Excitotoxicity: Wikis

  
  

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Low Ca2+ buffering and excitotoxicity under physiological stress and pathophysiological conditions in motor neuron (MNs). Low Ca2+ buffering in amyotrophic lateral sclerosis (ALS) vulnerable hypoglossal MNs exposes mitochondria to higher Ca2+ loads compared to highly buffered cells. Under normal physiological conditions, the neurotransmitter opens glutamate, NMDA and AMPA receptor channels, and voltage dependent Ca2+ channels (VDCC) with high glutamate release, which is taken up again by EAAT1 and EAAT2. This results in a small rise in intracellular calcium that can be buffered in the cell. In ALS, a disorder in the glutamate receptor channels leads to high calcium conductivity, resulting in high Ca2+ loads and increased risk for mitochondrial damage. This triggers the mitochondrial production of reactive oxygen species (ROS), which then inhibit glial EAAT2 function. This leads to further increases in the glutamate concentration at the synapse and further rises in postsynaptic calcium levels, contributing to the selective vulnerability of MNs in ALS. Jaiswal et al., 2009.[1]

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 (glutamate receptors) 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[2] (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.

Excitotoxicity may be involved in spinal cord injury, 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, alcoholism or alcohol withdrawal and Huntington's disease.[3][4] Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia[5] and status epilepticus.[6]

Contents

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.[7] Later, in 1969, John Olney discovered the phenomenon was not 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.[8]

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 also the major excitatory neurotransmitter in the mammalian CNS.[9] 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 for 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 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.[10]

Inadequate ATP production resulting from brain trauma can eliminate electrochemical gradients of certain ions. Glutamate transporters require the maintenance of these ion gradients 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.[11]

On the molecular level, calcium influx is not the only factor responsible for apoptosis induced by excitoxicity. Recently[12], 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.

See also

Sources

References

  1. ^ Jaiswal MK, Zech WD, Goos M, Leutbecher C, Ferri A, Zippelius A, Carrì MT, Nau R, Keller BU (2009). "Impairment of mitochondrial calcium handling in a mtSOD1 cell culture model of motoneuron disease". BMC Neurosci 10: 64. doi:10.1186/1471-2202-10-64. PMID 19545440. PMC 2716351. http://www.biomedcentral.com/1471-2202/10/64.  
  2. ^ 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.
  3. ^ 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
  4. ^ Hughes JR (February 2009). "Alcohol withdrawal seizures". Epilepsy Behav. doi:10.1016/j.yebeh.2009.02.037. PMID 19249388. http://linkinghub.elsevier.com/retrieve/pii/S1525-5050(09)00093-6.  
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ Temple MD, O'Leary DM, and Faden AI. The role of glutamate receptors in the pathophysiology of traumatic CNS 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.







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