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NEURAL SENSITIZATION: THE MEDICAL KEY TO TREATMENT
INTRODUCTION
Chemically-induced reactive airway disease (upper and lower respiratory tract), and migraines have the
mechanism of neural sensitization. Respiratory effects can include sinus congestion/pain; ear pain from
eustachian tube blockage (swelling), burning/sore tongue and throat, hoarseness, bronchial symptoms of
coughing, chest tightness and sometimes wheezing, and shortness of breath/ difficulty getting enough air.
Neural sensitization also affects the gastrointestinal (sometimes called “irritable bowel”) and genital urinary
tracts (sometimes called “irritable bladder”, etc.) the blood vessel linings (endothelium), conjunctiva and
skin. Burning is a common sensation in neurogenic inflammation.
This widespread inflammation results in aching, fatigue, adrenal and other endocrine disturbance,
and resultant depletion of amino acids, minerals and other nutrients. Inflammation and the free
radicals from neural sensitization damage lipid membranes, with disproportionate damage and loss of
omega 3 essential membrane lipids, because these are very vulnerable to free radical damage. This lipid
damage impairs the brain and nerve cell coating (myelin). It also damages function of cell membranes and
membranes of mitochondria (energy production), ribosomes (which make proteins, enzymes) DNA
(genetic material), and membrane receptor sites (hormones, etc.) cell messenger sites to communicate
with other cells and body organs.
The blood vessel neurogenic inflammation causes reduced blood flow, and thus reduced supply of
oxygen and nutrients to body organs. The red blood cell is 7 microns, the capillary only 3 microns, so
inflammation reduces the blood cell’s ability to pass through. The brain is a high oxygen-demanding organ:
it is only 3% of body weight but uses 20% of body oxygen at rest. Reduced blood flow in the brain in toxic
encephalopathy is documented1 and impairs brain functions, since all body functions depend on oxygen
supply.
BIOCHEMISTRY VICIOUS CYCLE
Neural sensitization can occur by activation of brain and nerve cell N-methyl-D-aspartate (NMDA), which
then increases brain nitric oxide (NO).2,3,4 Several vicious biochemical cycles are then set in motion. Nitric
oxide forms a tissue damaging free radical known as peroxynitrite.3,5,6,7 Peroxynitrite depletes energy
ATP,8,9 which then further increases the sensitization of NMDA.10,11
Peroxynitrite is a highly potent free radical that damages proteins (including enzymes), lipids (brain and,
cell walls, mitochondrial membranes, ribosomal membranes and genetic DNA membranes).12 Antioxidants
such as tocopherols (natural Vitamin E), ascorbic acid (vitamin C), and glutathione help protect against
these effects.12, 13 Cofactors for superoxide dismutase (zinc, copper and manganese) and glutathione
peroxidase (selenium) can also protect against damage.12, 13
Neural sensitization is thus associated with self-perpetuating neuroexcitation and excessive response to
further chemical exposure.20, 14 This NMDA activation with increased nitric oxide and peroxynitrite can
cause brain cell death and neurogenerative disease.3,7,11,15,16,17 Peroxynitrite also weakens the blood-brain
barrier, allowing chemicals to enter the brain more readily.18 Nitric oxide also damages the first
detoxification step involving the cytochrome p450 system,19 allowing chemicals (and many drugs) to build
up more in the body, further perpetuating the vicious chemical inflammation (neural sensitization) cycle.
Chemical Causation
Chemical exposure can induce neural sensitization.
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
Pesticides such as organophosphates inhibit acetylcholine, activating muscarinic receptors, which
increase nitric oxide. Formaldehyde activates NMDA.2,20
Petrochemicals (VOC’s, solvents) disrupt energy production in the mitochondria, increase superoxide
which increases peroxynitrite.21 This can then increase tissue-damaging free radicals in the brain.22
Peroxynitrite impairs energy metabolism by attaching proteins in the mitochondria. 23,24 Carbon
monoxide also induces increased activity of nitric oxide and its byproducts.25 Carbon monoxide is
released in all combustion: coal, gas, gasoline/diesel, wood, tobacco, and even natural products
(beeswax and other candles) and “aromatherapy”. Mitochondria are structures in body cells that
generate energy by producing ATP. Mitochondria damage has been documented in the vast
majority of patients with chronic illness from chemical injury.26
Formaldehyde stimulates the brain vanilloid receptor.27 This receptor induces sensitization by
increasing nitric oxide and activating the NMDA receptor,28 which then increases peroxynitrite
and sets in motion neural sensitization. Vanilloid stimulation also increases release of immune
substance P.29 Increased substance P is associated with reactive airway disease.30
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Irritants. Petrochemicals and many other chemicals are irritants31 that with exposure can cause
inflammation. Inflammation of sufficient duration can lead to chronic neurogenic inflammation.32
Inflammation results in increased cytokines, free radicals and further elevated nitric oxide.
This ongoing inflammation increases artherosclerosis, increased risk of neurodegenerative (Parkinsons,
Altzeimers, ALS), and other degenerative disease (osteoporosis, arthritis, etc.) and autoimmune disease,
all of which are now known to involve chronic inflammation.
THE SCIENCE OF TREATING NEURAL SENSITIZATION
This vicious cycle MUST therefore be interrupted to the maximum extent feasible. Because the
resulting symptoms of sensitization are warnings that other more silent toxic-induced organ damage of
the liver, pancreas, immune system, adrenals, mitochondria and other organs can be also
occurring,32,33,34 masking/blocking symptoms of this cycle is not recommended without healing the
disturbed biochemical mechanism. (This would be like turning off a battery warning light without fixing
the battery.)
Hydroxycobalamine (B12) is a nitric oxide scavenger and deficient in the majority of chemically ill
patients. The cyano form is not recommended (these patients don’t need cyanide and the hydroxy and
methyl forms work much better in brain and nerve cells).
Superoxide dismutase (SOD) is deficient in a significant portion of chemically ill patients and its
cofactors, copper, zinc, and manganese must be adequate.13 These are often reduced in chemically
injured patients and should be tested and replaced in well absorbed and transported forms, for example,
picolinates. Antioxidant function is usually inadequate in chemically ill patients, 33 and increased lipid
peroxides and other free radicals are common. These damage cell structures.13
Intervention to help reduce this vicious biochemical cycle includes: hydroxycobalamine (nitric oxide
scavenger) by nebulizer and nasal for rapid action in exacerbations (not oral due to poor absorption),
general antioxidants (C, E, selenium), glutathione (with hydroxycobalamine) by nebulizer due to poor oral
absorption, and ample alpha lipoic acid and riboflavin as cofactors to reactivate the glutathione in the many
damaged lipid tissues (cell membranes, mitochondria, lymph, brain, etc.). Sublingual cobalamine is also
absorbed and effective therapy, 35 although adding to nebulizer just prior to nebulizer use works faster and
better.
Trimethyl glycine is recommended as a methyl donor to reduce the effects of peroxynitrite. Magnesium
should be ample because deficiency is very common with toxic injury and adequate magnesium decreases
NMDA activation. Peroxynitrite scavengers such as a mixture of caretenoids are also recommended.
Caretenoids tend to be more organ-specific. An inclusion of gingko (brain), silimarin (liver), bilberry
(collagen stabilizing, capillary permeability, vision), cranberry (urinary) and other mixed caretenoids is
recommended.
Mineral levels should be measured and followed by intracellular (eg. RBC) or lipid functional (eg.
lymphocyte mitogenesis, a SpectraCell technology). Functional lymphocyte evaluation and follow-up of
glutathione, lipoic acid, total antioxidant function, C, E and zinc is also recommended. At this time this
technology is only available through SpectraCell laboratory.
Nasal hydroxycobalamine is rapidly absorbed, well tolerated,36,37 and increases body levels.37 Nasal
hydroxycobalamine is also effective in reducing frequency and severity of migraines, acting as a nitric oxide
scavenger.38
Alpha lipoic acid is a potent and lipophilic antioxidant, which protects lipid membranes 39 of cells, cell
structures (including the energy-generating mitochondria) and myelin.39 It has been used in Germany for
decades to treat neuropathy.40 Magnesium acts as a blocker of the NMDA nerve receptor, thus reducing
neuropathic pain and its resultant inflammation.41 Bilberry is a potent flavinoid antioxidant that reduces
capillary fragility and permeability42 and improves damaged neurologic function.43
REACTIVATION OF GLUTATHIONE
Glutathione is the most important intracellular antioxidant and detoxifying agent in the body.13
Glutathione is essential to reduce chemical damage to cell membranes. DNA, energy generating
structures (mitochondria) and cell substances.13 Thus, improving glutathione levels in the mid and
lower respiratory tract can help reduce respiratory responses to irritants and help to reduce the
severity and duration of the patient's reactions. A nasal form of glutathione may be used for
reactions that harm brain function. A glutathione nasal spray has also reduced symptoms in people
with chronic rhinitis.44 There is no blood- brain barrier between the nose and the brain.45 Scientific
studies document that substances being breathed into the nose directly enter the brain.46
Glutathione can also be absorbed through the lungs (delivered to the lungs as an aerosol) and
seems able to cross the blood- brain barrier.47 It is thus effectively delivered by nebulizer, avoiding
need of IV/injection use.48
Nebulizer technology is developing to allow rapid efficient delivery without noticeable noise or
vibration, eg AeronebGo (www.evomedical.com) available near cost through Key Pharmacy 800878-1322. The AeronebGo is polycarbonate: thus durable with minimal off gassing. It is small,
easily portable, and has a small battery pack (eg for travel) and separate plug in for electric outlets.
None of the above is a substitute for exposure controls at home, work and/or school: places where the
person spends most of their time. Humans are social beings, and these measures above gradually increase
the person’s ability to enjoy the company of others and use public places. When society is adequately
informed and takes public health reasonable accommodation measures to reduce irritants and toxins in
personal products and public places, this further promotes health and reduces sensitization.
Neural Sensitization Cycle
Carbon Monoxide
Solvents, VOC’s
Formaldehyde,
Pesticides
(Organophosphates, Carbamates)
Isocyanates
NMDA
RECEPTOR
SOD
Superoxide
NITRIC
OXIDE
Peroxynitrite
Tissue Injury Inflammation
Respiratory, GI, GU,
endothelial, skin)
1
P Gregersen, “Chronic Toxic Encephalopathy in Solvent-exposed Painters in Denmark 19761980: Clinical cases and social consequences after a 5-year follow-up”, Am J of Ind Med , 11:
399-417, 1987.
JE Haley etal., “Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical
nociception in the rat”, Brain Res 518:218-226, 1990.
3
M Lafon-Cazal etal., “Nitric oxide, superoxide and peroxynitrite: putative mediation of NMDA-induced
cell death in cerebellar cells”, Neuropharmacology 32:1259-1266, 1999.
4
IJ Reynolds and TG Hastings, “Glutamate produces production of reactive oxygen species in cultured
forebrain neurons following NMDA receptor activation”, J. Neurosci 15:3318-3327, 1995.
5
JS Beckman, “The double edged role of nitric oxide in brain function and superoxide-mediated injury”, J.
Dev Physiol 15:53-59, 1991.
6
M Lafon-Cazal etal., “NMDA-dependent superoxide production and neurotoxicity”, Nature 364:535-537,
1993.
7
JT Coyle and P Puttfarken, “Oxidative stress, glutamate and neuro generative disorders”, Science
262:689-695, 1993.
8
JS Beckman and JP Crow, “Pathologic implications of nitric oxide, superoxide and peroxynitrite
formation”, Biochem Soc Trans 21:330-333, 1993.
9
WA Pryor and GL Squadrito, “The chemistry of peroxynitrite: a product of the reaction of nitric oxide
and superoxide”, Am J. Physiol 268:L699-L722, 1995.
10
A Novelli etal., “Glutamate becomes neurotoxic via the NMDA receptor when intracellular energy levels
become reduced”, Brain Res 451:205-212, 1988.
11
JB Schultz etal., “The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of
neurodegenerative diseases”, Mol Cell Biochem 174:171-184, 1997.
12
AY Sun YM Chen, “Oxidative stress and neurodegenerative disorders”, J Biomed Sci, 5: 401-14, 1998.
13
CD Klassen, editor Cassarett and Doull’s Toxicology: The Basic Science of Poisons, McGraw Hill, New
York, NY, 2001.
14
WD Willis, Role of neurotransmitters in sensitization of pain responses,” Ann NY Acad Sci 933;175184, 2001.
15
A Doble, “NMDA and neurodegenerative conditions (reviews)”, Pharmacol Ther 81:163-221, 1999.
16
VL Dawson and TM Dawson, “Nitric oxide neurotoxicity”, J Chem Neuroanat 10:179-190, 1996.
17
BC Albenzi, “Models of brain injury and alterations in synaptic neuroplasticity”, J. Neurosci Res
65:279-283, 2001.
18
WG Mayhan, “Nitric oxide donor-induced increase in permeability of the blood-brain barrier”, Brain Res
866;101-108, 2000.
19
OG Khatsenko etal., “Nitric oxide is a mediator of the decrease in cytochrome p450-dependent
metabolism caused by immunostimulants”, Proc Nat Acad Sci USA 90:11147-11151, 1993.
20
SB McMahon etal., “Central excitability triggered by noxious inputs”, Current Opin Neurobiol 3:602610, 1993.
21
TR Garbe and H Yukama, “Common solvent toxicity: auto oxidation of respiratory redox-cyclers
enforced by membrane derangement”, Z Natur forsch 56:483-491, 2001.
22
CJ Mattia etal., “Toluene-induced oxidative stress in several brain regions and other organs”, Mol Chem
Neurophysiol 18:313-328, 1993.
23
JS Bechman and JP Crow, “Pathological implications of nitric oxide, superoxide and peroxynitrite
function”, Biochem Soc Trans 21: 330-334, 1993.
24
WA Pryor and G Squadrito, “The chemistry of peroxynitrite: a product of the reaction of nitric oxide and
superoxide”, Am J Physiol 268:L 699-L722, 1995.
25
A Verma, etal., “Carbonless Monoxide: A Putative Neural Messenger”, Science 259: 381-384, 1993.
2
26
G Ziem, “Profile of patients with chemical injury and sensitivity”, Int J Toxicol 18:401-409.
A Beiruth etal, “Spinal and supraspinal antinociceptive action of dipyrone in formalin, capsaicin and
glutamate tests. Study of the mechanism of action, “Env J Pharmacol 345: 233-245, 1998.
28
E Palazzo etal, “Interaction between vanilloid and glutamate receptors in the central modulation of
nociception:, Env J Pharmacol 439- 69-75, 2002.
29
H Kimata etal, “Effect of exposure to volatile organic compounds on plasma levels of neuropeptides,
nerve growth factor and histamine in patients with chemical sensitivity”, Int J Hyg Environ Health 15963, 2004.
30
WJ Meggs, “The toxic induction of asthma and rhinitis”, Clinical Toxicol 32: 487-501, 1994.
31
RE Lenga, Ed., Sigma-Aldrich Library of Chemical Safety Data. Sigma-Aldrich Corp, 1988.
32
GE Ziem, “Evaluation and Treatment of Patients with Chemical Injury and Sensitivity” presented to a
conference sponsored by the National Institute of Environmental Health Sciences, August 2001.
33
GE Ziem, “Profile of Patients with Chemical Injury and Sensitivity”, Int J Toxicol 18:401-409, 1999.
34
GE Ziem, Invited presentation: Endocrine changes in Patients with Chronic Illness Following Chemical
Overexposure.
35
G Delpre etal, Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral
cobalamin supplementation”. The Lancet Vol 354, Aug. 28, 1999.
36
D Z van Asselt etal., “Nasal absorption of hydroxycobalamine in healthy elderly adults”, Brit J Pharmacol
45: 83-86, 1998.
37
W B Slot, etal., “Normalization of plasma vitamin B12 by intranasal hydroxycobalamine in vitamin B12
deficient patients”, Gastroenterology 113: 430-433, 1997.
38
P H van der Kuy etal., “Hydroxycobalamine, a nitric oxide scavenger in the prophylaxis of migraine”,
Cephalgia 22: 513-519, 2002.
39
T Konrad etal, “Alpha-lipoic acid decreases serum lactate and pyruate and improves glucose
effectiveness in lean and obese patients with type 2 diabetes”, Diabetes Care 22: 280-287, 1999.
40
D Ziegler etal, Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current
evidence from clinical trials”, Exp Clin Endocrinol Diabetes 107: 421-430, 1999.
41
M Jones, “Chronic neuropathic pain: pharmacological in the new millennium”, Internat J.
Pharmaceurical Compounding, Jan-Feb 2000.
42
F Cohen-Boulakia et al, “In vivo sequential study of skeletal muscle capillary fragility in diabetic rats:
effects of anthocyanosides”. Metabolism 49: 880-885, 2000.
43
M Perossini etal, “Diabetic and hypertensive retinopathy therapy with vaccinium myrtillus
anthocyanosides: a double blind, placebo-controlled trial”, Ann Ofthalm Clin Ocul 113: 1173-1190,
1987.
27
44
Testa B, Mesolella M, Testa D. Glutathione in the upper respiratory tract. Ann Otol Rhinol Laryngol
1995;101:117-9.
45
Principals of Neurotoxicity Risk Assessment, US EPA, Fed Reg Aug 17, 1994.
P Gregersen, “Chronic Toxic Encephalopathy in Solvent-exposed Painters in Denmark 1976-1980:
Clinical cases and social consequences after a 5-year follow-up”, Am J of Ind Med , 11: 399-417, 1987.
46
47
R Buhl, etal. Oxidant-protease interaction in the lung. Prospects for anti oxidant therapy. Chest
110:267S-272S, 1996.