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Excitotoxins - The ultimate Brainslayer JoAnn Guest Jul 28, 2005 15:11 PDTby James South MAGlutamic acid (also called "glutamate") is the chief excitatoryneurotransmitter in the human and mammalian brain (1-3). Glutamateneurons make up an extensive network throughout the cortex, hippocampus,striatum, thalamus, hypothalamus, cerebellum, and visual/auditory system(4).As a consequence, glutamate neurotransmission is essential for cognition, memory, movement, and sensation (especially taste, sight,hearing) (3).Glutamate and its biochemical "cousin," aspartic acid or aspartate, arethe two most plentiful amino acids in the brain (5). Aspartate is also amajor excitatory neurotransmitter and aspartate can activate neurons inplace of glutamate (1,2).Glutamate and aspartate can be synthesized by cells from each other, andglutamate can be made from various other amino acids, as well. (5)Glutamate and aspartate are both common in foods also.Wheat gluten is 43% glutamate,the milk protein casein is 23% glutamate,and gelatin protein is 12% glutamate.One of the commonest food additives in the developed world is MSG(monosodium glutamate), a flavor enhancer. By 1972 576 million pounds of MSG were added to foods yearly, and MSG use has doubled every decadesince 1948 (2).Aspartic acid is one half of the now ubiquitous sweetener aspartame(NutraSweet®), which is the basis of diet desserts, low-calorie drinks,chewing gum, etc. (2,6) Thus, even a superficial look atglutamate/aspartate in brain chemistry, foods, and food additivetechnology indicates a major role for them in our lives.Without normal glutamate/aspartate neurotransmission, we would be deaf and blind mental and behavioral vegetables. Yet ironically glutamate andaspartate are the two major excitotoxins out of 70 so far discovered(1-3,6).Excitotoxins are biochemical substances (usually amino acids, amino acidanalogs, or amino acid derivatives) that can react with specializedneuronal receptors - glutamate receptors - in the brain or spinal cordin such a way as to cause injury or death to a wide variety of neurons.A broad range of chronic neurodegenerative diseases, such as Alzheimer'sdisease, Parkinson's disease, Huntington's chorea, stroke(multi-infarct) dementia, amyotrophic lateral sclerosis and AIDSdementia are now believed to be caused, at least in part, by theexcitotoxic action of glutamate/aspartate (1-3,7-10).Even the typical memory loss, confusion, and mild intellectualdeterioration that frequently occurs in late middle age/old age may becaused by glutamate/aspartate excitotoxity (2,6).Acute diseases and medical conditions such as stroke brain damage,ischemic (reduced blood flow) brain damage, alcohol withdrawal syndrome,
 
headaches, prolonged epileptic seizures, hypoglycemic brain damage, headtrauma brain damage, and hypoxic (low oxygen) /anoxic (no oxygen) braindamage (e.g. from carbon monoxide or cyanide poisoning, near-drowning,etc.) are also believed to be caused, at least in part, byglutamate/aspartate excitotoxicity (1-3, 7-11).Medical research is focusing more and more on ways to combatexcitotoxicity. A drug called "memantine" which blocks the mainglutamate-excitotoxicity site in neurons - the NMDA glutamate receptor (more on this later) - has been used clinically in Germany withsignificant success in treating Alzheimer's disease since 1991.(12) Memantine's NMDA glutamate-receptor blocking action has also shownpromise in Parkinson's disease, diabetic neuropathic pain, glaucoma, HIVdementia, alcohol dementia, and vascular (stroke or arteriosclerosis -caused dementia (12). (12). (12).Experimental NMDA - glutamate receptor blockers such as MK-801(dizocilpine) have also demonstrated the ability to reduce or eliminatebrain damage from acute conditions such as stroke,ischemia/hypoxia/anoxia, severe hypoglycemia, spinal cord injury andhead trauma (1-3).Yet the few available clinical or experimental excitotoxicity-blockingdrugs so far discovered have significant side effect potential - theymay block normal, essential glutamate neurotransmission as well asexcitotoxicity (1-3,12).Fortunately, a review of the basics of glutamate excitotoxicity revealsa host of preventative nutritional/life extension drug strategies thatwill minimize or even eliminate the excitotoxic "dark side" of glutamate/aspartate.EXCITOTOXICITY 101Glutamate and aspartate are neurotransmitters. Neurotransmitters are thechemicals that allow neurons to communicate with and influence eachother.Neurotransmitters serve either to excite neurons into action, or toinhibit them. Neurotransmitters are stored inside neurons in packagescalled "vesicles."When an electric current "fires" across the surface of a neuron, itcauses some of the vesicles to migrate to the synapses and release their neurotransmitter contents into the synaptic gap.The neurotransmitters then diffuse across the gap and "plug in" toreceptors on the receiving neuron. When enough receptors aresimultaneously activated by neurotransmitters, the neuron will either "fire" an electric current all over its surface membrane, if the,transmitter/receptors are excitatory, or else the neuron will beinhibited from electrically discharging, if theneurotransmitter/receptors are inhibitory.All the neural circuitry of our brains work through this interacting"'relay race" of neurotransmitters inducing electrical activation or inhibition.Glutamate receptors are excitatory - they literally excite the neuronscontaining them into electrical and cellular activity. There are 4 mainclasses of glutamate receptors: the NMDA (N-methyl-D-aspartate)
 
receptor, the quisqualate/AMPA receptor, the kainite receptor, and theAMPA metabotropic receptor.Each of these receptors has a different structure, and has somewhatdifferent effects on the neurons they excite. The NMDA is the mostcommon glutamate receptor in the brain (13). The NMDA, kainite andquisqualate receptors all serve to open ion channels.Looking at the NMDA receptor diagram, the NMDA receptor is the mostcomplex, and had more diverse and potentially devastating effects onreceiving neurons than the others.When glutamate or aspartate attaches to the NMDA receptor, it triggers aflow of sodium (Na) and calcium (Ca) ions into the neuron, and anoutflow of potassium (K).It is this ion exchange that triggers the neuron to "fire" an electriccurrent across its membrane surface, in turn triggering aneurotransmitter release to whatever other neurons the just-fired neuronsynaptically contacts.The kainite and AMPA ion channels primarily permit the exchange of Naand K ions, and generally cause briefer and weaker electric currentsthan NMDA receptors.Thus, when glutamate/aspartate acts through kainite/AMPA receptors, itis weakly excitatory, but when glutamate/aspartate act through NMDAreceptors, they are strongly excitatory. (14) NMDA receptor activationis the basis of long-term potentiation, which in turn is the basis for memory consolidation and long-term memory formation. (14)Looking at the NMDA receptor diagram it shows that there are receptor sites for chemicals other than glutamate.The zinc site can be occupied by the zinc ion, and this will block theopening of the ion channel. The PCP site can be occupied by the drug PCP("angel dust"), an animal tranquilizer; ketamine, an anesthetic; MK-801,an experimental NMDA antagonist; or the previously mentioned meantime.When the PCP is occupied, the opening of the ion channel is blocked,even when glutamate occupies its receptor site. (1-3) The mineralmagnesium (Mg) can occupy a site near to, or perhaps identical with, thePCP site.Magnesium blocks the NMDA channel in a "voltage dependent manner." Thismeans that as long as the neuron is able to maintain its normal restingelectrical potential of -90 millivolts, the magnesium blocks the ionchannel even with glutamate in its receptor.However, if for any reason (e.g. not enough ATP energy to maintain theresting potential) the surface membrane electrical charge of the celldrops to -65 millivolts, allowing the neuron to fire, the magnesiumblock is overcome, and the channel opens, allowing the sodium andcalcium to flood the neuron.(1-3) After the neuron has fired, membrane pumps then pump the excesssodium and calcium back outside the neuron. (15) This is necessary toreturn the neuron to its resting, non-firing state.
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