The NO/ONOO- Oxidative-Inflammatory Disease Model

Summarized from Dr. Pall's 2003 AAEM lecture & his new book Explaining "Unexplained Illnesses"

Many cases of the multisystem illnesses discussed in Dr. Pall's book Explaining "Unexplained Illnesses", such as fibromyalgia (FM), multiple chemical sensitivity (MCS), chronic fatigue syndrome (CFS), post traumatic stress disorder (PTSD), etc., are initiated by short-term stressors, such as viral or bacterial infection, physical or psychological trauma, or exposure to several classes of chemicals. Each of these stressors are known to stimulate responses that raise nitric oxide (NO) levels. They can all initiate the NO/ONOO- cycle in a common way. The symptoms are generated by elevated levels of these oxidants and other consequences of the oxidant effects on inflammatory mediators. Therapy should focus on down regulating the NO/ONOO- cyclebiochemistry rather than on treating symptoms.

Multisystem Illnesses Share Common Etiology

Quite a number of researchers who work with this group of conditions have noted that they have multiple overlaps and have suggested that they might share a common etiology. Specifically, they have overlapping symptoms. Many people are diagnosed as having more than one. Cases of each of these are initiated by a short-term stressor, followed by the chronic condition, so there is a pattern of induction by a short-term stressor leading to a chronic condition in all of these diseases.

Gulf War syndrome (GWS) exhibits evidence of all four of the other syndromes, and Dr. Pall has proposed a common mechanism for all four. Donnay and Ziem stated that these conditions may reflect aspects of a common medical condition. Claudia Miller and others proposed that all four of these and some other diseases may share a common etiology, which raises the question: Are we on the threshold of a new theory of disease (The Tenth Paradigm)?

The proposed etiology focuses on excessive levels of NO and its oxidant product peroxynitrite. NO does play important roles in the body, but excessive levels can lead to pathophysiology. NO can react with superoxide (both free radicals) to produce peroxynitrite, which is a potent oxidant.

The two tissues reported to be most active in producing NO are the brain and the immune system (radical production is part of the immune system's anti-microbial function). These are the tissues that are most often reported to be dysfunctional in these disorders. That is probably not a coincidence.

There are a number of short-term stressors that are presumably involved in inducing cases of these conditions. Commonly, CFS can be triggered by infection; FM is associated with a number of stressors, but commonly with physical trauma, such as an auto accident, a fall, etc.; MCS is triggered by chemical exposure; and PTSD is triggered by severe psychological stress.

So one must ask, how does a short-term stressor lead to a chronic medical condition? The proposal is that it initiates a vicious cycle mechanism involving excessive NO and peroxynitrite which perpetuates itself. For all of these conditions, one must distinguish between initial causes and ongoing causes. Ongoing causes involve the biochemistry and physiology that is being discussed. It is important to understand that there is a difference between the initial response and the chronic condition: the initial changes from a short-term stressor can cause initial illness or disease. The chemistry associated with that is initiated after the stress is long gone, the symptoms can change in some manner and create long-term illness. The long-term effects are due to a vicious cycle of free radicals that has been initiated. The redox balance has been changed, the antioxidant reserves can become depleted, and excessive free radicals can lead to inflammation and further antioxidant depletion, and an ongoing cycle develops, and then you have a vicious cycle, and it is important to distinguish between the two.

For example, infection is associated with CFS and FM: infection induces elevated levels of inflammatory cytokines; those in turn induce the inducible nitric oxide synthesis iNOS; and that produces excessive levels of NO. We know that NO can react with superoxide, which is generated from the mitochondria and then by other mechanisms to peroxynitrite. Peroxynitrite is a very potent oxidant and produces a lot of oxidative damage. Potent oxidants can stimulate a transcriptionfactor known as NF-kappaB, which can stimulate the synthesis of these inflammatory cytokines and the synthesis of iNOS itself.

So you can immediately see how the activity of peroxynitrite can lead to a potential vicious cycle, where levels of inflammatory compounds such as NF-kappaB are elevated, and in turn produce more NO.

We know that peroxynitrite can inactivate the manganese form of superoxide dismutase in mitochondria. With this enzyme damaged, superoxide will increase, which can lead to greater amounts of peroxynitrite.

Peroxynitrite and NO itself can react with the mitochondrial electron transport chain and generate further superoxide generation. A number of additional biochemical mechanisms can be suggested which lead to a vicious cycle mechanism that chronically elevates these oxidants.

A number of studies show that drugs that increase NO, such as nitroglycerin and nitroprusside, increase NO synthesis in those tissues. You can test these tissues in vitro, and they produce even more NO. In real live tissues, a vicious cycle can be generated. It is important to distinguish the difference between what the drug does directly (breaks down chemically to produce NO), and what the tissue response is (produces more NO enzymatically), and that distinction is what tells you there is a cycle present.

There are animal models for these conditions. For example, there is an animal model for MCS in which compelling evidence shows that NO has a role in producing the biological response. There is also an animal model for PTSD where NO plays a role.

Dr. Pall and colleagues have done studies on a drug called thiacetarsamide, which is reported to cure certain cases of chronic fatigue syndrome in animal models. These studies show that this drug is a scavenger for both NO and ONOO-, so this observation helps to support the model.

There is also data from animal models on MCS and PTSD, implicating excessive activity of the N-Methyl-D-Aspartate (NMDA) neurotransmitter receptor system. We know that when you have excessive stimulation of the NMDA receptors, that leads to increased synthesis of NO and ONOO-. So this is another mechanism in the model.

Dr. Pall has reviewed a substantial amount of evidence showing that in fibromyalgia patients, excessive NMDAactivity is present.

The symptoms of these conditions can be very diverse. One major symptom is fatigue, which is characteristically found in illnesses associated with energy metabolism dysfunction. Hypoxia, ischemia, anemia, hypoglycemia, mutations that alter mitochondria function, etc., can predictably lead to fatigue. Fatigue is an inevitable consequence of energy metabolism malfunction. There is extensive evidence that peroxynitrite can lead to mitochondrial dysfunction and therefore energy metabolism dysfunction.

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: There are probably several mechanisms involved because NO has several functions related to learning and memory. If NO levels are elevated, then that would be expected to have an impact on learning and memory.

Orthostatic intolerance: NO can produce vasodilation both locally in the vasculature and 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 hyperalgesia.

Depression: The NO/ONOO- cycle produces inflammatory cytokines, and there is evidence that depression can be a consequence of that.

The NO/ONOO- cycle

The elevated nitric oxide/peroxynitrite vicious cycle (NO/ONOO- cycle) predominantly involves those two compounds but involves many other elements. These include superoxide, intracellular calcium, the transcription factor NF-kappaB, inflammatory cytokines (upper right corner), oxidative stress, vanilloid receptor activity, and NMDA receptor activity. Mitochondrial (energy metabolism) dysfunction is also involved in certain pathways of the arrows. Each arrow represents the stimulation of one element by another, and the sequences of arrows constitute positive feedback loops that maintain the cycle.

The following is an excerpt from Dr. Pall's book Explaining "Unexplained Illnesses", from an extensive and valuable chapter on therapy for down-regulation of the NO/ONOO-cycle:

At least 30 therapeutic agents or classes of agents are available today that are expected to down-regulate the NO/ONOO- cycle biochemistry. Of these 30, clinical trial studies on chronic fatigue syndrome (CFS), multiple chemical sensitivity (MCS), and/or fibromyalgia (FM), have been performed on 12. All 12 of these showed evidence of efficacy in treatment of these multisystem diseases or closely related illnesses. Clinical observations and/or anecdotal reports suggest that 6 additional agents or classes of agents are also effective in treatment. None of these reach the effectiveness of a "magic bullet," providing, in most cases, only modest improvements. Given the complexity of the NO/ONOO- cycle, this is not surprising. The question that must be raised is whether combinations of several types of these agents will be more effective than individual agents alone.

Five physicians have independently developed therapy protocols using from 14 to 18 agents or classes of agents predicted to lower the cycle biochemistry. All five report substantial improvements in their patients. The patients involved in these therapies suffer from CFS, FM, chemical injury or unexplained chronic fatigue, and each of these types of patients show apparent substantial improvement. Two of these protocols have been tested and reported to be effective in clinical trials. It appears, therefore, that complex combinations of these agents are more effective than single agents in the treatment of these diseases.

Additionally, a number of prominent physicians have approached therapy for the multisystem diseases by treating with combinations of agents, many of which may be expected to down-regulate aspects of the NO/ONOO- cycle. These include Drs. Paul Cheney (North Carolina), Grace Ziem (Maryland), Scott Rigden (Arizona), Jacob Teitelbaum (Maryland), Sarah Myhill (United Kingdom), Gordon Baker (Washington State), David Buscher (Washington State), and Nash Petrovic (South Africa). The clinical observations of each of them suggest that combinations of agents acting to down-regulate various aspects of the cycle may be more effective than are individual agents.

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