Excitotoxicity

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Excitotoxicity is the pathological process by which neurons are damaged and killed by the overactivations of receptors for the excitatory neurotransmitter glutamate, such as the NMDA receptor and AMPA receptor. 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] to enter the cell. Ca⁺⁺ 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.

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), Fibromyalgia^[2], Parkinson's disease, and Huntington's disease^[3]. Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia and status epilepticus.

1 History
2 Pathophysiology
3 Aspartame
4 See also
5 Source
6 References
7 External link

[edit] 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^[4]. 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^[5].

[edit] 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 ^[6]. 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.

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. In addition, production of adenosine triphosphate (ATP) may be stopped, and ATP synthase may in fact begin hydrolysing ATP instead of producing it^[7].

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^[8].

On the molecular level, calcium influx is not the only thing responsible for apoptosis induced by excitoxicity. Recently ^[9] 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.

[edit] 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. [10], [11]

[edit] See also

[edit] Source

Kandel, E.R., Schwartz, J.H., Jessel T.M. Principles of Neural Science, 4th Edition, pp.928, McGraw Hill (2000).

[edit] References

↑ Manev H, Favaron M, Guidotti A, Costa E. Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol Pharmacol. 1989 Jul;36(1):106-12. PMID 2568579
↑ Smith JD, Terpening CM, Schmidt SO, Gums JG. Relief of fibromyalgia symptoms following discontinuation of dietary excitotoxins. Ann Pharmacother. 2001 Jun;35(6):702-6. PMID 11408989
↑ Kim AH, Kerchner GA, and Choi DW. Blocking Excitotoxicity. Chapter 1 in CNS Neuroproteciton. Marcoux FW and Choi DW, editors. Springer, New York. pp. 3 - 36 (2002).
↑ Lucas DR, Newhouse JP. The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol. 1957 Aug;58(2):193-201. PMID 13443577
↑ Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 1969 May 9;164(880):719-21. PMID 5778021
↑ 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. pp. 87- 113 (2001).
↑ Stavrovskaya IG and Kristal BS. 2005. 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. Volume 38, Issue 6, Pages 687-697.
↑ Siegel, G J, Agranoff, BW, Albers RW, Fisher SK, Uhler MD, editors. 1999. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects 6th ed. Philadelphia: Lippincott,Williams & Wilkins.
↑ Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002 May;5(5):405-14. PMID 11953750