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NO/ONOO-
A Brief Summary of the Work of Martin Pall, Ph.D.
Editor's note: Martin Pall Ph.D. has 23 publications out or in the press on what is now called the "NO/ONOO- cycle mechanism".
No….oh no!
It sounds like a cry of protest and pain, and indeed it is, certainly by those who suffer from chronic fatigue syndrome, fibromyalgia, Gulf War syndrome, post-traumatic stress and multiple chemical sensitivity.
But that succinct phrase is also the essence of biochemist Martin Pall’s therapeutic approach to five mystery illnesses. Pall has assembled an impressive body of data to demonstrate that elevated levels of nitric oxide (NO) and its highly damaging metabolite, peroxynitrite (ONOO-), are at the crux of a runaway cycle of free-radical damage in which inflammatory molecules are chronically elevated, damaging the immune and nervous systems. Peroxynitrite initiates a complex biochemical vicious cycle, known as the NO/ONOO- cycle, which is responsible for multiple chemical sensitivity, chronic fatigue syndrome, fibromyalgia, Gulf War syndrome and post-traumatic stress disorder. The basic concept here is actually quite simple. Stressors act mainly through peroxynitrite-derived free radicals to initiate the cycle and once the cycle is initiated it is the cause of continuing illness.
By correcting the high levels of NO and ONOO- with a range of natural antioxidants, a puzzling array of symptoms can be ameliorated and sometimes the illness itself can be completely reversed. (See Allergy Research Group® Newsletter Focus, July 2007.)
Pall suffered from severe chronic fatigue syndrom (CFS) and multiple chemical sensitivy (MCS) for 18 months, and cured himself, then set about dedicating his career to investigating the cause of these disabling conditions. Now his approach has started to garner widespread attention, with publication of an entire chapter by Pall in the upcoming General and Applied Toxicology, 3rd edition by (editors TK), published by John Wiley, Inc. In addition, a new pilot study from The Institute for Functional Medicine Clinic in Falun, Sweden demonstrates the effectiveness of this approach. Pall also has a forthcoming article on CFS in Current Opinion in Psychiatry.
As Pall points out, the acute stressor(s) that lead to CFS and MCS and the other mystery illnesses range from infections to toxic exposures to physical or mental trauma. But no matter what the initiating cause, the downstream effect is free radical damage mediated by raised levels of NO and ONOO-.
Very specifically:
The immune system: is impacted by inflammatory cytokines and NO itself. The immune system cells are particularly sensitive to oxidative stress.
Learning and memory dysfunction: NO has several functions related to learning and memory.
Orthostatic intolerance: NO can produce vasodilation locally in the vasculature and systemically through its effects on the sympathetic nervous system.
Pain: All the elements of the NO/ONOO- cycle have a role in the excessive pain of these conditions.
Depression: The NO/ONOO- cycle produces inflammatory cytokines, which are implicated in depression.
According to Pall, the largest single challenge in understanding MCS is how so many diverse chemicals can trigger sensitivity symptoms and produce a common response in the body. Toxic chemicals, such as organic solvents or pesticides, increase the activity of NMDA ((N-methyl D-aspartate) receptors. These are a specific type of glutamate receptor. Increased NMDA activity is known to produce increased calcium influx into cells, leading to increased activity of two calcium-dependent nitric oxide synthases, nNOS and eNOS, which produce, in turn increased nitric oxide. Nitric oxide reacts with superoxide to form peroxynitrite. So, ultimately, it is the final act, NO and ONOO- that cause the damaging response.
In CFS, peroxynitrite attacks important mitochondrial proteins, initiating a complex of reactions, each of which lowers oxygen utilization in the tissues. Peroxynitrite also oxidizes a compound known as tetrahydrobiopterin (BH4), which has a role in the production of important mood elevators such catecholamines and serotonin.
Pall suggests treating with specific nutrients that lower NO and ONOO-. Previous clinical studies of sixteen nutrients have demonstrated improvement, and the new Swedish study of nine patients supports their usefulness. These nutrients include:
- Trimethylglycine (betaine)
- Coenzyme Q10
- Folic acid (folate)
- Hydroxycobalamin (B12)
- Ecklonia cava extract
- Acetyl-L-carnitine
- Flavonoids
- Fish oil
- Magnesium
- Vitamin C
- Tocotrienols and Carotenoids
- Multivitamins and minerals
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