Excitotoxicity

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Mechanism of excitotoxicity

Excitotoxicity (from the Latin excitare = to drive and the Greek toxikon = poison), synonymous with excitotoxicity , in neurosciences denotes the death of a nerve cell through constant overstimulation .

properties

Overactivation of glutamate receptors (in particular the AMPA receptor and the NMDA receptor ) by glutamate or other agonists (in particular kainic acid and NMDA ) can increase the intracellular calcium concentration so much that apoptosis is triggered in the nerve cells. Some phospholipases , endonucleases and proteases (such as calpain ) are activated as calcium-dependent proteins . If excitotoxicity spreads in the tissue, larger areas of the brain can be damaged and die. The excitotoxicity can be increased by the release of TNF-α in the course of a parallel immune reaction .

Excitotoxicity plays a role in spinal cord injuries , head and brain trauma , stroke , poisoning with some neurotoxins and neurodegenerative diseases of the central nervous system (CNS) such as B. multiple sclerosis , Alzheimer's disease , amyotrophic lateral sclerosis (ALS), Parkinson's disease , alcoholism , Huntington's disease . Even with the hypoglycemia and status epilepticus increased glutamate concentration was observed around the neurons.

The structural analogue of glutamate , ss-N-methylamino-L-alanine (BMAA), is a cyanobacterial neurotoxin and an agonist of the NMDA receptor, which is believed to trigger the ALS / Parkinsonism-dementia complex of Guam . The action of the BMAA can be inhibited by the antagonist MK801 .

Individual evidence

  1. a b K. Szydlowska, M. Tymianski: Calcium, ischemia and excitotoxicity. In: Cell calcium. Volume 47, Number 2, February 2010, pp. 122-129, ISSN  1532-1991 . doi : 10.1016 / j.ceca.2010.01.003 . PMID 20167368 .
  2. ^ J. Puyal, V. Ginet, PG Clarke: Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: a challenge for neuroprotection. In: Progress in neurobiology. Volume 105, June 2013, pp. 24-48, ISSN  1873-5118 . doi : 10.1016 / j.pneurobio.2013.03.002 . PMID 23567504 .
  3. G. Olmos, J. Lladó: Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. In: Mediators of inflammation. Volume 2014, 2014, pp. 861231, ISSN  1466-1861 . doi : 10.1155 / 2014/861231 . PMID 24966471 . PMC 4055424 (free full text).
  4. M. Jia, SA Njapo, V. Rastogi, VS Hedna: Taming glutamate excitotoxicity: strategic pathway modulation for neuroprotection. In: CNS drugs. Volume 29, Number 2, February 2015, pp. 153-162, doi : 10.1007 / s40263-015-0225-3 , PMID 25633850 .
  5. H. Prentice, JP Modi, JY Wu: Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases. In: Oxidative medicine and cellular longevity. Volume 2015, 2015, p. 964518, doi : 10.1155 / 2015/964518 , PMID 26576229 , PMC 4630664 (free full text).
  6. ^ AE King, A. Woodhouse, MT Kirkcaldie, JC Vickers: Excitotoxicity in ALS: Overstimulation, or overreaction? In: Experimental neurology. Volume 275 Pt 1, January 2016, pp. 162-171, doi : 10.1016 / j.expneurol.2015.09.019 , PMID 26584004 .
  7. G. Ambrosi, S. Cerri, F. Blandini: A further update on the role of excitotoxicity in the pathogenesis of Parkinson's disease. In: Journal of neural transmission (Vienna, Austria: 1996). Volume 121, number 8, August 2014, pp. 849-859, doi : 10.1007 / s00702-013-1149-z , PMID 24380931 .
  8. A. Mehta, M. Prabhakar, P. Kumar, R. Deshmukh, PL Sharma: Excitotoxicity: bridge to various triggers in neurodegenerative disorders. In: European journal of pharmacology. Volume 698, Number 1-3, January 2013, pp. 6-18, ISSN  1879-0712 . doi : 10.1016 / j.ejphar.2012.10.032 . PMID 23123057 .
  9. MD Sepers, LA Raymond: Mechanisms of synaptic dysfunction and excitotoxicity disease, Huntington's. In: Drug discovery today. Volume 19, number 7, July 2014, pp. 990-996, doi : 10.1016 / j.drudis.2014.02.006 , PMID 24603212 .
  10. KJ Vyas, JH Weiss: BMAA - an unusual cyanobacterial neurotoxin. In: Amyotrophic lateral sclerosis: official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. Volume 10 Suppl 2, 2009, pp. 50-55, doi : 10.3109 / 17482960903268742 , PMID 19929732 .
  11. Chiu, AS; et al .: Excitotoxic potential of the cyanotoxin β-methyl-amino-l-alanine (BMAA) in primary human neurons. In: Toxicon (2012), Volume 60, Issue 6, pp. 1159-1165. doi : 10.1016 / j.toxicon.2012.07.169 .