Nitric Oxide (NO)
Another theory, mentioned by several speakers at the conference, relates to elevated levels of nitric oxide (NO). It’s a theory that has been put forth by Martin Pall, Ph.D., of Washington State University in Pullman, WA. The formation of NO is triggered by pro-inflammatory cytokines, the same substances that activate the Anti-Viral Pathway. NO goes on to form peroxynitrite and this conpound is a potent oxidant, more so than NO. It damages cell membranes, interrupts energy production in the mitochondria, reduces the ability of blood platelets to store pain-relieving serotonin for delivery to the tissues, and produces a situation that causes an increase in pro-inflammatory cytokines. According to Pall, once the process is set in motion, it becomes a vicious cycle!
Pall recently published a study that adds weight to this theory. Since NO is not a compound that can be easily measured, Pall tested the levels of citrulline, a stable compound that is formed by the production of NO (e.g., for every NO molecule that is formed, a molecule of citrulline is formed as well). Pall tested the serum citrulline levels in 36 CFS patients and 16 healthy controls. He found that the levels of citrulline were significantly higher in the CFS patients. In addition, he noted a trend between higher citrulline levels in the serum and greater symptom severity in the CFS patients.
Pall is not the only person to show an elevation in citrulline levels. Alice Larson, Ph.D., of the University of Minnesota in St. Paul, tested the spinal fluid of FM patients for various amino acids that may be linked to pain, including citrulline. She found elevated citrulline levels in the spinal fluid and noted that they correlated with pain levels. Larson concluded that NO could be implicated in FM, and emphasized its role in pain processing–particularly its ability to activate the NMDA receptors in the spinal cord which are known to cause pain amplication (i.e., windup). Based on her data, Larson could not conclude that NO was directly responsible for the pain of FM because it may be produced in response to other pain producing compounds that are generated in FM patients (such as substance P).
An additional study that found evidence of elevated levels of NO in the blood serum of patients with FM was performed by Laurence Bradley, Ph.D., and co-workers at the University of Alabama at Birmingham. Rather than testing for citrulline, Bradley measured the chemical breakdown product of NO plus perxoynitrite, called nitrite. He found that elevated nitrite levels correlated with the patient’s response to two different pain stimulus tests.
A comment by Suhadolnik sums up the NO problem in terms of its deleterious biochemical effects on cell membranes, mitrochondria, and ATP energy production: “We begin to see an explanation of some of these activities in terms of just two little molecules, NO and peroxynitrite. What we have is a reinforcement; that is a vicious cycle. The more TNF and other cytokines that we have, the more NO and peroxynitrite we get, along with more mitrochondrial damage, lipid peroxidation damage, and a downregulation of the hypothalamic-pituitary-adrenal (HPA) axis.” He adds that a reduced cortisol output from the adrenals could explain the weakened immune system and some of the fatigue patients experience.
Pall suggests several therapies for treatment of elevated levels of NO. For the most part, these therapies involve the use of antioxidants, which would also work to minimize the oxidative stress imbalance.
9. Pall ML. J Chronic Fatigue Syndrome 2000; 7(4):45-58.
10. Pall ML. Medical Hypotheses 2000; 54(1):115-125.
11. Pall ML. Medical Hypotheses 2001; 57(2)139-145.
12. Pall ML. J Chronic Fatigue Syndrome 2002; 10(3-4):37-41.
13. Larson AA. et. al. Pain 2000; 87(2):201-211.
14. Bradley LA., et. al. Arthritis Rheum 2000; 43 (suppl 9): S173, abs#638.
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