Tag: nitric oxide

Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response

Abstract:

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations.

First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients.

Second, the activation of the protein kinase R enzyme, a characteristic feature in at least subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasodilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension.

Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.

 

Source: Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P. Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Med Hypotheses. 2004;62(5):759-65. http://www.ncbi.nlm.nih.gov/pubmed/15082102

 

Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients

Abstract:

Protein carbonyl levels, a measure of protein oxidation, were found to be significantly elevated (p < 0.0005) in the sera of chronic fatigue syndrome (CFS) patients vs. controls. In contrast, the total protein levels in sera CFS patients were unchanged from those of controls. The elevated protein carbonyl levels confirm earlier reports suggesting that oxidative stress is associated with chronic fatigue syndrome and are consistent with a prediction of the elevated nitric oxide/peroxynitrite theory of chronic fatigue syndrome and related conditions.

 

Source: Smirnova IV, Pall ML. Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients. Mol Cell Biochem. 2003 Jun;248(1-2):93-5. http://www.ncbi.nlm.nih.gov/pubmed/12870659

 

Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity,chronic fatigue syndrome, and posttraumatic stress disorder

Abstract:

Various types of evidence implicate nitric oxide and an oxidant, possibly peroxynitrite, in MCS and chemical intolerance (CI). The positive feedback loops proposed earlier for CFS may explain the chronic nature of MCS (CI) as well as several of its other reported properties. These observations raise the possibility that this proposed elevated nitric oxide/peroxynitrite mechanism may be the mechanism of a new disease paradigm, answering the question raised by Miller earlier: “Are we on the threshold of a new theory of disease?”

 

Source: Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity,chronic fatigue syndrome, and posttraumatic stress disorder.  Ann N Y Acad Sci. 2001 Mar;933:323-9. http://www.ncbi.nlm.nih.gov/pubmed/12000033

 

Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite

Abstract:

Three types of overlap occur among the disease states chronic fatigue syndrome (CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS) and posttraumatic stress disorder (PTSD). They share common symptoms. Many patients meet the criteria for diagnosis for two or more of these disorders and each disorder appears to be often induced by a relatively short-term stress which is followed by a chronic pathology, suggesting that the stress may act by inducing a self-perpetuating vicious cycle. Such a vicious cycle mechanism has been proposed to explain the etiology of CFS and MCS, based on elevated levels of nitric oxide and its potent oxidant product, peroxynitrite.

Six positive feedback loops were proposed to act such that when peroxynitrite levels are elevated, they may remain elevated. The biochemistry involved is not highly tissue-specific, so that variation in symptoms may be explained by a variation in nitric oxide/peroxynitrite tissue distribution. The evidence for the same biochemical mechanism in the etiology of PTSD and FM is discussed here, and while less extensive than in the case of CFS and MCS, it is nevertheless suggestive. Evidence supporting the role of elevated nitric oxide/peroxynitrite in these four disease states is summarized, including induction of nitric oxide by common apparent inducers of these disease states, markers of elevated nitric oxide/peroxynitrite in patients and evidence for an inductive role of elevated nitric oxide in animal models.

This theory appears to be the first to provide a mechanistic explanation for the multiple overlaps of these disease states and it also explains the origin of many of their common symptoms and similarity to both Gulf War syndrome and chronic sequelae of carbon monoxide toxicity. This theory suggests multiple studies that should be performed to further test this proposed mechanism. If this mechanism proves central to the etiology of these four conditions, it may also be involved in other conditions of currently obscure etiology and criteria are suggested for identifying such conditions.

Copyright 2001 Harcourt Publishers Ltd.

Comment in: Nitric oxide and the etiology of chronic fatigue syndrome: giving credit where credit is due. [Med Hypotheses. 2005]

 

Source: Pall ML. Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Med Hypotheses. 2001 Aug;57(2):139-45. http://www.ncbi.nlm.nih.gov/pubmed/11461161

 

Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome

Abstract:

BACKGROUND: L-Arginine (L-Arg), one of the essential amino acids, has been reported to have an immunomodulatory effect. The precise mechanism of the L-Arg-induced natural killer (NK) cell activation remains unresolved,and the effect of L-Arg on NK cells in chronic fatigue syndrome (CFS) patients has not been estimated.

METHODS: NK cell function was evaluated in 20 subjects with CFS and compared with that in 21 healthy individuals.

RESULTS: In healthy control subjects, NK activity was significantly increased after treatment with L-Arg, an NK function enhancer, for 24 h, whereas the same treatment failed to enhance NK activity in the CFS patients. We thus focused on L-Arg metabolism, which involves nitric oxide (NO) production through NO synthase (NOS). The expression of inducible NO synthase (iNOS) transcripts in peripheral blood mononuclear cells was not significantly different between healthy control subjects and CFS patients. The L-Arg-mediated NK cell activation was abolished by addition of NG-monomethyl-L-arginine, an inhibitor for iNOS. Furthermore, incubation with S-nitroso-N-acetyl-penicillamine, an NO donor, stimulated NK activity in healthy control subjects but not in CFS patients.

CONCLUSION: These results demonstrate that the L-Arg-induced activation of NK activity is mediated by NO and that a possible dysfunction exists in the NO-mediated NK cell activation in CFS patients.

 

Source: Ogawa M, Nishiura T, Yoshimura M, Horikawa Y, Yoshida H, Okajima Y, Matsumura I, Ishikawa J, Nakao H, Tomiyama Y, Kanayama Y, Kanakura Y,Matsuzawa Y. Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome. Eur J Clin Invest. 1998 Nov;28(11):937-43. http://www.ncbi.nlm.nih.gov/pubmed/9824439