Cofactors for neurotransmitters

Tourette Syndrome, B6 dependency, allergy BonnieGr bonniegr at aol.com Thu Feb 8 13:19:55 EST 1996 I have been putting the puzzle pieces together on the subject of Tourette Syndrome, using medline documents, college textbooks, etc. Please read the following long rationale document that I have prepared, and comment by e-mail (BonnieGr at aol.com). It is my hope that more research will be done to validate my theory. Enjoy! The following addresses TS/OCD/ADD. The diagnosis would lie in the degree of vitamin B6 dependency/deficiency, and how long the person has been in this state. Carl Hansen, Jr. M.D. of Minneapolis describes celiac disease in several of his TS patients. This could be a pathway to vitamin B6 deficiency via malabsorption. Streptococcal infections have also been associated with TS. This could be a combination of the hyaluronidase's (an enzyme produced by the hemolytic strep that depolymerizes the ground substance of tissue) or streptokinase's actions on the blood brain barrier, the drain of vitamin B6 from the bacteria's own useage, the body's requirement of B6 for immunity, and the antibiotic's B6 antagonistic properties. A pre-exising B6 dependency/deficiency could be uncovered. TOURETTE SYNDROME, ALLERGY AND THE B6 DEPENDENCY STATE I have my Bachelor's degree in Biology, specializing in Medical Technology, and in graduate school, I took graduate courses in biochemistry. I work as a medical technologist performing and verifying clinical laboratory tests in Chemistry, Hematology and Blood Bank at Mt.Carmel East Medical Center in Columbus, Ohio. I do not have TS but my son, Jason (13 yrs old) has TS with OCD. ADD has not been formally diagnosed, although he has problems with organization, distractibility, and the ability to switch gears. My son has had allergies since he was a baby. He is sensitive to red dye #40 with tired splitting headaches which make him scream until he is exhausted and sleeps. This, of course, hasn't happened in several years since he has avoided the dye. He also is allergic to sulfa, molds, dust, grass, trees, and most airborn allergens. He has been on the vitamins below for 1.5 months and the teachers have said that he is a different kid. Medications that he had been on made him progressively worse, and so we made a personal decision to discontinue meds altogether. He now is motivated in school, concentrates and finishes his work, and is less disruptive with his tics in class. At home he still has his tics and compulsions, but they are shorter lived and occur less often. He has had a set back this week due to a new semester with a new schedule, plus a very moldy, rainy few days. We gave him a little extra calcium-magnesium and one extra vitamin B3. He said that this gave him relief from his symptoms (he has never said this before with anything else). I solidified my theory on the premise that Jason is probably mildly vitamin B6 dependent. He was either born requiring high amounts of B6, and/or B6 antagonists attacked early in his first year of life. B6 antagonists are hydrazines (plant growth regulators, tartrazine, etc), DOPA found in certain beans, penicillinamine, antioxidants in petroleum, many drugs including penicillin, erythromycin, phenobarbital, tetracycline, corticosteroids, sulfamethoxazole, etc. Amino acids began building up in his system, from decreased transamination, etc. Serotonin became decreased from tryptophan not being able to be utilized. Allergies developed (which is in association with low B6), I believe allergy produces swings in histamine levels which causes a constant fluctuation in neurotransmitters capable of producing mood swings and rages. The conservation of vitamin B6 (when not abundantly available) causes it to be used by the prevailing neurotransmitter system at any given time, leaving other neurotransmitter systems less than optimally functional. Histamine receptors have been found to trigger dopamine receptors directly. Histamine is also a neurotransmitter affected by deficient vitamin B6. Its receptor sites are probably increased to compensate. Kinins released into the body's tissues in response to immune complexes can damage the blood brain barrier, thus altering the sensitivity of brain cells to acetylcholine, serotonin, dopamine, histamine, epinephrine and norepinephrine. I found that L-dopa doesn't readily form dopamine in B6 deficiency, so probably dopamine is reduced causing an increase in dopamine receptor sites along with an increase the norepinephrine and epinephrine (which are formed from dopamine) receptors sites. These increased receptor sites make the nerves more excitable and false transmitters or true neurotransmitters can set them off with explosive qualities. These false transmitters can be phenolic substances, such as food additives, drugs, etc. The enzyme, phenol sulfotransferase (PST), detoxifies and eliminates phenolics (drugs, food additives, serotonin, dopamine (to name a few). In the brain, sulfation is used while glucuronidation prevails elsewhere. Cysteine requires B6 to enzymatically release sulfur for sulfation of these phenols by PST. Considering this, the neurotransmitters would would be conserved to a certain extent (their sulfation and elimination would be slowed down). ADD may happen when these false transmitters create background "noise", and if there is a real message to get through via other neurons, it is masked. When a true message is fired, it may have too strong of a signal, creating a strong impulsion, which can lead to the development of a tic or compulsion if the impulsion is acted upon and repeated creating a sort of conditioned reflex network of nerves. Mental, motor, and vocal tics can develop this way. According to my_ Biochemistry_ by Lehninger textbook from my graduate student in Biology days, tryptophan is broken down in Vitamin B3 deficiency to make nicotinic acid. Tryptophan is found in meat and is plentiful, if you are a meat eater. Tryptophan is the precursor for serotonin. I also looked up Vitamin B3 and how it could be connected to the issues of allergy and serotonin defiency in the brain. I found that Vitamin B3 is used to make NAD, NADP, which are coenzymes used in making histamine and serotonin (to name a few), and are essential in oxidative-reductive cellular metabolism. The B3 is needed due to tryptophan's inability to be broken down to nicotinic acid without adequate B6. So, if Vitamins B3 and B6 are being used for histamine production, then serotonin production suffers. Tryptophan then must be used in a higher frequency to make nicotinic acid. In Vitamin B6 deficiency, this cannot happen, because the enzyme kynurinase, that catalyzes the cleavage of 3 hydroxykynurine (an intermediate in tryptophan catabolism), contains pyridoxal phosphate (an active coenzyme form of Vitamin B6). In Vitamin B6 deficiency, large amounts of L-kynurenine are excreted in the urine, because of its high plasma levels. This is described in "Elevated plasma kynurenine in Tourette syndrome", _Molecular & Chemical Neuropathology_21(1): 55-60,1994 Jan. Kynurenine itself is metabolised to other substances, several of which are known to have effects on neurones. (per a research study done at University College London Medical School Harlow, England by Sheila L. Handley, BPharm, Ph.D. 1994) Large amounts of tryptophan which is broken down to ineffectively try to produce nicotinic acid reduces the amount of serotonin produced. Ineffective tryptophan utilization also uses alot of oxygen with tryptophan 2,3-dioxygenase. Low serotonin levels could cause obsessive compulsive behaviour, depression, and other mood related disorders. B6 is also required for the decarboxylase step of serotonin, histamine, and catecholamine pathways in the brain. In low B6, conservation takes place, so that B6 is used for fewer enzymes. When allergy strikes, the production of histamine causes a further imbalance of neurotransmitters, causing serotonin and/or catecholamine production to be further depleted. Sherry A Rogers, M.D., a specialist in environmental medicine, reports that all of the TS cases she has seen have a least one nutrient deficiency, and usually several. And she notes that all of these patients have hidden mold, dust, chemical and food sensitivities. ("Tourette Syndrome", _Health Counselor_, Vol.7, No.4) Acetylcholine is produced by acetyl CoA and choline. The choline is supplied through lecithin in Jason's supplements. In vitamin B6 deficiency, acetyl CoA would be made by fatty acid oxidation. So acetycholine could be functional with an adequate supply of fatty acids (evening primrose oil or flax oil might be useful). Acetylcholine could be in shorter supply in the parasympathetic system (relaxation) due to overuse in the sympathetic system where norepinephrine usually rules. The parasympathetic nervous system would need to have more acetylcholine in TS and associated disorders, it seems. Relaxation through the parasympathetic nervous system (which uses acetylcholine), where the heart rate is slowed, the blood pressure is lowered, the food is digested well, etc. is difficult in TS. Acetylcholine is probably overactive in the sympathetic autonomic nervous system, trying to stimulate the low supply of catecholamines, which would be decreased due to B6 deficiency/dependency. The receptors sites for catecholamines would be hyperexcitable and increased in number. The net usage of catecholamines could be normal to decreased due to increased stimulation by acetylcholine, depending on the availability of B6 in the body, and the conservation by low sulfation by PST. Conditions of emotional stress are known to produce more ticcing in TS. In short term stress, norepineprine, dopamine, and epineprine should be able to be produced by the conservation tactics of the body, but in long term stress, these would be exhausted, especially when another B6 dependent system is triggered. Likewise, the same would happen when histamine and serotonin are produced in short term and long term allergy. But as you might expect, the short term conditions would be explosive events with all of those increased receptor sites! Acetylcholine is also involved in the contraction of voluntary muscle cells and many other motor nerves, which are in heavy use in TS. Many people with TS are helped by exercise, where cardiac output and increased body temperature over a period of time inhibit the sympathetic nervous system. It may also help to clear toxic waste, such as kynurenine. Adequate water intake would be required to catabolize acetylcholine by cholinesterase. In my opinion acetylcholine is needed in B6 deficiency/dependency to run the nervous system. Fatty acids are essential to its success in this situation. Fatty acids require NADPH2, and NADH2 for their synthesis, and thus Vitamin B3. Water is also an utmost requirement in keeping acetylcholine from becoming a continuous firecracker. Jason has a water bottle close by most times and drinks tons of water. Water has always calmed him down. It may also dilute the kynurenine, excess amino acids and promote their excretion. If you look at the material written on the Canadian Mennonite families that have been studied with Tourette's disorder, you will see a high frequency of autoimmune and rare conditions. These findings are consistent with what one can expect with other Tourette's patients. For example, there is a high frequency of allergic conditions. My informal survey of TS and allergy results from the online TS support group are: With a total of 25 respondents with TS: 96% have allergies (24 out of 25) 56% have mold allergies 72% have obsessive complulsive traits (18 out of 25) 67% of those with obsessive compulsive traits have mold allergies 3 respondents thought they may have mold allergies, but weren't sure 52% have pollen allergies (ragweed, grass, tree, etc) 56% of those with obsessive compulsive traits have pollen allergy 48 % have animal allergies (cats, dogs, horse) 39% of those with obsessive compulsive traits have animal allergies 40% have dust allergy 39% of those with obsessive compulsive traits have dust allergy 20% have penicillin allergy 28 % of those with obsessive compulsive traits have penicillin allergy 20 % have miscellaneous allergies 11% of those with obsessive compulsive traits have miscellaneous allergies 16 % have food allergies 22 % of those with obsessive complulsive traits have food allergies 8% have sulfa allergy 11% of those with obsessive compulsive traits have sulfa allergy All of our frequent posters responded. The types of allergies are typically respiratory and airborne. Molds and pollens are the top allergens. 79% of the people with mold allergies also had pollen allergies, which are seasonal. Bonnie Grimaldi, BSMT (ASCP) 11283 Meadowcroft St. Pickerington, Ohio 43147 (614) 837-7545