For Now Avoid Excessive Precursors to Nitric Oxide
ALS Diet Pages
“In particular, nitric oxide [NO] heavily influences the excitatory neurotransmitter glutamate, mainly through NMDA receptors, and the inhibitory neurotransmitter GABA, mainly through GABA A receptors. Due to the involvement of glutamate and GABA in a delicate balance conditioning the functional status of the neural cells, this interaction suggests a role for NO in regulating neuronal excitability and its transition towards hyperexcitability phenomena.” Ferraro G, Sardo P. Nitric oxide and brain hyperexcitability. In Vivo. 2004 May-Jun;18(3):357-66
“During the past ten years, there has been a growing interest in L-arginine (LA), a semi-essential amino acid, which has recently been shown as a physiological precursor of nitric oxide (NO).” The nitric oxide pathway: is L-arginine a gate to the new millennium medicine? A meta-analysis of L-arginine effects. J Med. 1999;30(3-4):131-48.
“Nitric oxide (NO) mediates pathogenic changes in the brain…” Elevated endogenous nitric oxide increases Ca2+ flux via L-type Ca2+ channels by S-nitrosylation in rat hippocampal neurons during severe hypoxia and in vitro ischemia. Tjong YW et al. Free Radic Biol Med. 2007 Jan 1;42(1):52-63. Epub 2006 Sep 27.
“Recent findings indicate that nitric oxide (NO) over-production might be an important factor in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). Moreover, we also found increased copper and zinc superoxide dismutase activity the cerebrospinal fluid from SALS patients…. As copper and zinc superoxide dismutase can react with nitroxyl forming nitric oxide, the conditions for a closed, but continuous loop of nitric oxide biotransformation are present in the cerebrospinal fluid of ALS patients. Biotransformation of nitric oxide in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Kokic AN et al. Redox Rep. 2005;10(5):265-70.
“Markers of oxidative and nitrosative stress have been found in spinal cord, cortex, cerebrospinal fluid and plasma of patients affected by amyotrophic lateral sclerosis..” Effect of nitric oxide on lymphocytes from sporadic amyotrophic lateral sclerosis patients: toxic or protective role? Cereda C. et al Neurol Sci. 2006 Nov; 27(5):312-16.
“The data support roles for oxidative stress, protein nitration and aggregation, and excitotoxicity as participants in the process of motor neuron degeneration caused by mutant superoxide dismutase-1.” Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. J Comp Neurol. 2007 Jan1;500(1):20-46.
“The cascade of events that leads to neurons death is complex” but includes nitric oxide and excitotoxicity. Neurodegenerative diseases and oxidative stress. Emerit J et al. Biomed Pharmacother. 2004 Jan;58(1):39-46.
“To determine whether or not the occurrence of sporadic amyotrophic lateral sclerosis (sALS) is associated with both excess nitric oxide (NO) metabolites and decreased protective superoxide dismutase (SOD) activity in the cerebrospinal fluid (CSF), we measured nitrate concentration and SOD activity in the CSF of sALS patients …we found stable NO metabolite levels to be significantly higher and SOD activity lower… Raised nitrate concentration and low SOD activity in the CSF of sporadic ALS patients. Boll MC et al. Neurochem Res. 2003 May;28(5):699-703.
“Recent findings indicate that nitric oxide (NO*) over-production might be an important factor in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). As Cu,Zn-SOD can react with nitroxyl forming NO*, the conditions for a closed, but continuous, loop of NO* biotransformation are present in the CSF of ALS patients.” Kokic AN et al. Biotransformation of nitric oxide in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Redox Rep. 2005;10(5):265-70.
“Ingestion of a high-protein meat meal results in significant increases in renal plasma flow and glomerular filtration rate….the study…was designed to test the hypothesis that nitric oxide is involved in the renal hyperemic responses to a meat meal….the meat meal resulted in significant renal hyperemia” Salazar FJ et al. Role of nitric oxide in the renal hemodynamic response to a meat meal. Am J Physiol. 1994 Oct; 267(4Pt2): R1050-5.
It has been known for some time that oxidative stress, superoxide dismutase and zinc are involved in amyotrophic lateral sclerosis (ALS). It has also been determined that the disease is caused by the unexplained death of motor neurons in the spinal cord - neurons that control the movement of all voluntary muscles. Heretofore, mutations to the antioxidant enzyme superoxide dismutase (SOD) have been the only published cause of ALS. Additionally, recent research indicates that the loss of zinc from superoxide dismutase is what causes motor neurons to die in one type of ALS (familial). Work is currently underway to characterize how zinc is handled in motor neurons and why superoxide dismutase can become zinc deficient in ALS with the goal being to understand how mutations to superoxide dismutase causes ALS. The major function of superoxide dismutase is to scavenge the oxygen radical superoxide. So it is very interesting to note that a recent discovery by the Linus Pauling Institute is that a major target for superoxide is nitric oxide.
Nitric oxide was discovered to be a vasodilator by Koch-Weser in 1974. In the 1980’s L-arginine was discovered to be the building block of nitric oxide. Later, scientists discovered that nitric oxide plays the role of a “second messenger”, followed by glutamate stimulation of neurons in the central nervous system. Structurally, there is a very close relationship between nitric oxide and glutamate. Nitric oxide easily passes into the energy portion of the neuron, the mitochondria, and by a series of events causes an efflux of calcium out of the cell. This efflux of calcium out of the mitochondria permits the free movement of a large number of molecules in and out of the mitochondria leading to mitochondrial collapse, and cell death. In addition, nitric oxide causes the inhibition of glutamate transporters to do the job of eliminating excess glutamate which leads to a buildup of glutamate, excessive stimulation of neuron activity (excitotoxicity) and neuronal death.
A Press Release in 1998 informed the world of the discovery of even more varied roles of nitric oxide. Reports of this “free radical”, endogenous nitrovasodilator, sometimes good, sometimes evil molecule have been the focus of much study ever since. Indeed, until fifteen years ago, nitric oxide was only considered as a toxic air pollutant, damaging the lung and promoting cancer by damaging DNA. However, nitric oxide is also produced by cells lining the arterial walls to relax the underlying smooth muscle and increase blood flow. For example, nitric oxide is the active metabolite produced from nitroglycerin that stops angina in heart disease patients. Viagra works by prolonging the effects of nitric oxide in blood vessels in the penis to maintain erections. But research with ALS and other neurodegenerative diseases now focuses in on the damaging roles of nitric oxide, peroxynitrite and nitrotyrosine (all related molecules). In fact, nitric oxide, in reaction with superoxide produces the powerful oxidant peroxynitrite, which promotes oxidative damage to blood vessels, skin, heart, lung, kidney and brain
The folks at the Linus Pauling institute are characterizing the role of peroxynitrite in injuring cells and how cells respond to that damage. One sign of damage left by peroxynitrite is nitration of amino acids in proteins. They hypothesize that nitration is particularly important as a defense against viral infections, damaging proteins and RNA necessary for viral replication, but at the same time can be damaging to host tissues and cells, thereby contributing to acute injury and chronic disease.
In a 2005 study on how nitric oxide and it’s metabolites mediate microglial toxicity (phagocytic immune cells of the central nervous system) to oligodendrocytes (oligodendrocytes form myelin sheaths around axons to support rapid nerve conduction in the central nervous system (CNS). Damage to myelin can cause severe CNS disorders). They state that localized activation of microglia has been implicated in the pathogenesis of a number of neurological diseases, including ALS. They say that microglia are extremely responsive to environmental or immunological challenges and are the predominant cell type producing neurodegeneration. One of the functions of microglial cells is to engulf and remove toxic and foreign substances away from neural cells. However, the researchers in the 2005 study seem puzzled as to what could possibly be activating the microglia. A recent study by John Hopkins University found that similar excessive activation of the microglia were found in the autopsied brains of autistic people. Interestingly, a March 2006 “blog” on the internet launches into the story of how Albert Einstein’s brain was taken at autopsy and kept for over 40 years to be studied by scientists (http://notmercury.blogspot.com/2006/03/way-to-go-einstein.html). Among those studies was one where they found that Einstein’s brain had excessive activation of the microglia. Some went so far to say Einstein might have been autistic.
Shortly after the Hopkins study was published, Thimerosal® opponents were quick to point out that mercury is able to trigger microglial activation. In fact, in high concentrations mercury in the brain is primarily located within microglial cells. Exposure to certain toxins, including mercury, triggers expansion and proliferation of the brain's microglial immune cells because they are in charge of responding to and removing agents that can harm neural cells. They are merely trying to do their job. Mercury triggers microglial activity, and microglial activity is enhanced by nitric oxide. Nitric oxide in the small amounts made by the body and used to activate the immune system for example, is a normal process. But in excess, nitric oxide becomes a villain, participating in a cascade of events leading to neuronal death.
Nitric oxide, the aforementioned potent activator of microglial activity, is made from the amino acid arginine. All foods containing protein will have some degree of arginine, but those same foods will also have the amino acid lysine. Lysine can be viewed as arginine’s “opposite”. Viral replication is stimulated by arginine, and deterred by lysine. Doctors can now tell patients with confidence of the positive role of nitric oxide (and thus arginine) in cardiovascular health, the immune system and more. Nature has a way of “balance” and it follows with nitric oxide, which is good in the right amounts, and bad when there is too much or too little. As discussed earlier with glutamate, and the body making the tiny amounts it needs, in like manner, by consuming a diet favoring lysine over arginine, we can favorably influence a lessened production of nitric oxide. If we go back once again to the wisdom of nature, we could note that human milk (and what wise person among us would deny that breastfeeding an infant is anything but best) is approximately 1½ times higher in lysine than arginine. Using that fact as our starting point, a diet that prevents an excess of nitric oxide formation (and we’ll discuss other measures to do the same in other sections) would be anywhere from equal amounts of arginine to lysine to anything greater than a 1:1 ratio.
ALS Diet Pages
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Amyotrophic Lateral Sclerosis
Please click the PDF icon to the left to read or download the entire 36 page Amyotrophic Lateral Sclerosis Diet by Dr. David Steenblock
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