Excitotoxicity



Excitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when cytoskeleton, membrane, and DNA.

Excitotoxicity may be involved in stroke, traumatic brain injury and neurodegenerative diseases of the central nervous system (CNS) such as Multiple sclerosis, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease.[2] Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia[3] and status epilepticus.[4]

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 antagonists could stop the neurotoxicity.[6]

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.[7] During normal conditions, glutamate 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 metabolism).

One of the damaging results of excess calcium in the cytosol is the opening of the hydrolysing ATP instead of producing it.[8]

Inadequate Glutamate transporters require the maintenance 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.[9]

On the molecular level, calcium influx is not the only thing responsible for apoptosis induced by excitoxicity. Recently[10] it has been noted that extrasynaptic NMDA receptor activation, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activate a BDNF (brain-derived neurotrophic factor), not activating apoptosis.

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 hormones.[citation needed] This has been studied with rats. Soy lecithin is likely the worst of all the soy proteins.[citation needed]

See also

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

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. ^ 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
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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. The American Society for Nutritional Sciences. PMID 10736373. Retrieved on 2007-01-31.
 
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