heres a article dr. michale colgan ( famous nutritionist ) aslo author of famous book optmium sports nutrition , sent me about nitric oxide ( i ask him his feeling on this )
I chose this topic as I have been getting a lot of questions about nitric oxide, so I thought everyone might like to know the real chemistry. There are several l-arginine products on the market claiming to raise nitric oxide levels. This is not really something you want to do if you want to preserve your brain. However, taking l-arginine supplements does not dramatically increase nitric oxide, despite the marketing hype, because the body has built-in controls. If it didnít, every time you ate some protein food high in l-arginine, your bodyís chemistry would be out of control.
Nitric oxide is one of the many gaseous chemicals in the human body, which attest to the old jibe that we are full of hot air. It is manufactured by an enzyme called nitric oxide synthase, which turns the amino acid L-arginine into citrulline and nitric oxide, both of which serve multiple bodily functions. Throughout the brain, nitric oxide is an essential chemical messenger, which improves communication between neurons, release of neurotransmitters, and transmission and storage of information.1,2
Nitric oxide is also a free radical, what is called a reactive nitrogen species (RNS), but is relatively benign.1,3 Like many other biochemicals, however, it can multiply out of control. Then it cooks your brain. It happens like this. Various stressors, such as banging your head against a brick wall, cause certain defensive genes to turn on and cause the brain to manufacture pro-inflammatory gremlins called cytokines. These nasty little beggars stimulate the glial cells to produce large amounts of the inducible form of the enzyme nitric oxide synthase. The enzyme then gobbles up all the spare L-arginine and produces a ton of nitric oxide, which overwhelms other control chemicals and causes raging inflammation. Result: damaged brain cells all around.
If you bang your head ve-r-r-r-y carefully against a brick wall for years on end, as some martial artists do, then, after a while, the defensive genes continue to sleep through it, and no inflammation occurs. So you can take severe blows to the head without much damage. At least thatís the theory. Donít try this at home.
By Thought Alone
You donít need a wall or any other blunt object to cause brain damage. A typical brain stressor common to modern urban life, is the automatic fear and anger reaction at a near miss on the freeway. The wise realize they are unhurt, calm down immediately, and move back to the real purpose of life, a state of joyful ease. Those who let their emotions balloon into ďroad rage,Ē however, irreversibly damage their own brains.
Numerous animal studies show that fearful and angry thoughts readily cause brain damage, by the same process that occurs with the physical damage from banging your head on a wall. In a new study, representative of the evidence, De Cristobal and colleagues at Universidad Complutense, Madrid, restrained rats, but did not physically harm them. The rats went ballistic with fear and rage, and severely damaged their brains by excess production of nitric oxide.4
Being dumb animals, rats could not understand what was going on. Being not quite so dumb, we know that fear and anger do not exist in any object or situation, but are creations of our own consciousness. Thus, in any event where no physical harm occurs, we always have the choice to avoid negative emotions. By now gentle reader you are coming to appreciate, that by lifestyle choices alone, even your choice of thoughts, you can profoundly influence gene expression, and either protect or endanger the physical structure of your brain.
Air pollution provides a good example of a physical brain stressor just as damaging as a brick wall, yet unfelt and invisible. It is also impossible to avoid in urban life. In a typical recent study by the Toxicology Department of the University of North Carolina, researchers measured the brains of new-born dogs exposed to the air pollution of Mexico City, and compared them with dogs living in an unpolluted area. The dogs living in polluted air, showed large increases in the enzyme nitric oxide synthase, with a consequent cascade of events that damaged neurons throughout the brain. They also showed deposition of plaque and neurofibrillary tangles, and increased apoptosis (cell death), very like those found in Alzheimerís disease.5
Highly polluted cities such as Los Angeles, New York or Toronto produce similar brain damage in everyone who lives there. I have urged readers in previous books to arrange their lives so as to flee the city, to protect their health against cancer and cardiovascular disease. The new discoveries of unavoidable urban sources of brain damage, give you even more reason for doing so.
The Glutamate Ė Nitric Oxide Link
Fear, anger and air pollution, also damage the mitochondria and reduce the supply of ATP.2,4,5 The protective electric fences around outer cell membranes lose power, and unwanted substances leak into the cell. Particularly opportunistic is the neurotransmitter glutamate, responsible for fast, excitatory neural transmission, just the sort of brain activity that increases in fear and anger situations. Glutamate attacks what is called the n-methyl-d-aspartate (NMDA) receptors on neurons, making a sort of hole through which calcium and other nasties can leak into the cell.2
Calcium is very nasty when it gets into the wrong place, as anyone who has had a heel spur or a calcified artery can attest. In brain cells it converts an enzyme called xanthine dehydrogenase to xanthine oxidase, a process which produces a mass of superoxide free radicals.6,7 Then all hell breaks loose. The excess nitric oxide already being produced by the brain stressor, combines with the superoxide to make the extremely damaging free radical peroxynitrite (0N00-).6,7 Peroxynitrite damages mitochondria, DNA, other proteins in brain cells and any other tissues that get in its way.6,8
Some of these clues come from recent research on the brain damage caused by drugs such as methamphetamine, damage that is very like early Alzheimerís. In a representative study, Imam and colleagues at the US National Center for Toxicological Research, in Jefferson, Arkansas, showed that peroxynitrite is the major culprit.8 With every step of evidence, science is tying the brain damage caused by a wide variety of stressors to the major forms of dementia.
Links To Alzheimerís
Cholinergic neurons in the hippocampus of our basal forebrain, express the neurotransmitter acetylcholine. These cells are more primitive in evolution than cholinergic cells in the cerebral cortex. They evolved in the brains of short-lived, ferocious animals, and are designed for shorter, more violent life than those in the cerebral cortex. They have higher levels of nitric oxide, to speed neural transmission for violent action, and lower levels of endogenous antioxidants, because they did not have to last very long. So they are more vulnerable to damage, and are the first to go in neurodegeneration.
It is exactly these hippocampus structures that show the most damage in Alzheimerís disease, with large numbers of dead and dying cells, amyloid plaque blocking neural transmission, damage to mitochondrial DNA, and useless tangles of neurofibrils.9 In cell culture studies, the amyloid plaque itself causes further release of nitric oxide, thereby creating a vicious and progressive cycle of damage.10 Alzheimerís patients also have increased brain levels of inflammatory cytokines, which as we saw above, increase production of nitric oxide even further.11
Links To Other Dementias
03-25-2005, 05:28 PM #1
Nitric Oxide Dangers ... a must read
03-25-2005, 05:29 PM #2
Similar mechanisms have now been found in multiple sclerosis. Inflammatory cytokines stimulate glial cells to produce nitric oxide by way of the enzyme nitric oxide synthase, which then increases peroxynitrite to cause extensive mitochondrial damage.12 Bagastra and colleagues at Thomas Jefferson University, recently found excess levels of nitric oxide synthase in every one of the brains of deceased multiple sclerosis patients, but in none of the control brains of people who had died without brain disease.13 Induced Parkinsonís disease in animals in which the substantia nigra cells are deliberately damaged, shows the same pattern of enzyme activation.14 So does Huntingtonís disease.15
Stroke patients also show large increases in inflammatory cytokines and nitric oxide synthase, even up to three months after the stroke.16 Cerebral ischemia (restriction of blood supply) is also related to excessive glutamate stimulation of the NMDA receptor, with elevation of intracellular calcium and induction of nitric oxide synthase, which then raises nitric oxide levels.7
There are now hundreds of similar studies in the medical literature. In a major review of the research in October 2000, renowned expert on brain chemistry, Vittorio Calabrese, of the University of Catana in Italy, shows how this process occurs repeatedly with the stresses of usual urban life. He also reviews numerous other studies, showing that damage caused by excess nitric oxide is crucially involved in Alzheimerís, Parkinsonís, Lou Gehrigís disease (amyotrophic lateral sclerosis, ALS) Huntingtonís disease and multiple sclerosis.1 Other researchers have shown that the same process of damage is a major determinant of the dementia caused by stroke, and by other forms of oxygen deprivation of the brain, and of various forms of brain seizure.15,16 Finally, the same process is implicated in common forms of epilepsy.17
Overall, the evidence shows that the brain degeneration caused in almost every one of us by excess nitric oxide, is also a major part of all common dementias, stroke and even epilepsy. I have covered only a fraction of these new discoveries in this short chapter, but I hope it is a representative and convincing fraction. If you fail to protect the brain from excess nitric oxide, then all other efforts to maintain your intelligence will come to naught.
03-25-2005, 05:32 PM #3
Protecting Yourself from Nitric Oxide
The discovery that excess nitric oxide is a major cause of the brain damage of usual aging, and of all major neurodegenerative diseases, has pharmaceutical companies scrabbling like rats up a curtain, to be first to market with drugs that inhibit nitric oxide synthase, the enzyme that makes nitric oxide in your body. To formulate these drugs, and to prove that they work, researchers have to give animals poisons that damage their brains in similar ways to the damage found in Alzheimerís, Parkinsonís and other diseases.
One particular toxin that produces the same brain damage in the substantia nigra, and the same symptom as Parkinsonís, is methyl-phenyl-tetrahydropyradine (MPTP). This poison works in two major ways. First, it increases nitric oxide production. Second, it reduces ATP production by the mitochondria, thereby reducing power to the electric fences protecting brain cells and their receptors. The neurotransmitter glutamate then attacks the NMDA receptor, allowing calcium to leak into the cell and produce the superoxide free radical. Superoxide then combines with nitric oxide to make the free radical peroxynitrite. This Satan of free radicals promptly kills large numbers of cells in the substantia nigra, causing irreversible tremor, weakness, and loss of muscle, and eventually dementia.
From numerous animal studies over the last five years, we know that anything which inhibits nitric oxide synthase can stop this whole scenario. In a typical study, baboons were given the nitric oxide synthase inhibitor 7-nitroindazole. When subsequently given the poison MPTP, they were completely protected against cell death in the substantia nigra, and showed no physical symptoms of Parkinsonís.18 7-nitroindazole is not yet commercially available, and has some nasty side-effects. But simpler, non-toxic substances work equally well. Genistein, extracted from soybeans, specifically inhibits nitric oxide production.19 Genistein is also neuroprotective in mouse models of Lou Gehrigís disease (amyotrophic lateral sclerosis), and stroke, and in protecting post-menopausal women from Alzhiemerís.20,21
Another inexpensive, non-toxic chemical that strongly inhibits nitric oxide synthase is allicin, extracted from garlic. In the latest study, Schwartz and colleagues at Tel Aviv Sourasky Medical Center in Israel, show that allicin also inhibits the transport of arginine, from which nitric oxide is manufactured. So this simple herbal offers double-whammy brain protection.22
A third non-toxic herbal that regulates nitric oxide levels is ginkgo. In animal experiments, ginkgo effectively prevents the changes in nitric oxide levels caused by induced brain trauma, such as subarachnoid hemorrhage.23 In studies of Alzheimerís patients, gingko stabilizes, and in less severe cases, improves cognitive performance.24
The final herbal I want to include in this chapter is the known liver protective agent Silymarin (milk thistle extract). It does not inhibit nitric oxide production, but can indirectly stop nitric oxide turning into peroxynitrite. Silymarin specifically inhibits production of the enzyme xanthine oxidase which, as a side-effect, produces the superoxide radical, the other half of peroxynitrite.25
One of the so-called smart drugs, aminoguanidine, is also an inhibitor of nitric oxide synthase. This chemical has low toxicity and is now being tried against multiple sclerosis. In the mouse model of multiple sclerosis called, encephalomyelitis, aminoguanidine suppresses nitric oxide production very effectively and reduces the disease.26
Then there is aspirin. For the last 18 years most clients of the Colgan Institute over age 35, have been taking a baby aspirin each day to inhibit platelet aggregation and clot formation, and prevent heart attacks. Little did they know that they are also protecting their brains. Recent animal studies show that small amounts of aspirin, the equivalent in humans of one adult aspirin per day (325 mg), effectively prevent the rise in nitric oxide which occurs in response to fear and anger caused by stressors such as immobilization.4
Another non-toxic substance that inhibits the excess nitric oxide scenario, is the omega-3 fat, docosohexaenoic acid (DHA) in fish oil. This nutrient works by inhibiting release of inflammatory cytokines that trigger nitric oxide production by brain glial cells.27
Thus we have an arsenal of substances with virtually no toxicity which can stop nitric oxide running amok in the brain, genistein, allicin, gingko, silymarin, aminoguanidine, aspirin, and docosohexaenoic acid. Make sure that you only take these in conjunction with a good multiple vitamin and mineral program.
You need to add to these supplements by fleeing the city and its stressors. You also need to program your mind, as detailed in a chapter ahead, to eliminate negative emotions. Follow these steps plus the strategies in previous chapters, and your brain will likely be good for more than a hundred years.
1. Calabrese V, et al. NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: the role of oxidant/antioxidant balance. Neurochem Res, 2000;25:1315-1341.
2. Bashkatova VG, Rayevsky KS. Nitric oxide in mechanisms of brain damage induced by neurotoxic effect of glutamate. Biochemistry, 1998;63:866-873.
3. Iadecola C, Alexander M. Cerebral ischemia and inflammation. Curr Opin Neurol, 2001;14:89-94.
4. De Cristobal J, et al. Aspirin inhibits stress-induced increase in plasma glutamate, brain oxidative damage and ATP fall in rats. Neuroreport, 2002;13:217-221.
5. Calderon-Garciduenas L, et al. Air pollution and brain damage. Toxicol Pathol, 2002;30:373-389.
6. Beckman JS. The double role of nitric oxide in brain function and superoxide mediated injury. J Dev Physiol, 1991;15:53-59.
7. Chan PH, et al. SOD-1 transgenic mice as a model for studies of neuroprotection in stroke and brain trauma. Ann N Y Acad Sci, 1994;738:97-103.
8. Imam SZ, et al. Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage. Ann N Y Acad Sci, 2000;914:157-171.
9. Sugaya K. Glial activation and brain aging. Nippon Yakurigaku Zasshi, 2001;118:251-257.
10. Goodwin H, et al. Microglial release of nitric oxide by the synergistic action of beta amyloid and INF-gamma. Brain Res, 1995;692:207-214.
11. Tarkowski E, et al. Intrathecal release of nitric oxide in Alzheimerís disease and vascular dementia. Dement Geriatr Cogn Disord, 2000;11:322-326.
12. Heales SJ, et al. Nitric oxide, mitochondria and neurological disease. Biochim Biophys Acta, 1999;1410:215-228.
13. Bagastra G, et al. Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Nat Acad Sci, USA, 1995;92:12041-12045.
14. Wu DC, et al. Blockade of microglial activation is neuroprotective in the l-methyl-4-phenyl-1,2,3,6-tetrahydopyridine mouse model of Parkinson disease. J Neurosci, 2002;22:1763-1771.
15. Beal MF. Mitochondria, NO and neurodegeneration. Biochem Soc Symp, 1999;66:43-54.
16. Tarkowski E, et al. Intrathecal release of nitric oxide and its relation to final brain damage in patients with stroke. Cerebrovasc Dis, 2000;10:200-206.
17. Raevskii KS, et al. The role of nitric oxide in brain glutaminergic pathology. Vestn Ross Akad Med Nauk, 2000;(4):11-15.
18. Hantraye P, et al. Inhibition of neuronal nitric oxide synthase prevents MPTP-induced Parkinsonism in baboons. Nat Med, 1996;2:1017-1021.
19. Sheu F, et al. Suppression effect of soy isoflavones on nitric oxide production in RAW 264.7 macrophages. J Agric Food Chem, 2001;49:1767-1772.
20. Trieu VN, Uckun FM. Genistein is neuroprotective in murine models of familial amytrophic lateral sclerosis and stroke. Biochem Biophys Res Commun, 1999;258:685-688.
21. Kim H, et al. Attenuation of neurodegeneration-relevant modifications of brain proteins by dietary soy. Biofactors, 2000;12:243-250.
22. Schwartz IF, et al. Garlic attenuates nitric oxide production in rat cardiac myocytes through inhibition of inducible nitric oxide synthase and the arginine transporter CAT-2 (cationic amino acid transporter-2). Clin Sci, 2002;102:487-493.
23. Sun BL, et al. Effects of Gingko biloba extract on somatosensory evoked potential, nitric oxide levels in serum and brain tissue in rats with cerebral vasospasm after subarachnoid hemorrhage. Clin Hemorheol Microcirc, 2000;23:139-144.
24. Le Bars PH, et al. A placebo-controlled double-blind trial of an extract of gingko biloba for dementia. JAMA, 1997;278:1327-1332.
25. Sheu SY, et al. Inhibition of xanthine oxidase by purpurogallin and silymarin group. Anti-cancer Res, 1998;18:263-267.
26. Cross AH, et al. Aminoquanidine, an inhibitor of inducible nitric oxide synthase ameliorates experimental encephalopathies in SIL Mice. Clin Invest, 1994;93:2684-2690.
27. Perlmutter D. Functional therapies in neurodegenerative disease. J Appl Nutr. 1999;51:3-13.
28. Saito K, Yoshioka H. Protective effect of spin trap agent, N-tert-butyl-alpha-phenylnitrone on hyperoxia-induced oxidative stress and its potential as a nitric oxide donor. Free Rad Res, 2002;36:143-149.
03-25-2005, 07:30 PM #4
03-26-2005, 01:33 PM #5
03-26-2005, 02:40 PM #6
03-27-2005, 01:09 PM #7
03-30-2005, 12:03 AM #8
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08-23-2009, 07:19 PM #9
11-25-2012, 07:44 PM #10
anyway we can get some more specific information? you say an excess of nitric oxide cooks your brain but what is your definition of an excess? how much damage is actually done? I know you lose brain cells everyday so if a 200% nitric oxide increase kills another 5 cells a day it not exactly the same as say 50000 cells a day. I love nitric oxide but i love my brain more, only reason im asking
08-07-2013, 10:50 PM #11
I have been taking L-Arginine plus L-Citrulline because it lowers my blood pressure and I was able to quit taking my blood pressure medicine. It L-Arginine causes brain damage then perhaps I should quit taking it and go back to taking my blood pressure medication. I have been off of my blood pressure for a few months now, the L-Arginine keeps my blood pressure in the 120's over 70's. Without it, my Blood pressure will soar up to 160/100. I really hate to go back to my blood pressure medication that was prescribed to me because it is expensive, and a lot of times it doesn't work as well as the L-Arginine. But, now I am afraid to take the L-Arginine because it might cause brain cell damage from what I read in your post. What do you think I should do.
06-17-2014, 06:02 AM #12
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07-06-2014, 01:56 PM #14
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