By Dr. Martin L. Pall
Professor of Biochemistry and Basic Medical Sciences
Washington State University
A novel theory of the cause of Chronic Fatigue Syndrome (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.
Peroxynitrite acts via six known biochemical mechanisms to increase the levels of both nitric oxide and superoxide which react to produce more peroxynitrite. 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 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 Q10, 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 (e.g., 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 fibromyalgia?
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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 that 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 to be 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:
1. Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Medical Hypotheses 2000;54:115-125.
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. Annals of the New York Academy of Science, 2001;933:323-329.
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.
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.
7A. Keenoy BM, Moorkens G, Vertommen J, DeLeeuw I. Antioxidant strotus and lipoprotein oxidation in chronic fatigue syndrome. 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.
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.
(c) Dr. Martin L. Pall. This article is reprinted with the author’s permission. For more information, please visit http://molecular.biosciences.wsu.edu/Faculty/pall.html.