Multiple Chemical Sensitivity, Fibromyalgia and Electromagnetic Sensitivity as NO/ONOO- Cycle Diseases Martin L. Pall Professeur émérite de biochimie et sciences médicales fondamentales, Université d’Etat Washington et Directeur de recherche, Groupe de recherche sur le 10e paradigme 1

Plusieurs groupes de recherche pensent que le syndrome de fatigue chronique (SFC), la fibromyalgie (FM), l’hypersensibilité chimique multiple (MCS) et dans certains cas, le syndrome de stress post-traumatique (SSPT) pourraient avoir la même étiologie (cause). Ils présentent : Des symptômes communs Une comorbidité, souvent Ces troubles chroniques sont souvent provoqués par un agent déclencheur à court terme. Le syndrome de la guerre du Golfe présente des éléments de ces 4 troubles. 2

L’idée que le SFC, le MCS, le SSPT, la FM et plusieurs autres maladies puissent partager une même étiologie a été proposée par Miller, qui s’est demandé : “Sommes-nous au seuil d’une nouvelle théorie à propos de ces maladies ?" Toxicol Indust Health 1999;15:284-294 3

Par exemple, Buchwald et Garrity ont conclu lors d’une étude des patients atteints de SFC, MCS et FM que : “malgré des diagnostics différents, les données existantes, bien que limitées, suggèrent que ces maladies sont des troubles semblables sinon identiques…” Arch Inter Med 1994;154:2049-2053. 4

Donnay et Ziem ont considéré que le SFC, la FM et le MCS “pourraient simplement refléter différents aspects d’un même trouble médical sous-jacent." J Chronic Fatigue Syndr 1999;5:71-80. 5

Cet exposé se concentrera sur le MCS Cet exposé se concentrera sur le MCS. Une des grandes énigmes à propos du MCS est la suivante : Comment les agents chimiques divers qui déclenchent des cas de MCS et provoquent des réactions chez les personnes déjà hypersensibles, peuvent-ils produire la même réaction de l’organisme ?? 6

Solvants organiques et composés apparentés Parmi les agents chimiques connus pour déclencher des cas de MCS, on trouve : Solvants organiques et composés apparentés Pesticides organophosphorés/ au carbamate Pesticides organochlorés Pesticides au pyréthrinoïde mais également : Sulfure d’hydrogène Monoxyde de carbone Mercure 7

Les solvants organiques, les pesticides organophosphorés, organochlorés et au pyréthrinoïde augmentent tous l’activité des récepteurs NMDA ! 8

Hydrogen sulfide, carbon monoxide and mercury (acting via methylmercury) also act to increase NMDA activity. One can greatly lower the toxicity of all seven classes of chemicals in the body by treating with an NMDA antagonist. This shows not only that increased NMDA activity is produced by these chemicals but that this increased activity has a major role in producing the toxic responses in the body! So in other words, we not only know that the NMDA response occurs, but that it is important for toxic responses to all seven classes of chemicals. Le sulfure d’hydrogène, le monoxyde de carbone et le mercure (via le méthylmercure) augmentent aussi l’activité des récepteurs NMDA. Il est possible de réduire grandement la toxicité de ces 7 groupes d’agents chimiques dans l’organisme en prenant un antagoniste NMDA. Ceci démontre non seulement que l’augmentation de cette activité est due à ces agents chimiques, mais aussi que l’augmentation de l’activité NMDA a un rôle majeur dans les réactions toxiques de l’organisme ! En d’autres termes, on sait non seulement qu’il existe une réponse NMDA mais aussi qu’elle est importante pour les réponses toxiques aux 7 groupes de agents chimiques. 9

Six autres observations en faveur d’un rôle NMDA dans le MCS: 1. MCS patients are sensitive to monosodium glutamate and glutamate is the physiological agonist of the NMDA receptors. 2. An allele of the CCK-B receptor gene that produces increased NMDA activity is associated with increased prevalence and therefore incidence of MCS. 3. The NMDA antagonist dextromethorphan is reported from clinical observations to produce lowered response to chemical exposures in MCS patients. 4. Bell and others have proposed that neural sensitization has a key role in MCS and the probable mechanism for such neural sensitization, called long term potentiation, is known to involve increased NMDA activity. 5. Elevated NMDA activity has been shown to play an essential role in several animal models of MCS. 6. Elevated NMDA activity appears to play a role in such related illnesses as fibromyalgia, chronic fatigue syndrome and post-traumatic stress disorder, with the most extensive evidence for such a role being found in fibromyalgia (Pall, 2006 and 2007a). Nous avons les preuves incontestables d’une réponse toxicologique commune ! 10

6 gènes impliqués dans le métabolisme de ces agents chimiques déterminent la réceptivité au MCS 11

One thing that you should note from the preceding discussion is that the receptors for these various toxic chemicals are NOT the olfactory receptors. It has been repeatedly stated that MCS is a response to odors, but this is not the case! And MCS sufferers with their nasal passages blocked off still react to chemicals. Some MCS patients are anosmic, completely lacking any sense of smell. I am not saying that the olfactory system is never impacted in MCS, but rather that the basic mechanism is not olfactory. Les récepteurs impliqués ne sont PAS les récepteurs olfactifs. Le MCS est une réaction aux agents chimiques, pas aux odeurs. 12

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La théorie étiologique que je défends se fonde sur le fait que l’oxyde nitrique réagit avec le superoxyde pour former le peroxynitrite, un puissant oxydant. .NO + .OO- ONOO- Nitric superoxide peroxynitrite oxide 14

17 différents agents déclencheurs à court terme peuvent initialiser ces maladies et tous peuvent augmenter l’oxyde nitrique dans l’organisme 15

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Cinq principes 1. Short-term stressors initiate these multisystem illnesses by stimulating nitric oxide or other cycle elements. Les agents déclencheurs à court terme initialisent ces maladies multisystème en stimulant l’oxyde nitrique ou d’autres éléments du cycle. 2. The increases in NO and peroxynitrite initiate the NO/ONOO- cycle which then causes these chronic illnesses. L’augmentation d’oxyde nitrique et de peroxynitrite déclenche le cycle NO/ONOO qui provoque ensuite ces maladies chroniques. 17

3. The symptoms and signs of these illnesses are caused by the elevated elements of the NO/ONOO- cycle, nitric oxide, superoxide, peroxynitrite, NF-B, oxidative stress, TRPV1 activity, NMDA activity, etc. Les symptômes et signes de ces maladies sont causés par l’augmentation des éléments du cycle NO/ONOO : oxyde nitrique, superoxyde, peroxynitrite, NF-B, stress oxydatif, activité TRPV1, activité NMDA, etc. 4. The basic biochemistry of the cycle is local, because nitric oxide, superoxide and peroxynitrite have limited half lives in biological tissues and because the positive feedback mechanisms that maintain the cycle act at the cellular level. La biochimie élémentaire du cycle est locale, car l’oxyde nitrique, le superoxyde et le peroxynitrite ont une demi-vie limitée dans les tissus biologiques et parce que le mécanisme de régulation positive qui maintient le cycle agit au niveau cellulaire. 5. Therapy should focus on down-regulating parts of the NO/ONOO- cycle, rather than on symptomatic relief. La thérapie devrait se concentrer sur le ralentissement du cycle NO/ONOO plutôt que sur l’apaisement des symptômes.

Tableau 14-1 Principaux paradigmes de la maladie 1. Infectious diseases / Maladies infectieuses 2. Genetic diseases / Maladies génétiques 3. Nutritional deficiency diseases / Maladies de carence 4. Hormone dysfunction diseases / Dérèglement hormonal 5. Allergies / Allergies 6. Autoimmune diseases / Maladies auto-immunes 7. Somatic mutation/selection (cancer) / Mutation/sélection somatique (cancer) 8. Ischemic cardiovascular diseases / Maladies cardiovasculaires ischémiques 9. Amyloid (including prion) diseases / Maladies amyloïdes (y compris dues au prion) 10. NO/ONOO- cycle diseases / Maladies du cycle NO/ONOO 19

Il existe des explications pour de nombreux symptômes et signes communs au SFC, au MCS, à la FM et au SSPT. Parmi eux, des symptômes tels que troubles du sommeil, fatigue, troubles circulatoires, du système immunitaire et même symptômes psychiatriques, tous basés sur les éléments du cycle NO/ONOO. There are explanations for many of the shared symptoms and signs of CFS, MCS, FM and PTSD. These include symptoms such as sleep changes, fatigue, changes in the circulatory system, immune system and even psychiatric symptoms, all based on NO/ONOO- cycle elements. 20

Symptom or Sign: Proposed Cause: Fatigue Peroxynitrite attack on energy metabolism Immune dysfunc- Inflamm. cytokines, oxidative stress, tion, low NK cell superoxide function Learning and Elevated brain nitric oxide, low energy memory dysfunction metabolism in brain Orthostatic intolerance Nitric oxide-mediated vasodilation and nitric oxide influence on autonomic activity. Pain (often multi- Roles for all of the elements of the NO/ Organ) ONOO- cycle Depression Inflamm. cytokines, nitric oxide 21

Symptom or sign: Proposed Cause: Anxiety Excessive NMDA activity in the amygdala region of the brain Sleep dysfunction Inflamm. cytokines; nitric oxide; NF-B Oxidative stress Peroxynitrite Abnormal SPECT Peroxynitrite-mediated oxidative stress; scans (brain) blood flow effects of nitric oxide and peroxynitrite Abnormal PET Energy metabolism effects of peroxy- scans (brain) nitrite; blood flow changes (see above) 22

However, the properties of MCS, cannot be understood solely in terms of the NO/ONOO- cycle. It is the interaction of the cycle with other mechanisms also implicated in MCS that is needed to understand MCS. Specifically, MCS needs to be interpreted also in terms of neural sensitization in regions of the brain, as proposed by Bell and others. Neural sensization is a process produced by a something called long term potentiation, a mechanism involved in learning and memory. 23

The brain-derived sensitivity symptoms in MCS have been proposed to be caused by neural sensitization by Iris Bell and others. Iris Bell et d’autres ont pensé que les symptômes d’hypersensibilité liés au cerveau étaient provoqués par une sensibilisation neurale. Neural sensitization is produced by a process known as long term potentiation. Cette sensibilisation neurale est causée par un processus appelé potentialisation à long terme. And long term potentiation involves elevated NMDA activity, as well as other NO/ONOO- cycle elements such as intracellular calcium, nitric oxide and superoxide. So you can see how increased NMDA activity leading into the cycle will trigger neural sensitization. Et la potentialisation à long terme implique une activité élevée des récepteurs NMDA ainsi que d’autres éléments du cycle NO/ONOO comme le calcium intracellulaire, l’oxyde nitrique et le superoxyde. On comprend pourquoi une augmentation de l’activité des NMDA au sein du cycle déclenchera une sensibilisation neurale. 24

Voici un schéma très simplifié d’une partie du processus. An oversimplified diagram of how some of this may play out is shown on the next slide. Voici un schéma très simplifié d’une partie du processus. 25

Cycle de sensibilisation neurale Stimulation de la libération de neurotransmetteurs (cellule présynaptique) Messager rétrograde Stimulation des NMDA (cellule postsynaptique) Appauvrissement ATP (énergie) Plus d’oxyde nitrique Plus de peroxynitrite 26

Il existe 9 mécanismes qui pourraient avoir un rôle important dans le déclenchement de l’hypersensibilité chimique dans le cadre de MCS Nitric oxide acting as a retrograde messenger, increasing NMDA stimulation. Peroxynitrite acting to decrease energy metabolism, producing increased NMDA sensitivity to stimulation. Peroxynitrite acting to decrease energy metabolism, producing less transport of glutamate, leading to increased NMDA stimulation. Peroxynitrite can nitrate a residue on the NMDA receptor, producing a permanently open channel. Peroxynitrite can also nitrate the glutamine synthetase protein leading to glutamate accumulation in the cell and in the extracellular fluid, leading to increased NMDA stimulation. Chemical action to increase NMDA activity in regions of brain where the NO/ONOO- cycle is already up-regulated due to previous chemical exposure. Nitric oxide, acting to inhibit cytochrome P450 metabolism producing slowed detoxification and therefore possible increased sensitivity to some chemicals metabolized in this way. Oxidants lead to increased TRPV1 and TRPA1 activity, leading to increased sensitivity to chemicals acting via these receptors. Peroxynitrite, producing breakdown of the blood brain barrier, leading to increased chemical access to the brain. 27

Dr. William Meggs, a physician scientist on the medical faculty in North Carolina has described studies that he and others have made showing chemical sensitivity in other regions of the body. This peripheral sensitivity occurs in the lower lungs, in the upper respiratory tract, in the skin and in the gastrointestinal (GI) tract. William Meggs, médecin chercheur à la faculté de médecine en Caroline du Nord, a décrit ses études et celles d’autres sur l’hypersensibilité chimique dans d’autres régions du corps. Cette hypersensibilité périphérique se produit dans les poumons, les voies respiratoires supérieures, au niveau de la peau et du tube gastrointestinal. Meggs and also Heuser have reported two additional mechanisms involved in these peripheral sensitivities--called neurogenic inflammation and mast cell activation. Both of these are compatible with the NO/ONOO- cycle mechanism. Meggs ainsi que Heuser ont rapporté 2 autres mécanismes impliqués dans cette hypersensibilité périphérique : l’inflammation neurogène et l’activation des mastocytes. Ils sont tous deux compatibles avec le mécanisme du cycle NO/ONOO. 28

1. Changement de l’EEG (Bell et associés) Dans un certain nombre d’études, les patients MCS répondent à une faible exposition chimique de manière mesurable : 1. Changement de l’EEG (Bell et associés) 2. Changement de la sensibilité à la toux en réponse à une faible dose de capsaïcine (Millqvist et associés). Marqueurs inflammatoires dans le sang y compris histamine et facteur de croissance nerveux (Kimata). Marqueurs inflammatoires dans le nez (nombreuses études). 5. Changement dans les tomographies à émission de positons du cerveau (Hillert). 6. Changement dans la conductivité de la peau ( Joffres). Ces changements pourraient bien être des spécificités des patients MCS et ils sont tous compatibles avec le modèle du cycle NO/ONOO. Ils devraient être considérés comme possibles “biomarqueurs spécifiques” du MCS. 29

Fibromyalgia also appears to be a NO/ONOO- cycle disease Fibromyalgia also appears to be a NO/ONOO- cycle disease. We have no time to discuss the diverse types of evidence supporting that mechanism. What I want to focus on is how the excessive pain is produced in fibromyalgia. The widespread excessive pain that is the cardinal symptom of fibromyalgia provides a major challenge for a NO/ONOO- cycle mechanism for this disease. How can such widespread excessive pain be generated by the impact of the cycle (a primarily local mechanism) on a single region of the body? After all, unlike the excessive pain seen in other, related diseases, the properties of fibromyalgia pain is that it seems to be turned on almost like a switch, over most of the body. The model that I will discuss here is that impact of the cycle on the thalamus is the cause of this widespread, excessive pain. While the thalamus is not the only part of the brain which is often impacted in fibromyalgia, it does seem to be impacted in most if not all cases. 30

Other types of evidence supporting this view include the following: Larson et al reported mast cell activation in the thalamus of fibromyalgia patients. Staud’s group and more recently the Italian Fibromyalgia Network have reported greatly increased pain processing (windup) in the dorsal horn regions of fibromyalgia patients. This interpretation of fibromyalgia pain is supported by a possible rat model of fibromyalgia (Goettl, 2002) involving reduced serotonin release in the ventrobasal thalamus, leading to increased NMDA activity and nitric oxide levels and producing widespread neuropathic pain. 32

Electromagnetic sensitivity (EMS): Three important linkages to MCS suggest a similar mechanism for EMS: 1. EMS is often comorbid with MCS, that is they often occur in the same individuals. 2. Patients with both often improve with a therapy previously used to treat MCS patients. I think that these therapies act by lowering parts of the NO/ONOO- cycle. 3. Both MCS and EMS produce high level sensitivities, suggesting a common mechanism. Because of the great importance of the NMDA receptors in the process of neural sensitization, I think it is highly likely that electromagnetic fields act at least in part by producing excessive NMDA activity in EMS, even though there is very little evidence supporting this view. . 33

Il existe 9 mécanismes qui pourraient avoir un rôle important dans le déclenchement de l’hypersensibilité chimique dans le cadre de MCS Nitric oxide acting as a retrograde messenger, increasing NMDA stimulation. Peroxynitrite acting to decrease energy metabolism, producing increased NMDA sensitivity to stimulation. Peroxynitrite acting to decrease energy metabolism, producing less transport of glutamate, leading to increased NMDA stimulation. Peroxynitrite can nitrate a residue on the NMDA receptor, producing a permanently open channel. Peroxynitrite can also nitrate the glutamine synthetase protein leading to glutamate accumulation in the cell and in the extracellular fluid, leading to increased NMDA stimulation. Chemical action to increase NMDA activity in regions of brain where the NO/ONOO- cycle is already up-regulated due to previous chemical exposure. Nitric oxide, acting to inhibit cytochrome P450 metabolism producing slowed detoxification and therefore possible increased sensitivity to some chemicals metabolized in this way. Oxidants lead to increased TRPV1 and TRPA1 activity, leading to increased sensitivity to chemicals acting via these receptors. Peroxynitrite, producing breakdown of the blood brain barrier, leading to increased chemical access to the brain. 34

I have argued for a role for the NO/ONOO- cycle, for neural sensitization and for excessive NMDA activity in EMS. What evidence do we have on any of these other than the linkages to MCS that we discussed previously? The answer is not very much. There is published evidence that electromagnetic fields can elevate levels of inflammatory cytokines, oxidative stress, nitric oxide and NMDA activity. But even this is not completely consistent. For example there is some published evidence that EMF fields can produce decreases in cytokine levels in some situations. There is evidence that EMF fields can activate the plasma membrane enzyme, NADH oxidase, an enzyme that produces superoxide as a product. So these various types of evidence are consistent with a NO/ONOO- cycle mechanism, but we still have relatively little evidence. A possible role for NADH oxidase does NOT tell us that it is a direct target of EMF fields. 35

Probable or possible NO/ONOO- cycle etiology Excessive NMDA activity In summary, then, we have a number or types of evidence and arguments that the three diseases that are the focus of this meeting have a number of important things in common: Neural sensitization Probable or possible NO/ONOO- cycle etiology Excessive NMDA activity The strongest evidence for these is for MCS and fibromyalgia, with much weaker evidence for EMS. Each of these diseases may well help us to understand the etiologic mechanism of the others and each may be useful in helping us to effectively treat the others, as well. 36 36

I have no time to talk about therapy, here, about MCS, fibromyalgia or EMS. But I want to say a few words about the principles which underlie effective therapy of all NO/ONOO- cycle diseases: 1. Avoid stressors that will up-regulate the cycle and thus make things worse - such as chemical or electrical exposure, although there are many others that may be relevant. 2. Use combinations of agents each of which lowers one or more aspects of the NO/ONOO- cycle. In other words, we need to treat the cause, not the symptoms. 37 37

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1. Tinnitus/ acouphènes 2. Post-Radiation Syndrome/ syndrome post-radiation 3. Multiple Sclerosis (MS)/ sclérose en plaques 4. Autism/ autisme 5. Overtraining Syndrome/ syndrome de surentraînement 6. Silicone Implant Associated Syndrome/ syndrome associé aux implants en silicone 7. Sudeck’s Atrophy/ atrophie de Sudeck 8. Post-Herpetic Neuralgia (Pain)/ algie post-zona 9. Chronic Whiplash Associated Disorder/ trouble associé au coup du lapin chronique 10. Amyotrophic Lateral Sclerosis (ALS)/ sclérose latérale amyotrophique 11. Parkinson’s Disease/ maladie de Parkinson 12. Alzheimer’s Disease/ maladie d’Alzheimer 13. Asthma/ asthme 14. Irritable Bowel Syndrome/ syndrome du colon irritable Suggestions d’autres maladies qui pourraient être dues au cycle NO/ONOO-, proposées dans mon livre 39

Tableau 14-1 Principaux paradigmes de la maladie 1. Maladies infectieuses 2. Maladies génétiques 3. Maladies de carence 4. Dérèglement hormonal 5. Allergies 6. Maladies auto-immunes 7. Mutation/sélection somatique (cancer) 8. Maladies cardiovasculaires ischémiques 9. Maladies amyloïdes (y compris dues au prion) 10. Maladies du cycle NO/ONOO 40