An abundant supply of glutamine synthase is essential for our health since the biosynthesis of glutamine is the process through which the body eliminates excess ammonia. As we will see later, glutamine synthase is of incredible importance in brain function. One could say that our very survival depends on it along with the glial cells that secrete it.
Thus, MSG is the sodium salt of glutamic acid, while "glutamate," (as the term is used most often these days), is the ionic form of glutamic acid. It's true that the body can use MSG as a source of glutamate but there is also abundant sodium coming in perhaps causing sodium/potassium imbalance, dehydration, and disturbances in the constriction and dilation of blood vessels. Dehydration alone is enough to cause the kind of dull headache that some Western patrons of Chinese restaurants have complained about. Most likely, Westerners eat much larger portions than Asians, thus, consume more MSG in one meal than is typical of Asians.
Nevertheless, those prone to migraines should avoid MSG and aspartame and all of us should avoid these compounds in large doses. There is no question that very high doses of MSG can overwhelm brain defenses and cause neural damage. It is interesting that young children with immature nervous systems are most susceptible to MSG damage -- not the elderly.
Actually, only a small percentage of people are truly sensitive to the small doses of MSG used as a seasoning. Billions of Asians consume it daily. The Japanese also consume seaweed, the richest natural source of monosodium glutamate. This chronic long-term consumption does not seem to cause any problems. In regard to Alzheimer's disease in particular, the Asian rates (including Japan) are a fraction of what they are in the West. It is also of interest that infusions of MSG are used in mainstream clinical practice to reduce high ammonia levels in the blood (hyper-ammonemia) by stimulating the conversion of glutamate to glutamine. Thus, both glutamate (as MSG) and glutamine are used by conventional medicine for treating several serious conditions.
Stroke and Neurotransmitters
In addition, we need to remember that most of the glutamate is used for energy production rather than as a neurotransmitter. As for the possibility of insomnia, it seems that some people take glutamine at bedtime as a growth hormone releaser, yet complaints of insomnia are not prevalent in the literature. And, in clinical settings, as much as 40 g of glutamine may be administered and yet the literature makes no mention of any side effects. On the contrary, the non-toxicity of glutamine is emphasized as an important advantage. With some important exceptions that will be summarized at the end of this article, it seems that even the severely ill have no trouble metabolizing glutamine.
Glutamic acid is very hard to find. Glutamine, on the other hand, is very popular with bodybuilders. One of the ironies is that glutamine is used mainly by the very fit and the very sick.
The glutamine cycle in the brain is simple and elegant. Glutamine readily crosses the blood-brain barrier. Neurons take up glutamine and convert it to glutamate or GABA (through the additional step of decarboxylating glutamate). Some glutamate is used for energy, some for synthesis of glutathione and niacin and, some as a neurotransmitter. After either glutamate or GABA are released into the synaptic junction, the supportive cells called glia take up the glutamate or GABA and re-synthesize glutamine -- detoxifying ammonia in the process. The glutamate that is not converted to l-glutamine is used by the glia as a source of energy and also to produce energy nutrients alanine and alpha-ketoglutarate which are then released to the neurons.
If excess glutamine accumulates through the action of the glia, the brain donates it to the body. Normally, however, very little glutamine is released by the brain in contrast to muscle and adipose tissue which donate a lot. In the brain, it's pretty much an internal affair. What we see is the glutamine / glutamate / GABA / glutamine cycle.
An interesting development related to glutamate is the increasing use of ampakines which is a new class of drugs for Alzheimer's disease. Apparently an important factor in the pathogenesis of Alzheimer's disease is stroke or a series of undiagnosed mini-strokes. During stroke, the dying neurons release glutamate which then unfortunately can cause more neuron death. Furthermore, ischemic episodes damage the glutamate receptors so that later the glutamate can't work as a neurotransmitter. Without glutamate, there is no memory and no learning. Ampakines amplify the glutamate signal through a yet unknown mechanism possibly by rebuilding glutamate receptors. In healthy people and in animals, ampakines have been shown to enhance cognitive performance and can thus be classified as "smart drugs."
AIDS and Cancer
At normal physiological levels, glutamate is beneficial and safe. It is an indispensable neurotransmitter that the brain produces according to need. When the central nervous system is aroused, surprisingly enough, we do not see higher glucose consumption. Instead, some of the glucose is converted to glutamate. The other source of glutamate is, of course, glutamine. An abundant supply of glutamine makes it easier for the brain to maintain neurotransmitter balance by increasing the production of glutamate when required for alertness, learning, memory, and the production of GABA when its inhibitory properties are needed. In fact, some people report feeling more centered and calm after they start taking glutamine. Others report consistently better moods.
Glutamate is our chief excitatory neurotransmitter. It is essential for learning and both short-term and long-term memory. Problems arise only if the normal process of glutamate removal and conversion to glutamine malfunctions and an excess of this excitatory neurotransmitter builds up in the synaptic junctions. Excess glutamate causes excessive influx of calcium ions into the neurons causing excitotoxicity and ultimately even death of the neurons. It also destroys glutathione - a crucial brain-protective antioxidant. Low levels of brain glutathione are associated with neurodegenerative disorders. Glutathione depletion further leads to neuronal death.
Under what conditions do we see excess levels of glutamate at the synapses? Not surprisingly, we see evidence of damage associated with excess glutamate in Alzheimer's, AIDS patients, and cancer patients. HIV inhibits glutamate uptake by the glia. According to one hypothesis, cancer starts with brain dysfunction and in those who have suffered a severe brain injury. Very high fever or artificially induced hyperthermia can also result in excess glutamate release, leading to seizures.
The Healthy Brain is Very Well Equipped to Deal with Glutamate
Pro-inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha inhibit the induction of glutamine synthase. These pro-inflammatory cytokines are released after a brain injury and in neurodegenerative disorders. Thus, neuronal death may occur because the inflammatory process interferes with the conversion of glutamate into glutamine.
It appears plausible that reducing inflammation can prevent glutamate excitotoxicity by protecting the glia. This may be a partial explanation for the role of anti-inflammatories in the prevention of Alzheimer's disease. In addition, it has been shown that normal levels of anti-inflammatory hormones called glucocorticoids induce glutamine synthase. Excess cortisol, however, can inhibit the uptake of glutamate by the glia.) Bioflavonoids, such as the catechins in green tea or proanthocyanidins in grape seed extract, can help protect against the excitotoxic injury due to glutamate build-up. Uric acid (one of our endogenous antioxidants) and the amino acid taurine are also beneficial in controlling glutamate build-up. It seems that the brain can produce its own taurine. Nevertheless, if high doses of glutamine are taken or if foods seasoned with MSG are regularly consumed, it might be an extra precaution to take supplemental taurine.
Certain B vitamins, including methylcobalamin (one of the active forms of vitamin B12), are likewise protective. The real star here, however, seems to be ginkgo biloba. A Chinese study found that a ginkgo extract as well as one of its constituents, ginkolide B, protects against glutamate excitotoxicity by reducing the rise in calcium ions. Thus, it is an excellent idea to include ginkgo in your supplement regimen. You may also consider drinking green tea or taking green tea extract, as well as eating berries or taking bilberry extract, in order to obtain a good dose of flavonoids for general neural protection and prevention of neurodegenerative diseases.
Retinal damage in diabetes is also partly due to excitotoxic glutamate buildup. In this case, we again see insufficient conversion of glutamate to glutamine probably due to the malfunction of glial cells (both insufficient or excessive glucose levels can lead to cell dysfunction; diabetics also show higher levels of free radicals).
Finally, alcohol also inhibits glutamine synthase which explains, at least in part, the neurotoxicity of alcohol. Certain drugs including many anti-epileptic drugs likewise inhibit glutamine synthase and this may be partly responsible for their toxic side effects. One anti-epileptic drug, however, a fairly new medication called vigabatrin, has been shown to raise both GABA and glutamine while decreasing glutamate. This drug is considered both safe and effective.
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