Information AboutExcitotoxicity |
| CATEGORIES ABOUT EXCITOTOXICITY | |
| neurotrauma | |
| neurochemistry | |
| food safety | |
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Excitotoxicity may be involved in Stroke , Traumatic Brain Injury and other CNS Neurodegenerative Disease s such as Multiple Sclerosis and Alzheimer Disease . Other common conditions that cause excessive glutamate concentrations around neurons are Hypoglycemia and Status Epilepticus , and excitotoxicity may also be linked to Amyotrophic Lateral Sclerosis (ALS), Fibromyalgia , Parkinson's Disease , and Huntington's Disease . HISTORY The process was first 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 . Later, in 1969, John Olney discovered the phenomenon wasn't restricted to the retina but occurred throughout the Brain and coined the term excitotoxic. He also assessed that Cell Death was restricted to Postsynaptic neurons, that glutamate Agonist s were as neurotoxic as their efficiency to activate glutamate receptors, and that glutamate Antagonist s could stop the neurotoxicity. PATHOPHYSIOLOGY Excitotoxicity can occur from substances produced within the body ( Endogenous excitotoxins). A prime example of an excitotoxin in the brain is glutamate, which is paradoxically also the major excitatory neurotransmitter in the mammalian Central Nervous System . During normal conditions, glutamate Concentration can be increased up to 1 MM 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 . 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 ). 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 causes mitochondria to swell and release proteins that can lead to apoptosis. The pore can also cause mitochondria to release more calcium, further stressing the cell. In addition, production of Adenosine Triphosphate (ATP) may be stopped, and ATP Synthase may in fact begin Hydrolysing ATP instead of producing it. Inadequate Adenosine Triphosphate production resulting from brain trauma can eliminate Electrochemical Gradient s of certain ions. Glutamate Transporter s 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. On the Molecular level, calcium influx is not the only thing responsible for apoptosis induced by excitoxicity. Recently 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. ASPARTAME The most well-known (to the general public) excitotoxic concern is the current debate over Aspartame , also known as Nutrasweet . Approximately 40% of aspartame (by mass) is broken down into Aspartic Acid , 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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3670074&query_hl=2 SEE ALSO SOURCE
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