Excitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are overactivated. Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions^[1] (Ca²⁺) to enter the cell. Ca²⁺ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. Drawing by Santiago Ramón y Cajal of neurons in the pigeon cerebellum. ... In biochemistry, a receptor is a protein on the cell membrane or within the cytoplasm or cell nucleus that binds to a specific molecule (a ligand), such as a neurotransmitter, hormone, or other substance, and initiates the cellular response to the ligand. ... Glutamic acid (Glu), also referred to as glutamate (the anion), is one of the 20 proteinogenic amino acids. ... The NMDA receptor (NMDAR) is an ionotropic receptor for glutamate (NMDA (N-methyl d-aspartate) is a name of its selective specific agonist). ... The α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). ... NMDA (N-methyl-D-aspartic acid) is an amino acid derivative acting as a specific agonist at the NMDA receptor, and therefore mimics the action of the neurotransmitter glutamate on that receptor. ... Kainic acid is an acid present in some algae. ... Calcium plays a vital role in the anatomy, physiology and biochemistry of organisms and of the cell, particularly in signal transduction pathways. ... Drawing of the structure of cork as it appeared under the microscope to Robert Hooke from Micrographia which is the origin of the word cell. Cells in culture, stained for keratin (red) and DNA (green). ... A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. ... Endonucleases are enzymes that cleave the phosphodiester bond within a nucleotide chain. ... Peptidases (proteases [pronounced pro-tea-aces] and proteolytic enzymes are also commonly used) are enzymes which break peptide bonds of proteins. ... Calpain is calcium-dependent, non-lysosomal proteolytic enzyme found in the brain (Castillo and Babson, 1998). ... The eukaryotic cytoskeleton. ... The cell membrane (also called the plasma membrane, plasmalemma or phospholipid bilayer) is a semipermeable lipid bilayer common to all living cells. ...

Excitotoxicity may be involved in stroke, traumatic brain injury and neurodegenerative diseases of the central nervous system (CNS) such as autism,^[2] Multiple sclerosis, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), fibromyalgia^[3], tinnitus^[4], Parkinson's disease, and Huntington's disease.^[5] Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia^[6] and status epilepticus.^[7] Stroke (or cerebrovascular accident or CVA) is the clinical designation for a rapidly developing loss of brain function due to an interruption in the blood supply to all or part of the brain. ... Traumatic brain injury (TBI), traumatic injuries to the brain, also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage. ... Neurodegenerative disease (Greek νέυρο-, néuro-, nerval and Latin dēgenerāre, to decline or to worsen) is a condition in which cells of the brain and spinal cord are lost. ... A diagram showing the CNS: 1. ... Autism is classified by the World Health Organization and American Psychological Association as a developmental disability that results from a disorder of the human central nervous system. ... Amyotrophic lateral sclerosis (ALS, sometimes called Lou Gehrigs Disease, Maladie de Charcot or motor neurone disease) is a progressive, fatal, neurodegenerative disease caused by the degeneration of motor neurons, the nerve cells in the central nervous system that control voluntary muscle movement. ... Fibromyalgia (FM or FMS) is a chronic syndrome (constellation of signs and symptoms) characterized by diffuse or specific muscle, joint, or bone pain, fatigue, and a wide range of other symptoms. ... Tinnitus (IPA pronunciation: or ,[1] from the Latin word for ringing[2]) is the perception of sound in the human ear in the absence of corresponding external sound(s). ... Hypoglycemia (hypoglycæmia in the UK) is a medical term referring to a pathologic state produced by a lower than normal level of sugar (glucose) in the blood. ...

History

The negative effects of glutamate were first observed in 1954 by T. Hayashi, a Japanese scientist who noted that direct application of glutamate to the CNS caused seizure activity, though this report went unnoticed for several years. The toxicity of glutamate was then observed by D. R. Lucas and J. P. Newhouse in 1957 when the feeding of monosodium glutamate to newborn mice destroyed the neurons in the inner layers of the retina.^[8] Later, in 1969, John Olney discovered the phenomenon wasn't restricted to the retina but occurred throughout the brain and coined the term excitotoxicity. He also assessed that cell death was restricted to postsynaptic neurons, that glutamate agonists were as neurotoxic as their efficiency to activate glutamate receptors, and that glutamate antagonists could stop the neurotoxicity.^[9] CNS can refer to: in air traffic control, Communication, Navigation, Surveillance often associated with the acronym ATM (Air Traffic Management) as CNS/ATM. the central nervous system the title granted to a Clinical Nurse Specialist the mnemonic for the demogroup Conspiracy the IATA code for Cairns International Airport This is... This article is about the medical term, epileptic seizure, as distinct from a non-epileptic seizure. ... This article is about monosodium glutamate as a food additive. ... Feral mouse A mouse (plural mice) is a rodent that belongs to one of numerous species of small mammals. ... Human eye cross-sectional view. ... Italic text // ahh addiing sum spiice iin hurr`` For other uses, see Brain (disambiguation). ... Programmed cell death (PCD) is the deliberate suicide of an unwanted cell in a multicellular organism. ... A synapse is a connection between two neurons: presynaptic and postsynaptic. ... Agonists An agonist is a substance that binds to a receptor and triggers a response in the cell. ... Antagonists In medicine and biology, a receptor antagonist is a ligand that inhibits the function of an agonist and inverse agonist for a specific receptor. ...

Pathophysiology

Excitotoxicity can occur from substances produced within the body (endogenous excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is paradoxically also the major excitatory neurotransmitter in the mammalian CNS.^[10] During normal conditions, glutamate concentration can be increased up to 1mM in the synaptic cleft, which is rapidly decreased in the lapse of milliseconds. When the glutamate concentration around the synaptic cleft cannot be decreased or reaches higher levels, the neuron kills itself by a process called apoptosis. The word endogenous means arising from within. Compare exogenous. ... In chemistry, concentration is the measure of how much of a given substance there is mixed with another substance. ... The mole (symbol: mol) is the SI base unit that measures an amount of substance. ... Synapses allow nerve cells to communicate with one another through axons and dendrites, converting electrical signals into chemical ones. ... A section of mouse liver showing an apoptotic cell indicated by an arrow // Apoptosis is a process of deliberate life relinquishment by a cell in a multicellular organism. ...

This pathologic phenomenon can also occur after brain injury. Brain trauma or stroke can cause ischemia, in which blood flow is reduced to inadequate levels. Ischemia is followed by accumulation of glutamate and aspartate in the extracellular fluid, causing cell death, which is aggravated by lack of oxygen and glucose. The biochemical cascade resulting from ischemia and involving excitotoxicity is called the ischemic cascade. Because of the events resulting from ischemia and glutamate receptor activation, a deep chemical coma may be induced in patients with brain injury to reduce the metabolic rate of the brain (its need of oxygen and glucose) and save energy to be used to remove glutamate actively. (It must be noted that the main aim in induced comas is to reduce the intracranial pressure, not brain metabolism). Brain damage or brain injury is the destruction or degeneration of brain cells. ... This article needs to be cleaned up to conform to a higher standard of quality. ... Stroke (or cerebrovascular accident or CVA) is the clinical designation for a rapidly developing loss of brain function due to an interruption in the blood supply to all or part of the brain. ... In medicine, ischemia (Greek ισχαιμία, isch- is restriction, hema or haema is blood) is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. ... Human blood smear: a - erythrocytes; b - neutrophil; c - eosinophil; d - lymphocyte. ... Aspartic acid, also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... In some animals, including mammals, the two types of extracellular fluids are interstitial fluid and blood plasma. ... General Name, Symbol, Number oxygen, O, 8 Chemical series nonmetals, chalcogens Group, Period, Block 16, 2, p Appearance colorless (gas) very pale blue (liquid) Standard atomic weight 15. ... Glucose (Glc), a monosaccharide (or simple sugar), is the most important carbohydrate in biology. ... A Biochemical Cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. ... The ischemic cascade is a series of biochemical reactions that take place in the brain after seconds to minutes of ischemia (inadequate blood supply) (Arnold, 2003). ... This article does not cite its references or sources. ... Sodium-Potassium pump, an example of Primary active transport secondary active transport Active transport (sometimes called active uptake) is the mediated transport of biochemicals, and other atomic/molecular substances, across membranes. ... Intracranial pressure, (ICP), is the pressure exerted by the cranium on the brain tissue, cerebrospinal fluid (CSF), and the brains circulating blood volume. ... A few of the metabolic pathways in a cell. ...

One of the damaging results of excess calcium in the cytosol is the opening of the mitochondrial permeability transition pore, a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release proteins that can lead to apoptosis. The pore can also cause mitochondria to release more calcium. In addition, production of adenosine triphosphate (ATP) may be stopped, and ATP synthase may in fact begin hydrolysing ATP instead of producing it.^[11] Mitochondrial permeability transition, or MPT, is an increase in the permeability of the mitochondrial membranes to molecules of less than 1500 Daltons in molecular weight. ... In cell biology, a mitochondrion is an organelle found in the cells of most eukaryotes. ... A section of mouse liver showing an apoptotic cell indicated by an arrow // Apoptosis is a process of deliberate life relinquishment by a cell in a multicellular organism. ... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... An ATP synthase (EC 3. ... Hydrolysis is a chemical reaction or process in which a chemical compound reacts with water. ...

Inadequate adenosine triphosphate production resulting from brain trauma can eliminate electrochemical gradients of certain ions. Glutamate transporters require the maintanance of these ion gradients in order to remove glutamate from the extracellular space. The loss of ion gradients results not only in the halting of glutamate uptake, but also in the reversal of the transporters, causing them to release glutamate and aspartate into the extracellular space. This results in a buildup of glutamate and further damaging activation of glutamate receptors.^[12] Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... In cellular biology, an electrochemical gradient refers to the electrical and chemical properties across a membrane. ... Glutamate transporters exist in the membranes of neurons and glial cells to remove excess amounts of the amino acid neurotransmitters glutamate and aspartate from the synapse. ... In cell biology, molecular biology and related fields, the word extracellular means outside the cell. It is used in contrast to intracellular (inside the cell). ...

On the molecular level, calcium influx is not the only thing responsible for apoptosis induced by excitoxicity. Recently^[13] it has been noted that extrasynaptic NMDA receptor activation, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activate a CREB (cAMP response element binding protein) shut-off, which in turn, caused loss of mitochondrial membrane potential and apoptosis. On the other hand, activation of synaptic NMDA receptors only activated the CREB pathway which activates BDNF (brain-derived neurotrophic factor), not activating apoptosis. Molecular biology is the study of biology at a molecular level. ... CREB (top) is a transcription factor capable of binding DNA (bottom) and regulating gene expression. ... Structure of cAMP cAMP represented in three ways, the left with sticks-representation, the middle with structure formula, and the right with space filled representation. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... In cell biology, a mitochondrion is an organelle found in the cells of most eukaryotes. ... In biochemistry, a metabolic pathway is a series of chemical reactions occurring within a cell, catalyzed by enzymes, resulting in either the formation of a metabolic product to be used or stored by the cell, or the initiation of another metabolic pathway (then called a flux generating step). ... Brain-derived neurotrophic factor (BDNF) is exactly as it states; a neurotrophic factor usually derived in the brain. ...

Excitotoxins in food additives

The most well-known (to the general public) excitotoxic concern is the current debate over aspartame, also known as NutraSweet, and monosodium glutamate (MSG) . Approximately 40% of aspartame (by mass) is broken down into the amino acid aspartic acid (also known as aspartate), an excitotoxin. Because aspartame is metabolized and absorbed very quickly (unlike aspartic acid-containing proteins in foods), it is known that aspartame could spike blood plasma levels of aspartate.^[14] However, blood plasma amino acid levels are not necessarily harmful. Glutamate does not normally cross the blood-brain barrier in most parts of the brain without active uptake by transporters.^[15] Glutamate concentrations in the blood are normally higher than those in the extracellular space around brain cells.^[15] Aspartame has been the subject of a vigorous public controversy regarding its safety and the circumstances around its approval. ... NutraSweet is the company that makes and sells aspartame, an artificial sugar substitute. ... This article is about monosodium glutamate as a food additive. ... Aspartame (or APM) (IPA: ) is the name for an artificial, non-saccharide sweetener, aspartyl-phenylalanine-1-methyl ester; i. ... Aspartic acid (Asp, D), also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... A few of the metabolic pathways in a cell. ... Freeze-fracture morphology of the blood-brain barrier of a rat The blood-brain barrier (abbreviated BBB) is a membranic structure that acts primarily to protect the brain from chemicals in the blood, while still allowing essential metabolic function. ... In cell biology, molecular biology and related fields, the word extracellular (or sometimes extracellular space) means outside the cell. This space is usually taken to be outside the plasma membranes, and occupied by fluid. ...

See also

• Neurotoxicity
• Glutamate receptor
• Glutamatergic system
• Monosodium glutamate
• Aspartame controversy
• NMDA receptor antagonist

Neurotoxicity occurs when the exposure to natural or manmade toxic substances ,which are called neurotoxins, alters the normal activity of the nervous system. ... Glutamate is a neurotransmitter in nerve cells which binds to all glutamate receptors located on neuron membranes, and is an example of a transmembrane receptor. ... The glutamatergic neurotransmitter system plays a crucial role in memory formation and information processing. ... This article is about monosodium glutamate as a food additive. ... Aspartame has been the subject of a vigorous public controversy regarding its safety and the circumstances around its approval. ... NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the NMDA receptor (NMDAR). ...

Sources

• Kandel ER, Schwartz JH, and Jessel TM. 2000. Principles of Neural Science, 4th Edition, Page 928, McGraw Hill
• Blaylock RL. 1996. Excitotoxins: The Taste That Kills Health Press, ISBN 0929173252

Eric Richard Kandel (born November 7, 1929) is a psychiatrist, a neuroscientist and professor of biochemistry and biophysics at Columbia University. ... Principles of Nerual Science cover First published in 1981, Principles of Neural Science is a neuroscience textbook edited by Eric R. Kandel, James Schwartz, and Thomas Jessell. ...

References

1. ^ Manev H, Favaron M, Guidotti A, and Costa E. Delayed increase of Ca²⁺ influx elicited by glutamate: role in neuronal death. Molecular Pharmacoloy. 1989 Jul;36(1):106-112. PMID 2568579. Retrieved on January 31, 2007.
2. ^ Blaylock, R.L. The central role of excitotoxicity in autism spectrum disorders. DORway.com. Retrieved on January 31, 2007.
3. ^ Smith JD, Terpening CM, Schmidt SO, and Gums JG. Relief of fibromyalgia symptoms following discontinuation of dietary excitotoxins. Annals of Pharmacotherapy. 2001 Jun;35(6):702-6. PMID 11408989. Retrieved on January 31, 2007.
4. ^ http://www.freepatentsonline.com/20050214338.html
5. ^ Kim AH, Kerchner GA, and Choi DW. Blocking Excitotoxicity. Chapter 1 in CNS Neuroproteciton. Marcoux FW and Choi DW, editors. Springer, New York. 2002. Pages 3-36
6. ^ Camacho A and Massieu L. Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Archives of Medical Research. 2006. 37(1): 11-18. PMID 16314180. Retrieved on January 31, 2007.
7. ^ Fujikawa DG. Prolonged seizures and cellular injury: understanding the connection. Epilepsy & Behavior. 2005 Dec;7 Suppl 3:S3-11. Published online 2005 Nov 8. PMID 16278099. Retrieved on January 31, 2007.
8. ^ Lucas DR and Newhouse JP. The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Archives of Ophthalmology. 1957 Aug;58(2):193-201. PMID 13443577. Retrieved on January 31, 2007.
9. ^ Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 1969 May 9;164(880):719-21. PMID 5778021. Retrieved on January 31, 2007.
10. ^ Temple MD, O'Leary DM, and Faden AI. The role of glutamate receptors in the pathophysiology of traumatic central nervous system injury. Chapter 4 in Head Trauma: Basic, Preclinical, and Clinical Directions. Miller LP and Hayes RL, editors. Co-edited by Newcomb JK. John Wiley and Sons, Inc. New York. 2001. Pages 87-113.
11. ^ Stavrovskaya IG and Kristal BS. The powerhouse takes control of the cell: Is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death? Free Radical Biology and Medicine. 2005. 38(6): 687-697. PMID 15721979. Retrieved on January 31, 2007.
12. ^ Siegel, G J, Agranoff, BW, Albers RW, Fisher SK, Uhler MD, editors. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects 6th ed. Philadelphia: Lippincott, Williams & Wilkins. 1999.
13. ^ Hardingham GE, Fukunaga Y, and Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neuroscience. 2002 May;5(5):405-414. PMID 11953750. Retrieved on January 31, 2007.
14. ^ Stegink LD, Filer LJ Jr, Bell EF, Ziegler EE. Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. Metabolism. 1987 May;36(5):507-512. PMID 3574137. Retrieved on January 31, 2007.
15. ^ ^{a b} Smith, QR (2000). "Transport of glutamate and other amino acids at the blood-brain barrier". The Journal of nutrition 130 (Supplement 4S): 1016S-1022S. PMID 10736373. Retrieved on 2007-01-31. 

January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... Year 2007 (MMVII) is the current year, a common year starting on Monday of the Gregorian calendar and the AD/CE era. ... January 31 is the 31st day of the year in the Gregorian calendar. ...

External link

• Blaylock RL. 1996. Excitotoxins, Neurodegeneration and Neurodevelopment Describes the possible presence of excitotoxins in food additives. DORway.com. Retrieved on January 31, 2007.