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Glutamic acid (glutamate): An amino acid that is a particularly potent nerve cell killer.
Glutamic acid (glutamate): An amino acid found in all MSG.

For some time now, experimental drugs have been investigated because they block the actions of glutamic acid (glutamate).  Following is a very brief overview of glutamate toxicity, some of  drugs being designed to overcome glutamate toxicity, and disease conditions that drug manufacturers hope to ameliorate.

Glutamate Toxicity

"Glutamate is a powerful excitatory neurotransmitter that is released by nerve cells in the brain. It is responsible for sending signals between nerve cells, and under normal conditions it plays an important role in learning and memory.  There are two general ways, however, that glutamate can actually be damaging to nerve cells and the brain as a whole. First, there can be too much glutamate around; abnormally high concentrations of glutamate can lead to overexcitation of the receiving nerve cell. Second, the receptors for glutamate on the receiving nerve cell can be oversensitive, such that less glutamate molecules are necessary to excite that cell.

"In both cases, cells activated by glutamate become overexcited. This overexcitation can lead to effects that can cause cell damage and/or death. For this reason, glutamate is referred to as an excitotoxin when it causes cellular damage."

-- (HOPES: Huntington's Outreach Project for Education, at Stanford, 8/30/2005: http://www.stanford.edu/group/hopes/treatmts/antiglut/l0.html)

"The excitatory neurotransmitter glutamate plays an important part in the development of neurodegenerative diseases like dementia. About 70 % of all excitatory synapses in the central nervous system are stimulated by the neurotransmitter glutamate. Dysfunction of glutamatergic neurotransmission is involved in pathomechanism of neurodegenerative dementia. The excitatory effect of chronically released glutamate effects the degeneration of cortical and subcortical neurons, thus leading to the occurrence of dementia symptoms."
-- (Merz, 3/12/06: http://www.memantine.com/en/mode_of_action/)



Disease conditions for which glutamate blocking drugs are being used or investigated

Huntington's disease (HD)

"Scientists have found that certain glutamate receptors in the nerve cells of patients with HD tend to be oversensitive to glutamate. For some patients with HD, glutamate can act as an excitotoxin, even if its levels are not particularly high. Treatments that attempt to inhibit glutamate activity therefore may have some therapeutic potential."

-- (HOPES: Huntington's Outreach Project for Education, at Stanford, 8/30/2005: http://www.stanford.edu/group/hopes/treatmts/antiglut/l0.html)

"The lowered amount of energy available in the nerve cells of patients with HD is thought to cause NMDA receptors to be oversensitive to glutamate. Therefore, normal physiological levels of glutamate can cause overexcitation of the NMDA receptor, leading to the influx of calcium ions into the cell. Excess calcium ion entry can lead to cell death through a combination of events."

-- (HOPES: Huntington's Outreach Project for Education, at Stanford, 12/3/2004: http://www.stanford.edu/group/hopes/treatmts/antiglut/l2.html)

"Huntington’s disease is associated with both problems in energy metabolism and glutamate toxicity....

"Energy metabolism is the process by which cells produce energy. Normally, cells prefer a form of energy metabolism called aerobic respiration due to its efficiency and high-energy yield. The altered huntingtin protein in people with HD is believed to interfere with aerobic respiration, resulting in the inability of HD cells to perform aerobic respiration efficiently. Instead, HD cells must resort to anaerobic respiration, another form of energy metabolism that is less efficient. This impairment in energy metabolism results in various negative effects that eventually lead to cell death....

"One of the effects of the impairment in energy metabolism in HD cells is an increased sensitivity to glutamate. Glutamate is one of the major neurotransmitters in the nervous system, used to transmit messages from nerve cell to another.  Increased activation of receptors that receive glutamate has been observed in people with HD. Increased glutamate activity, in turn, has been associated with nerve cell death."

-- (HOPES: Huntington's Outreach Project for Education, at Stanford, 12/3/2004: http://www.stanford.edu/group/hopes/treatmts/antiglut/l3.html)

Alzheimer's disease

"Normal glutamatergic neurotransmission -- Under physiological conditions, the NMDA receptor is blocked by magnesium ions, thereby protecting the neuron against glutamatergic excitotoxicity. During physiological learning and memory processes, high concentrations of synaptic glutamate are transiently released. Due to its strong voltage-dependency, magnesium leaves the NMDA receptor. Calcium enters into the cell, and through secondary processes, the signal is recognized. This is clearly discernible behind the low background noise.

"Alzheimer dementia -- The pathological, sustained release of low glutamate concentrations, from both neurones and surrounding glia cells, also displaces magnesium from the NMDA receptor channel. There is a continuous influx of calcium into the cell, increasing the calcium pool. In the case of learning and memory processes, the transient synaptic release of glutamate causes more calcium to flow into the cell. However, due to the already elevated calcium concentration, the signal can no longer be detected (occurrence of dementia symptoms).

"In the course of the disease, the chronic release of glutamate and the permanently increased intracellular calcium concentration leads to neuronal degeneration (neurodegeneration)."

-- (Merz, 3/12/06: http://www.memantine.com/en/mode_of_action/)
Amyotrophic Lateral Sclerosis (ALS)

"Prolonged excitation is toxic to nerve cells. Neurobiologists recognize that the nerve cell messenger, glutamate, can cause harm when its messages are overwhelming. Normally glutamate is swiftly cleared from the nerve cell junctions to keep the messages brief. Molecules called transporters aid in keeping glutamate in proper concentrations around nerve cells. Abundant evidence points to glutamate as a destructive factor in ALS and investigators are working to find out how this can be changed. Gene therapy approaches are under investigation to deliver glutamate transporters to cells affected by ALS. Other avenues towards control of glutamate in ALS are also under active investigation."

-- (ALS Association, 3/12/06: http://www.alsa.org/research/article.cfm?id=826)

"Glutamate is one of the chemical messengers or neurotransmitters in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the serum and spinal fluid. Laboratory studies have demonstrated that neurons begin to die off when they are exposed over long periods to excessive amounts of glutamate. Now, scientists are trying to understand what mechanisms lead to a buildup of unneeded glutamate in the spinal fluid and how this imbalance could contribute to the development of ALS."

-- (National Institute of Neurological Disorders and Stroke, 1/23/06:
http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophiclateralsclerosis.htm#51014842)

Parkinson's Disease (PD)
<>".... of interest in PD are processes that occur in an area of the brain called the subthalamic nucleus. Here, receptors known as glutamatergic N-methyl-D-aspartate (NMDA) become persistently overexcited and produce high levels of calcium ions within brain cells. This in turn leads to a cascade of events that trigger oxygen-free radicals and cell damage."
-- (About.com, 3/12/06): http://adam.about.com/reports/000051.htm)

"A number of experimental drugs are being investigated for Parkinsons disease because they block the actions of glutamate, an amino acid that is a particularly potent nerve cell killer. Some of these drugs block a receptor group to glutamate called N-methyl-D-aspartate (NMDA). Investigative NMDA antagonists include remacemide, memantine, riluzole, and budipine."

-- (About.com, 3/12/06): http://adam.about.com/reports/000051_7.htm)

Epilepsy (seizures)

"Alexander hypothesizes that in epilepsy patients, the protective receptors may not function well or that glutamate production may be abnormal. A treatment that targets these protective glutamate receptors has the potential to block the pathway involved in seizures, with the added benefit of allowing normal communication to continue."

-- (Medical News Today: Possible new treatment target for epilepsy. Article Date: 03 Jul 2005 - 15:00pm (UK):  http://www.medicalnewstoday.com/medicalnews.php?newsid=26883)


"CURRENT LITERATURE IN BASIC SCIENCE
EXCITABLE BUT LACKING IN ENERGY: CONTRADICTIONS IN THE HUMAN EPILEPTIC HIPPOCAMPUS

"Extracellular Metabolites in the Cortex and Hippocampus of Epileptic Patients
Cavus I, Kasoff WS, Cassaday MP, Jacob R, Gueorguieva R, Sherwin RS, Krystal JH, Spencer DD, Abi-Saab WM
Ann Neurol 2005 Feb;57(2):226–235


"Interictal brain energy metabolism and glutamate– glutamine cycling are impaired in epilepsy and may contribute to seizure generation. We used the zero-flow mi-
crodialysis method to measure the extracellular levels of  glutamate, glutamine, and the major energy substrates glucose and lactate in the epileptogenic and the nonepilep-togenic cortex and hippocampus of 38 awake epileptic patients during the interictal period. Depth electrodes attached to microdialysis probes were used to identify the epileptogenic and the nonepileptogenic sites. The epileptogenic hippocampus had surprisingly high basal glutamate levels, low glutamine/glutamate ratio, high lactate levels, and indication for poor glucose utilization.

"The epileptogenic cortex had only marginally increased glutamate levels. We propose that interictal energy deficiency in the epileptogenic hippocampus could contribute to impaired glutamate reuptake and glutamate-glutamine cycling, resulting in persistently increased extracellular glutamate, glial and neuronal toxicity, increased lactate production together with poor lactate and glucose utilization, and ultimately worsening energy metabolism. Our data suggest that a different neurometabolic process underlies the neocortical epilepsies.

COMMENTARY

"Glutamate is the principal excitatory neurotransmitter in mammalian brain and has long been implicated in the generation of epileptic discharges. Administration of glutamate or glutamate analogues to experimental animals can elicit seizures, whereas glutamate antagonists are both anticonvulsant and neuroprotective (1). Glutamate receptor sub-units are upregulated in hippocampal tissue resected from patients with chronic temporal lobe epilepsies; electrophysiological recordings from human epileptic hippocampal slice preparations demonstrate a glutamate-dependent hyperexcitability; and in vivo microdialysis studies show an elevation in extracellular glutamate during seizures (2). These observations point to glutamate as potentially crucial in the generation and maintenance of seizures in localization-related epilepsies.

"Glutamate is synthesized from glutamine in glutamatergic neurons via the action of the enzyme glutaminase and, following synaptic release, is removed into both nerve terminals and glial cells by selective energy-dependent transporters. Glial cells subsequently reconvert glutamate into glutamine, via the enzyme glutamine synthetase, and glutamine is finally transferred to glutamatergic neurons, completing the so-called glutamate–glutamine cycle (3). Glutamate homeostasis is critical to the
normal functioning of the nervous system, and in this regard, glial glutamate uptake is believed to be of principal importance (4). Glutamate is not only a neurotransmitter but also an excitotoxic agent that, in high concentrations, has the potential to cause cell death. As a result, it is maintained at low levels in  the "extracellular fluid of the brain by efficient, but energetically expensive uptake into glial cells.

"The evidence to support glutamatergic dysfunction in temporal lobe epilepsies is compelling and yet, until recently, has been largely circumstantial. Although seizures are almost certainly associated with increased extracellular glutamate concentrations, with the potential for localized glial and neuronal damage, the source of elevated glutamate and the distinction between cause and effect have proved elusive. Much of the understanding to date has come from animal models, which may not adequately mirror the human situation, or from the ex vivo analysis of surgical and postmortem tissue, which is subject to a multitude of confounding factors. However, recent advances in brain imaging and the ongoing development of intracerebral microdialysis for human use, pioneered by During and Spencer in the 1990s (5), have significantly improved the ability to perform real-time investigations of brain neurochemistry in disease states.

"A recent study by Cavus and colleagues employed intracerebral microdialysis to investigate extracellular concentrations of glutamate, glutamine, and the major energy substrates, glucose and lactate, in epileptogenic and nonepileptogenic regions of the hippocampus and cortex in conscious epilepsy patients during the interictal period. The investigators reported elevated glutamate levels in the epileptogenic hippocampus, together with a low glutamine/glutamate ratio, increased lactate, and evidence of reduced glucose utilization. Interestingly, these phenomena did not extend to epileptogenic regions of the cortex. This is the first study to report concentrations of multiple seizure-related neurometabolites in conscious epilepsy patients and serves to confirm many previously held suspicions. The authors hypoth-
esized that an unspecified energy deprivation, possibly related to mitochondrial injury, could be responsible for the neurochemical profile observed. Energy deficiency could, in theory, lead to functional impairment of both glutamate transporters and glutamine synthetase, which could in turn result in poor glutamate clearance from the synapse and an increase in the nonvesicular release of glutamate from the glial compartment, leadingtoneurotoxicityandpoorutilizationofavailableglucose and lactate.

"This hypothesis is supported by previous observations of hypometabolism in the epileptic focus (6) and reduced activity of glutamine synthetase in surgically excised epileptic tissue (7). However, several questions remain to be answered. Because glutamate is causal to the generation of seizures and is chronically elevated in the epileptogenic hippocampus, one would expect seizures and neurotoxicity to propagate uninterrupted—unless some type of protective mechanism is equally upregulated. Similarly, the suggestion that energy deprivation leads to glutamatergic dysfunction, and thereby impaired glucose utilization, would appear to be a circular argument and difficult to reconcile in the absence of evidence to support ever-worsening energy metabolism and the catastrophic failure of local neuronal function. The 10-fold variation in basal glutamate concentrations in the epileptogenic hippocampus, from low normal values to neurotoxic levels, would suggest considerable heterogeneity in the study population, sufficient to question the experimental design and statistical power of the investigation. Finally, the
potentially confounding influence of antiepileptic drug treatment cannot be taken lightly. Although the authors did not observe any specific drug-related effects, possibly as a result of the low number of patients analyzed and the use of combination therapy, subanalyses based on principal drug mechanisms or comparison with untreated individuals may have been more revealing.

"Intracerebral microdialysis may offer significan tadvantages over previous investigational approaches by providing a direct measure of brain metabolite concentrations in living subjects, without the confounding influence of general anesthesia or the inherent limitations of ex vivo tissue analysis. The differences in hippocampal and cortical neurochemistry reported in this study are intriguing and not only merit further investigation but also may, in time, encourage consideration of focal epilepsies in terms of their distinctive neurobiology rather than just their anatomical localization. If nothing else, the use of microdialysis in conscious epilepsy patients should begin to offer unprecedented insights into the neurochemistry of the epileptic focus."

by Graeme J. Sills, PhD
Epilepsy Currents, Vol. 6, No. 1 (January/February) 2006 pp. 6–7
Blackwell Publishing, Inc.
c American Epilepsy Society

References
1. Chapman AG. Glutamate receptors in epilepsy. Prog Brain Res 1998;116:371–383.
2. Scheyer RD. Involvement of glutamate in human epileptic activities. Prog Brain Res 1998;116:359–369.
3. Petroff OAC, Errante LD, Rothman DL, Kim JH, Spencer DD. Glutamate-glutaminecyclingintheepileptichumanhippocampus. Epilepsia 2002;43:703–710.
4. Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation and physiological function. Glia 2000;32:1–14.
5. During MJ, Spencer DD. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 1993;341:1607–1610.
6. Lamusuo S, Jutila L, Ylinen A, Kalviainen R, Mervaala E, Haaparanta M, Jaaskelainen S, Partanen K, Vapalahti M, Rinne J. [ 18 F]FDG-PET reveals temporal hypometabolism in patients with temporal lobe epilepsy even when quantitative MRI and histopathological analysis show only mild hippocampal damage. Arch Neurol 2001;58:933–939.
7. Eid T, Thomas MJ, Spencer DD, Runden-Pran E, Lai JCK, Malthankar GV, Kim JH, Danbolt NC, Ottersen OP, de Lanerolle NC. Loss of glutamine synthetase in the human epileptogenic hippocampus: Possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 2004;363:28–37.

-- (American Epilepsy Society, Jan/Feb 2006: http://64.233.179.104/search?q=cache:JELjhGF41HIJ:
www.aesnet.org/Visitors/pdf/currents_pdf/epc_0078.pdf+seizures,+glutamate&hl=en&gl=us&ct=clnk&cd=10&ie=UTF-8
)


Drugs with glutamate-blocking potential
(http://www.stanford.edu/group/hopes/treatmts/antiglut/l0.html)

Remacemide: An anti-glutamate drug and energy buffer

"Remacemide (RMC) is a drug that Huntington's disease (HD) researchers hope can alleviate glutamate toxicity in the brains of HD patients. Remacemide is an NMDA antagonist – it inhibits the binding of glutamate to NMDA receptors, preventing glutamate from exerting its toxic effects on the nerve cell. Although, it has been shown to transiently improve motor performance in mouse models of HD, the few human clinical trials that have been performed have not produced statistically significant improvements in brain or motor function. Patients have also experienced side effects such as lightheadedness, dizziness, vomiting, nausea, and gastrointestinal disturbance...

"Remacemide, sometimes referred to as Remacemide Hydrochloride, is under investigation as a treatment for HD because it acts as a non-competitive inhibitor of the NMDA receptor. This means that remacemide decreases the receptor’s ability to bind glutamate by docking to a site on the receptor other than the glutamate binding site, and changing the shape of the receptor such that glutamate has a difficult time binding. Researchers hope that by inhibiting the NMDA receptor, the toxic effects of glutamate in the neurons of patients with HD can be lessened."

-- (HOPES: Huntington's Outreach Project for Education, at Stanford, 12/3/04: http://www.stanford.edu/group/hopes/treatmts/antiglut/l2.html)

Memantine: An anti-glutamate drug

"Memantine is an anti-glutamate and energy-buffering drug. As an NMDA antagonist, memantine prevents the neurotransmitter glutamate from leading to nerve cell degeneration by inhibiting glutamate´s binding to the receptor. Memantine has been clinically used to treat dementia and Alzheimer´s disease. Current research on its effects in other diseases of the central nervous system (CNS), including HD, looks promising because memantine appears to be well-tolerated as well as beneficial in terms of learning facilitation. It is possible that memantine may even be able to disrupt the progression of HD.

"According to a theory known as the excitotoxicity theory, lower energy levels in the nerve cells of people with HD cause them to be overly sensitive to glutamate. Consequently, even normal levels of glutamate can overactivate the glutamate receptors on the nerve cells. When these receptors (also known as NMDA receptors) are activated, calcium ions enter the nerve cells. Excessive activation causes a buildup of these calcium ions, which then leads to the death of the nerve cell....

"HD researchers believe that memantine may have strong potential to slow the progression of HD by decreasing the NMDA receptor´s sensitivity to glutamate. Memantine is an NMDA antagonist. As an antagonist, memantine prevents the excessive binding of glutamate to NMDA receptors, inhibiting the pathway to excessive NMDA activation and nerve cell death. Memantine is also a non-competitive antagonist. "Non-competitive" means that memantine binds to a site on the NMDA receptor that is different from glutatmate´s binding site. By binding to one portion of the NMDA receptor, memantine changes the overall shape of the receptor, making it more difficult for glutamate to bind to the other portion of the receptor."

-- (HOPES: Huntington's Outreach Project for Education, at Stanford,  5/3/2005: http://www.stanford.edu/group/hopes/treatmts/antiglut/l5.html)

Riluzole: An anti-glutamate drug and energy buffer.

"Riluzole has been shown to have energy-buffering and anti-glutamate properties. It has been associated with increased energy metabolism efficiency and inhibition of glutamate activity, and is currently used as a treatment for Amyotrophic Lateral Sclerosis (ALS) .... as well as Huntington’s disease...."

Riluzole is used to deal with the problem of aerobic inefficiency. "Energy metabolism is the process by which cells produce energy. Normally, cells prefer a form  energy metabolism called aerobic respiration due to its efficiency and high-energy yield. The altered huntingtin protein in people with HD is believed to interfere with aerobic respiration, resulting in the inability of HD cells to perform aerobic respiration efficiently. Instead, HD cells must resort to anaerobic respiration, another form of energy metabolism that is less efficient. This impairment in energy metabolism results in various negative effects that eventually lead to cell death.

"Studies have reported that riluzole treatment improves motor abnormalities associated with administration of a toxin that blocks energy metabolism. The improvements indicate that riluzole may have positive effects on cells with defective metabolism. However, the mechanism by which riluzole improves energy metabolism is still unknown....

Riluzole is also used to deal with the problem of glutamate sensitivity. "One of the effects of the impairment in energy metabolism in HD cells is an increased sensitivity to glutamate. Glutamate is one of the major neurotransmitters in the nervous system, used to transmit messages from nerve cell to another. Increased activation of receptors that receive glutamate has been observed in people with HD. Increased glutamate activity, in turn, has been associated with nerve cell death.

"Studies have demonstrated that riluzole may act as an anti-glutamate drug in two ways: 1) by inhibiting the release of glutamate and 2) by interfering with the effects of glutamate on nerve cells.

"It is thought that riluzole inhibits the release of glutamate by interfering with sodium (Na+) channels that are required for normal glutamate release."

-- (HOPES: Huntington's Outreach Project for Education, at Stanford, 12/3/2004: http://www.stanford.edu/group/hopes/treatmts/antiglut/l3.html)

Lamotrigine - An anti-glutamate and anticonvulsant drug

"Lamotrigine belongs to a group of medications called anticonvulsants, which are used to control seizure disorders. Lamotrigine acts on the central nervous system to control the number and severity of seizures. It is thought to suppress the activity of certain parts of the brain and the abnormal firing of nerve cells that cause seizures. In psychiatry, lamotrigine may be used as a mood stabilizer. In the laboratory, researchers have found that lamotrigine also inhibits release of the neurotransmitter glutamate. This is important because glutamate may play a role in nerve cell degeneration in the brains of people with HD, so reducing the amount of glutamate released makes lamotrigine a potential treatment for HD."

-- (HOPES: Huntington's Outreach Project for Education, at Stanford, 6/24/05: http://www.stanford.edu/group/hopes/treatmts/antiglut/l4.html)

 Budipine

Budipine and Other Glutamate Blockers. A number of experimental drugs are being investigated for Parkinsons disease because they block the actions of glutamate, an amino acid that is a particularly potent nerve cell killer. Some of these drugs block a receptor group to glutamate called N-methyl-D-aspartate (NMDA). Investigative NMDA antagonists include remacemide, memantine, riluzole, and budipine. Budipine is of particular interest. It not only blocks NMDA, but it increases levels of two enzymes involved in the production of dopamine. Studies suggest that it reduces tremor in PD and it proving to be beneficial in combination with levodopa.

-- (About.com, 3/12/06): http://adam.about.com/reports/000051_7.htm)

Gabapentin

"Gabapentin - [Brand Name: Neurotin] is a FDA approved medication for the treatment of seizures (epilepsy). Gabapentin is thought to decrease the production of glutamate. Glutamate is an excitatory amino acid in the brain. It acts as the major excitory neurotransmitter in the central nervous system. Glutamate, in excessive amounts, is toxic to motor neurons. Studies have shown that ALS patients have high levels of glutamate in their brain as well as a defect in the glutamate transport mechanism. Gabapentin is hoped to slow the rate of motor neuron death. A small number of patients on gabapentin report decreased muscle spasms and/or decreased muscle fasciculations and improved sleep."

--(The University of Miami ALS Clinical and Research Center: http://www.miami-als.org/drugs.htm)

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This page was last updated on March 12, 2006


IF MSG ISN'T HARMFUL, WHY IS IT HIDDEN?