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Novel chronic fatigue syndrome (CFS) theory finally produces detailed

explanations for many CFS observations:

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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.

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). 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.

Other sites with thoughtful presentations that you may wish to access

are as follows:

http://www.cfsresearch.org/cfs/

http://www.square-sun.co.uk/cfs-nim/

http://www3.sympatico.ca/me-fm.action/

References:

1. Pall ML. Elevated, sustained peroxynitrite levels as the cause of

chronic fatigue syndrome. Medical Hypotheses 2000;54:115-125. (link)

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.

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. ls of

the New York Academy of Science, 2001;933:323-329.

5. s RS, TK, Mathers MB, 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. s RS, TK, McGregor NR, RH, Butt HL. Blood

parameters indicative of oxidative stress are associated with symptom

expression in chronic fatigue syndrome. Redox Rep 2000;5:35-41.

(link)

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. (link)

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, 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. (link)

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.