Excitotoxic Cell Death

  • John W. Olney
  • Masahiko J. Ishimaru


In recent years, the excitatory amino acids (EAAs), glutamate (Glu) and aspartate (Asp), have become recognized as the Jekyll/Hyde molecules of the central nervous system (CNS). These common acidic amino acids, which are naturally present in higher concentrations than any other amino acids in the CNS, serve vitally important metabolic, neurotrophic and neurotransmitter roles, but also harbor treacherous neurotoxic (excitotoxic) potential. Recent advances in understanding the excitotoxic properties of these compounds include the identification of several receptor subtypes that mediate Glu/Asp excitotoxicity, the generation of evidence potentially linking excitotoxins of both exogenous and endogenous origin to both acute and chronic neurodegenerative disorders and the development of antiexcitotoxic drugs for protecting against such disorders. Currently, in addition to classical excitotoxicity resulting from hyperactivation of EAA ionotropic receptors, new information is beginning to emerge pertaining to other forms of excitatory transmitter neurotoxicity. Surprisingly, some of the new forms are triggered not by hyperactivation but by hypoactivation of EAA receptors. Over the past several years we have witnessed an explosion in the molecular biology of Glu receptors; over 20 receptor subunits or subtypes having been cloned and sequenced within the past five years. In addition, several Glu transporter receptors have recently been cloned and are currently being studied for their potential role in neurodegenerative diseases. These important new developments are certain to accelerate progress in understanding the relationship between Glu receptor systems and both physiological and pathological processes in the mammalian CNS.


Amyotrophic Lateral Sclerosis NMDA Receptor Kainic Acid Domoic Acid Cell Death Process 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Curtis DR, Watkins JC. The excitation and depression of spinal neurons by structurally related amino acids. J Neurochem 1960, 6: 117–141.PubMedCrossRefGoogle Scholar
  2. 2.
    Lucas DR, Newhouse JP. The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol 1957, 58: 193–201.PubMedCrossRefGoogle Scholar
  3. 3.
    Olney JW. Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science 1969, 164: 719–721.PubMedCrossRefGoogle Scholar
  4. 4.
    Olney, JW. Glutamate-induced neuronal necrosis in the infant mouse hypothalamus: an electron microscopic study. J Neuropathol Exp Neurol 1971, 30: 75–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Olney JW, Ho OL, Rhee V. Cytotoxic effects of acidic and sulphur-containing amino acids on the infant mouse central nervous system. Exp Brain Res 1971, 14: 61–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Olney JW. Toxic effects of glutamate and related amino acids on the developing central nervous system, in Heritable Disorders of Amino Acid Metabolism (Nyhan WN, ed.), John Wiley, New York, 1974, pp. 501–512.Google Scholar
  7. 7.
    Watkins JC, Evans RH. Excitatory amino acid transmitters. Ann Rev Pharmacol Toxicol 1981, 21: 165–204.CrossRefGoogle Scholar
  8. 8.
    Olney JW, Labruyere J, Collins JF. D-Aminophosphonovalerate is 100-fold more powerful than d-alpha-aminoadipate in blocking N-methylaspartate neurotoxicity. Brain Res 1981, 221: 207–210.PubMedCrossRefGoogle Scholar
  9. 9.
    Olney JW, Price MT, Fuller TA, Labruyere J, Samson L, Carpenter M, Mahan K. The anti-excitotoxic effects of certain anesthetics, analgesics and sedative-hypnotics. Neurosci Lett 1986a, 68: 29–34.PubMedCrossRefGoogle Scholar
  10. 10.
    Olney J, Price M, Shahid Salles K, Labruyere J, Frierdich G. MK-801 powerfully protects against N-methyl aspartate neurotoxicity. Eur J Pharmacol 1987, 141: 357–361.PubMedCrossRefGoogle Scholar
  11. 11.
    Boulter J, Hollmann M, O’Shea-Greenfield A, Hartley M, Deneris E, Maron C, Heinemann S. Molecular cloning and functional expression of glutamate receptor subunit genes. Science 1990, 249: 1033–1037.PubMedCrossRefGoogle Scholar
  12. 12.
    Nakanishi S. Molecular diversity of glutamate receptors and implications for brain function. Science 1992, 258: 597–602.PubMedCrossRefGoogle Scholar
  13. 13.
    Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 1992, 256: 1217–1221.PubMedCrossRefGoogle Scholar
  14. 14.
    Schoepp DS. Novel functions for subtypes of metabotropic glutamate receptors. Neurochem Int 1994, 24: 439–449.PubMedCrossRefGoogle Scholar
  15. 15.
    Monyer H, Seeburg PH, Wisden W. Glutamate-operated channels: developmentally early and mature forms arise by alternative splicing. Neuron 1991, 6: 799–810.PubMedCrossRefGoogle Scholar
  16. 16.
    Gregor P, Reeves RH, Jabs EW, Yang X, Dackowski W, Rochelle JM, Brown RH, Haines JL, O’Hara BF, Uhl GR, Seidin MF. Chromosomal localization of glutamate receptor genes: Relationship to familial amyotrophic lateral sclerosis and other neurological disorders of mice and humans. Proc Natl Acad Sci USA 1993, 90: 3053–3057.PubMedCrossRefGoogle Scholar
  17. 17.
    Hollmann M, Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci 1994, 17: 31–108.PubMedCrossRefGoogle Scholar
  18. 18.
    Chen Q, Olney JW, Lukasiewicz P, Romano C. Mechanisms of kainate-induced excitotoxicity in retina: unique role of chloride. Neurosci Abstr 1996, 22: 1278.Google Scholar
  19. 19.
    Romano C, Price MT, Olney JW. Delayed excitotoxic neurodegeneration induced by excitatory amino acid agonists in isolated retina. J Neurochem 1995, 65: 59–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Olney JW, Labruyere J, Price, MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989, 244: 1360–1362.PubMedCrossRefGoogle Scholar
  21. 21.
    Fix AS, Schoepp DD, Olney JW, Vestre WA, Griffey KI, Johnson JA, Tizzano JP. Neonatal exposure to D,L-2-amino-3-phosphonopropionate (D,L-AP3) produces lesions in the eye and optic nerve of adult rats. Dev Brain Res 1993, 75: 223–233.CrossRefGoogle Scholar
  22. 22.
    Corso TD, Sesma MA, Tenkova TI, Der TC, Wozniak DF, Farber NB, Olney JW. Multifocal brain damage induced by phencyclidine is augmented by pilocarpine. Brain Res 1997, 752: 1–14.PubMedCrossRefGoogle Scholar
  23. 23.
    Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995, 52: 998–1007.PubMedCrossRefGoogle Scholar
  24. 24.
    Schoepp, Johnson BG. Inhibition of excitatory amino acid-stimulated phosphoinositide hydrolisis in the neonatal rat hippocampus by 2-amino-3-phosphonopropionate. J Neurochem 1989, 53: 273–278.PubMedCrossRefGoogle Scholar
  25. 25.
    Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW, Farber N, Wozniak DF, Olney JW. Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (Dizocilipine Maleate): A light and electron microscopic evaluation of the rat retrosplenial cortex. Exp Neurol 1993, 123: 204–215.PubMedCrossRefGoogle Scholar
  26. 26.
    Price MT, Romano C, Fix AS, Tizzano JP, Olney JW. Blockade of the second messenger functions of the glutamate metabotropic receptor is associated with degenerative changes in the retina and brain of immature rodents. Neuropharmacology 1995, 34: 1069–1079.PubMedCrossRefGoogle Scholar
  27. 27.
    Perl TM, Bedard L, Kosatsky T, Hockin JC, Todd ECD, Remis RS. An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. New Engl J Med 1990, 322: 1775–1780.PubMedCrossRefGoogle Scholar
  28. 28.
    Teitelbaum JS, Zatorre RJ, Carpenter S, Gendron D, Evans AC, Gjedde A, Cashman NR. Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. N Eng J Med 1990, 322: 1781–1787.CrossRefGoogle Scholar
  29. 29.
    Stewart GR, Zorumski CF, Price MT. Domoic acid: A dementia-inducing excitotoxic food poison with kainic acid receptor specificity. Exp Neurol 1990, 110: 127–138.PubMedCrossRefGoogle Scholar
  30. 30.
    Clifford DB, Olney JW, Benz AM, Fuller TA, Zorumski CF. Ketamine, phencyclidine and MK-801 protect against kainic acid induced seizure-related brain damage. Epilepsia 1990, 31: 382–390.PubMedCrossRefGoogle Scholar
  31. 31.
    Rothman SM. Synaptic release of excitatory amino acid neurotransmitter mediates anoxie neuronal death. J Neurosci 1984, 4: 1884–1891.PubMedGoogle Scholar
  32. 32.
    Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 1986, 19: 105–111.PubMedCrossRefGoogle Scholar
  33. 33.
    McDonald JW, Silverstein FS, Johnston MV. MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur J Pharmacol 1987, 140: 359–361.PubMedCrossRefGoogle Scholar
  34. 34.
    Ikonomidou C, Price MT, Mosinger JL, Frierdich G, Labruyere J, Shahid Salles K, Olney JW. Hypobaric-ischemic conditions produce glutamate-like cytopathology in infant rat brain. J Neurosci 1989, 9: 1693–1700.PubMedGoogle Scholar
  35. 35.
    Faden AI, Demediuk S, Panter S, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989, 244: 798–800.PubMedCrossRefGoogle Scholar
  36. 36.
    Ikonomidou C, Qin YQ, Labruyere J, Olney JW. Motor neuron degeneration induced by excitotoxin agonists has features in common with that seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 1996a, 55: 211–224.PubMedCrossRefGoogle Scholar
  37. 37.
    Wieloch T. Hypoglycemia-induced neuronal damage prevented by an N-methyl-D-aspar-tate antagonist. Science 1985, 230: 681–683.PubMedCrossRefGoogle Scholar
  38. 38.
    Olney JW, Collins RC, Sloviter RS. Excitotoxic mechanisms of epileptic brain damage, in Basic Mechanisms of the Epilepsies: Molecular and Cellular Approaches (Delgado-Escueta AV, Ward AA, Woodbury DM, Porter RJ, eds.), Raven, New York, 1986b, pp: 857–877.Google Scholar
  39. 39.
    Benveniste H, Drejer J, Schousboe A. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 1984, 43: 1369–1374.PubMedCrossRefGoogle Scholar
  40. 40.
    Henneberry RL, Novelli A, Cox JA, Lysko PG. Neurotoxicity at the N-methyl-D-aspartate receptor in energy-compromised neurons. An hypothesis for cell death in aging and disease. Ann NY Acad Sci 1989, 568: 225–233.PubMedCrossRefGoogle Scholar
  41. 41.
    Di X, Harpold T, Watson JC, Bullock MR. Excitotoxic damage in neurotrauma: fact or fiction. Neurol Neurosci 1996, 9: 231–241.Google Scholar
  42. 42.
    Olney J, Wozniak D, Ishimaru M, Farber N. NMDA receptor dysfunction in Alzheimer’s disease, in Alzheimer Disease: From Molecular Biology to Therapy (Becker R, Giacobini E, eds.), Birkhäuser, Boston, 1996, pp. 107–112.Google Scholar
  43. 43.
    Spencer PS, Schaumburg HH, Cohn DF, Seth PK. Lathyrism: a useful model of primary lateral sclerosis, in Research Progress in Motor Neurone Disease (Rose FC, ed.), Pitman, London, 1984, pp. 312–327.Google Scholar
  44. 44.
    Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Annal Neurol 1995, 38: 73–84.PubMedCrossRefGoogle Scholar
  45. 45.
    Rosen DR, Siddique T, Patterson D, et al. Mutations in the Cu/Zn Superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 362: 59–62.PubMedCrossRefGoogle Scholar
  46. 46.
    Gurney M, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu, Zn Superoxide dismutase mutation. Science 1994, 264: 1772–1775.PubMedCrossRefGoogle Scholar
  47. 47.
    Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisoda SS, Cleveland DW, Price DL. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 1995, 14: 1105–1116.PubMedCrossRefGoogle Scholar
  48. 48.
    Ikonomidou C, Qin Y, Labruyere J, Kirby C, Olney JW. Prevention of trauma-induced neurodegeneration in infant rat brain. Peiatr Res 1996, 39: 1020–1027.CrossRefGoogle Scholar
  49. 49.
    Bensimon TG, Lacomblez L, Meininger V. ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994, 330: 585–591.PubMedCrossRefGoogle Scholar
  50. 50.
    Beal MF. Role of excitotoxicity in human neurologic disease. Curr Opinion Neurobiol 1992, 2: 657–662.CrossRefGoogle Scholar
  51. 51.
    Burke JR, Enghild JJ, Martin ME, Jou YS, Myers RM, Roses AD, Vance JM, Strittmatter WJ. Huntingotn and DRPLA protiens selectively interact with the enzyme GAPDH. Nature Med 1996, 2: 347–350.PubMedCrossRefGoogle Scholar
  52. 52.
    Koh J, Yang LL, Cotman CW. Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxin damage. Brain Res 1990, 533: 315–320.PubMedCrossRefGoogle Scholar
  53. 53.
    Farber E. Programmed cell death: Necrosis versus apoptosis. Mod Pathol 1994, 7: 605–609.PubMedGoogle Scholar
  54. 54.
    Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics. Br J Cancer 1972, 26: 239–257.PubMedCrossRefGoogle Scholar
  55. 55.
    Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980, 68: 251–306.PubMedCrossRefGoogle Scholar
  56. 56.
    Ishimaru M, Der TC, Tenkova TI, Sesma MA, Thurston JH, Olney JW. Three types of excitotoxicity evaluated for “apoptosis” signals. Soc Neurosci Abst 1995, d21: p. 1584.Google Scholar
  57. 57.
    Charriaut-Marlangue C, Ben-Ari Y. A cautionary note on the use of the TUNEL stain to determine apoptosis. Neuroreport 1995, 7: 61–64.PubMedGoogle Scholar
  58. 58.
    Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Shulte-Hermann R. In situ detection of fragmented DNA (TUNEL Assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 1995, 21: 1465–1468.PubMedGoogle Scholar
  59. 59.
    Collins RJ, Harmon BV, Gobé GC, Kerr JFR. Internucleosoma DNA cleavage should not be the sole criterion for identifying apaptosis. Int J Radiat Biol 1992, 61: 451–453.PubMedCrossRefGoogle Scholar
  60. 60.
    Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 1992, 119: 493–501PubMedCrossRefGoogle Scholar
  61. 61.
    Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA. NMDA antagonist neurotoxicity: Mechanism and prevention. Science 1991, 254: 1515–1518.PubMedCrossRefGoogle Scholar
  62. 62.
    Olney JW, Misra CH, Rhee C. Brain and retinal damage from the lathyrus excitotoxin, b-N-oxalyl-L-ab-diaminopropionic scid (ODAP). Nature 1976, 264: 659–PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • John W. Olney
  • Masahiko J. Ishimaru

There are no affiliations available

Personalised recommendations