Novel chronic fatigue syndrome (CFS) theory finally produces detailed explanations for many CFS observations

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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. 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.

(see drawing)

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

â€

“ 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.

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