitric oxide
synthase, is reported to be elevated in MCS.

* Markers of oxidative stress are reported to be elevated in
MCS, as predicted if excessive peroxynitrite is involved.

* In animal models of MCS, there is convincing evidence for
an essential role for both excessive NMDA activity (where such
activity is known to induce excessive nitric oxide) and for
excessive nitric oxide synthesis itself. If one blocks the
excessive nitric oxide synthesis in these animal models, the
characteristic biological response is also blocked. This and
other evidence shows the nitric oxide has an essential role (4).



Somewhat similar evidence is available suggesting an elevated
nitric oxide/peroxynitrite mechanism for both PTSD and FM (9).
PTSD is thought to be induced by excessive NMDA stimulation,
which, as discussed above, is known to produce excessive nitric
oxide and peroxynitrite (9). Two inflammatory cytokines known to
induce increased synthesis of nitric oxide have been reported to
be elevated in PTSD. PTSD animal model studies have
reported an essential role for both excessive NMDA stimulation
and nitric oxide synthesis in producing the characteristic
biological response.

Interestingly, a recent study of FM implicates elevated nitric
oxide and also elevated NMDA stimulation (8), and such NMDA
stimulation is known to increase nitric oxide synthesis. As in the
other conditions discussed here, there is a pattern of evidence
from studies of FM patients, consistent with the proposed nitric
oxide/peroxynitrite mechanism (9). The theory that elevated nitric
oxide/peroxynitrite is responsible for the etiology of CFS, MCS,
PTSD and FM appears to be the only mechanism to be
proposed that explains the multiple overlaps among these four
conditions. While the pattern of evidence supporting it cannot be
considered definitive, the many types of evidence providing
support for this view must be considered highly suggestive.

What does this proposed mechanism suggest about CFS
treatment? As discussed in ref. 1, there are a number of agents
that may be useful in the treatment of CFS, based primarily on
anecdotal evidence, that are expected to lower the
consequences of the proposed nitric oxide/peroxynitrite
mechanism. Possibly the most intriguing such mechanism
relates to the widespread use of vitamin B12 injections in
treatment of CFS (3). Two forms of vitamin B12 are being used
here, hydroxocobalamin, which is a nitric oxide scavenger and
cyanocobalamin, which is converted to hydroxocobalamin by
Pall human cells (3). These observations suggest that the nitric
oxide/peroxynitrite proposed mechanism for CFS makes useful
predictions for effective treatment. It is hoped that this proposed
mechanism may allow us to optimize the use of these and other
agents for treatment of CFS and related conditions.

Literatuur

1. Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Medical Hypotheses 2000;54:115-125.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10790736&form=6&db=m&Dopt=b

2. Pall ML. Elevated peroxynitrite as the cause of chronic fatigue syndrome: Other inducers and mechanisms of symptom generation. Journal of Chronic Fatigue Syndrome, 2000;7:45-58.
http://listserv.nodak.edu/scripts/wa.exe?A2=ind0103C&L=co-cure&P=R1753

3. Pall ML. Cobalamin used in chronic fatigue syndrome therapy is a nitric oxide scavenger. Journal of Chronic Fatigue Syndrome, 2001;8:39-44.

4. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome and posttraumatic stress disorder. Annals of the New York Academy of Science, 2001;933:323-329.
http://listserv.nodak.edu/scripts/wa.exe?A2=ind0205B&L=co-cure&P=R2378

5. Richards RS, Roberts TK, Mathers MB, Dunstan RH, McGregor NR, Butt HL. Investigation of erythrocyte oxidative damage in rheumatoid arthritis and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 2000;6:37-46.

6. Richards RS, Roberts TK, McGregor NR, Dunstan RH, Butt HL. Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep 2000;5:35-41.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10905542&form=6&db=m&Dopt=b

7. Fulle S, Mecocci P, Fano G, Vecchiet I, Vecchini A, Racciotti
D, Cherubini A, Pizzigallo E, Vecchiet L, Senin U, Beal MF.
Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radicals in Biology and Medicine 2000;15:1252-1259.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11118815&dopt=Abstract

7A. Keenoy BM, Moorkens G, Vertommen J, DeLeeuw I. Antioxidant strotus and lipoprotein oxidation in chronic fatigue syndrom. Life Sciences 2001;68:2037-2049.

8. Larson AA, Giovengo SL, Russell IJ, Michalek JE. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain 2000;87:201-211.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=10924813&form=6&db=m&Dopt=b

9. Pall ML. Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite, Medical Hypotheses, 2001;57:139-145.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11461161&dopt=Abstract



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


College of Science
School of Molecular Biosciences,
Washington State University,
Pullman, WA 99164-4660 USA
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