Introduction and Historical Notes

Excitotoxicity in Neurologic Diseases
  • M. Flint Beal


Excitotoxicity refers to neuronal death caused by activation of excitatory amino acid receptors. Several lines of evidence have linked excitotoxic cell death to the pathogenesis of both acute and chronic neurologic diseases. The initial observation that glutamate was neurotoxic was that of Lucas and Newhouse, who found that administration of glutamate to mice resulted in retinal degeneration (Lucas and Newhouse, 1957). Subsequent studies of Olney and colleagues linked neurotoxicity to the activation of excitatory amino acid receptors, and the term “excitotoxin” was coined (Olney, 1969). Further advances were those of Rothman linking release of excitatory amino acids to anoxic cell death in hippocampal cultures (Rothman, 1984), and of Choi linking calcium influx to delayed cell death caused by excitatory amino acids (Choi, 1987). More work has linked activation of excitatory amino acid receptors to free radical generation and nitric oxide, both of which may lead to oxidative stress (Dawson et al., 1991: Lafon-Cazal et al., 1993).


Electron Paramagnetic Resonance Excitatory Amino Acid Kainic Acid Quinolinic Acid Cereb Blood Flow 
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  1. Aarts M., Liu Y., Liu L., Besshoh S., Arundine M., Gurd J.W., Wang Y.T., Salter M.W., Tymianski M. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 2000, 298:846–850CrossRefGoogle Scholar
  2. Abele A.E. and Miller R.I. Potassium channel activators abolish excitotoxicity in cultured hippocampal pyramidal neurons. Neurosci Lett 1990, 115:195–200PubMedCrossRefGoogle Scholar
  3. Albin R.L. and Greenamyre J.T. Alternative excitotoxic hypotheses. Neurology 1992, 42:733–738PubMedCrossRefGoogle Scholar
  4. Anegawa N.J., Lynch D.R., Verdoom T.A., et al. Transfection of N-methyl-D-aspartate receptors in a nonneuronal cell line leads to cell death. J Neurochem 1995, 64:2004–2012PubMedCrossRefGoogle Scholar
  5. Ankarcrona M., Dypbukt J.M., Bonfoco E., Zhivotovsky B., Orrenius S., Lipton SA., Nicotera P. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995, 15:961–973PubMedCrossRefGoogle Scholar
  6. Babbedge R. C., Bland-Ward P.A., Hart S.L., et al. Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles. Br J Pharmacol 1993, 110, 225–228PubMedCrossRefGoogle Scholar
  7. Bartus R.T., Baker K.L., Heiser A.D., et al. Postischemic administration of AK275, a calpain inhibitor, provides substantial protection against focal ischemic brain damage. J Cereb Blood Flow Metab, 1994, 14:537–544PubMedCrossRefGoogle Scholar
  8. Beal M. F. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 1992, 31:119–130PubMedCrossRefGoogle Scholar
  9. Bondy S.C. and Lee D. K. Oxidative stress induced by glutamate receptor agonists. Brain Res 1993, 610:229–233PubMedCrossRefGoogle Scholar
  10. Bridges R.J., Koh J.Y., Hatalski C.G., et al. Increased excitotoxic vulnerability of cortical cultures with reduced levels of glutathione. Eur J Pharmacol 1991, 192:199–200PubMedCrossRefGoogle Scholar
  11. Caner H., Collins J. L. Harris S.M., et al. Attenuation of AMPA-induced neurotoxicity by a calpain inhibitor. Brain Res 1993, 607:354–356.PubMedCrossRefGoogle Scholar
  12. Chan P.H., Chu L., Chen S.F., et al. Reduced neurotoxicity in transgenic mice overexpressing human copper-zinc superoxide dismutase. Stroke 1990, 21:III80PubMedGoogle Scholar
  13. Choi D.W. Ionic dependence of glutamate neurotoxicity. J Neurosci 1987, 7: 369–379PubMedGoogle Scholar
  14. Chow H.S., Lynch I. J.J., Rose K. et al Trolox attenuates cortical neuronal injury induced by iron, ultraviolet light, glucose deprivation or AMPA. Brain Res 1994, 639: 102–108.PubMedCrossRefGoogle Scholar
  15. Dawson V.L., Dawson T.M., Bartley D.A. et al. Mechanisms of nitric oxide mediated neurotoxicity in primary brain cultures. J Neurosci 1993, 13:2651–2661PubMedGoogle Scholar
  16. Dawson V.L.. Dawson T.M., London E.D. et al. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 1991, 88:6368–6371PubMedCrossRefGoogle Scholar
  17. Dugan L. L., Sensi S.L. Canzoniero L. M.T. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J Neurosci 1995, 15:6377–6388PubMedGoogle Scholar
  18. Dykens J.A. Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated Ca2+ and Na+: implications for neurodegeneration. J Neurochem 1994, 63:584–591PubMedCrossRefGoogle Scholar
  19. Dykens J.A., Stern A., Trenkner E. Mechanisms of kainate toxicity to cerebellar neurons in vitro is analogous to reperfusion tissue injury. J Neurochem 1987, 49:1222–1228PubMedCrossRefGoogle Scholar
  20. Eimerl S. and Schramm M. The quantity of calcium that appears to induce neuronal death. J Neurochem., 1994, 62:1223–1226PubMedCrossRefGoogle Scholar
  21. Favit A., Nicoletti F., Scapagnini U. et al. Ubiquinone protects cultured neurons agonist spontaneous and excitotoxin-induced degeneration. J Cereb Blood Flow Metab 1992, 12:638–645PubMedCrossRefGoogle Scholar
  22. Frandsen A., and Schousboe A. Dantrolene prevents glutamate cytotoxicity and Ca2+ release from intracellular stores in cultured cerebral cortical neurons. J Neurochem 1991, 56:1075–1078.PubMedCrossRefGoogle Scholar
  23. Hartley D.M., Kurth M.C., Bjerkness L., et al. Glutamate receptor-induced Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J Neurosci 1993, 13: 1993–2000.PubMedGoogle Scholar
  24. Heyes M.P., Swartz K.J., Markey S.P., et al. Regional brain and cerebrospinal fluid quinolinic acid concentrations in Huntington’s Disease. Neurosci Lett 1991, 122:265–269PubMedCrossRefGoogle Scholar
  25. Hong S-C, Goto Y, Lanzino G., et al., Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke 1994, 25, 663–669PubMedCrossRefGoogle Scholar
  26. Huang Z., Huang P.L., Panahian N., et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994, 265:1883–1885PubMedCrossRefGoogle Scholar
  27. Lafon-Cazal M., Pietri S., Culcasi M., et al. NMDA-dependent superoxide production and neurotoxicity. Nature 1993, 364:535–537PubMedCrossRefGoogle Scholar
  28. Lee K.S., Frank S., Vanderklish P., et al. Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci USA 1991, 88:7233–7237PubMedCrossRefGoogle Scholar
  29. Lees G.T. and Leong W. The sodium-potassium ATPase inhibitor ouabain is neurotoxic in the rat substantia nigra and striatum. Neurosci Lett 1995, 188:113–116PubMedCrossRefGoogle Scholar
  30. Lei S.Z., Zhang D., Abele A.E. et al. Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+ prevents neurotoxicity. Brain Res 1992, 598:196–202PubMedCrossRefGoogle Scholar
  31. Lerner-Natoli M., Rondouin G., de Block F., et al. Chronic NO synthase inhibition fails to protect hippocampal neurons against NMDA toxicity. Neuroreport 1992, 3:1109–1112PubMedCrossRefGoogle Scholar
  32. Lucas D.R. and Newhouse J. P. The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch. Ophthalmol., 1957, 58:193–201.CrossRefGoogle Scholar
  33. Majewska M.D. and Bell J.A. Ascorbic acid protects neurons from injury induced by glutamate and NMDA. NeuroReport 1990, 1:194–196PubMedCrossRefGoogle Scholar
  34. Manev H., Favaron M., Siman R., et al. Glutamate neurotoxicity is independent of calpain 1 inhibition in primary cultures of cerebellar granule cells. J Neurochem 1991, 57: 1288–1295PubMedCrossRefGoogle Scholar
  35. Massieu L., Morales-Villagran A., Tapia R. Accumulation of extracellular glutamate by inhibition of its uptake is not sufficient for inducing neuronal damage: an in vivo microdialysis study. J. Neurochem, 1995, 64:2262–2272PubMedCrossRefGoogle Scholar
  36. Moncada C., Lekieffre D., Arvin B., et al. Effect of NO synthase inhibition on NMDA-and ischaemia-induced hippocampal lesions. Neuroreport 1992, 3:530–532PubMedCrossRefGoogle Scholar
  37. Moore P.K., Wallace P., Gaffen Z., et al. Characterization of the novel nitric oxide synthase inhibitor 7-nitroindazole and related indazoles. Antinociceptive and cardiovascular effects. BrJ Pharmacol 1993, 110:219–224CrossRefGoogle Scholar
  38. Nicholls D.G. and Budd S.L. Mitochondria and neuronal survival. Physiol Rev 2000, 80:315–360PubMedGoogle Scholar
  39. Novelli A., Reilly J.A., Lysko P.G., et al. Glutamate becomes neurotoxic via the N-methylD-aspartate receptor, when intracellular energy levels are reduced. Brain Res 1988, 451:205–212PubMedCrossRefGoogle Scholar
  40. Olney J.W. Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science, 1969, 164: 719–721.PubMedCrossRefGoogle Scholar
  41. Randall R.D. and Thayer S.A. Glutamate-induced calcium transient triggers delayed calcium overload and neurotoxicity in rat hippocampal neurons. J Neurosci 1992, 12: 1882–1895PubMedGoogle Scholar
  42. Reynolds I.J. and Hastings, T.G. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosc 1995, 15:3318–3327Google Scholar
  43. Rothman S.R. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 1984, 4: 1884–1891PubMedGoogle Scholar
  44. Sattler R., Xiong Z., Lu W.Y., Hafner M., MacDonald J.F., Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 1999, 284:1845–1848PubMedCrossRefGoogle Scholar
  45. Schulz J.B., Henshaw D.R., Siwek D. et al. Involvement of free radicals in excitotoxicity in vivo. J Neurochem 1995, 64:2239–2247PubMedCrossRefGoogle Scholar
  46. Schulz J.B., Matthews R.T., Henshaw D.R., et al. Inhibition of neuronal nitric oxide synthase (NOS) protects against neurotoxicity produced by 3-nitropropionic acid, malonate and MPTP. Soc Neurosci Abst 1994, 20:1661Google Scholar
  47. Siman R. and Noszek J. C. Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron 1988, 1:279–287PubMedCrossRefGoogle Scholar
  48. Stout A.K., Raphael H.M., Kanterewicz B.I., Klann E., Reynolds I.J. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1998, 1:366–373PubMedCrossRefGoogle Scholar
  49. Sun A.Y., Cheng Y., Bu Q., et al. The biochemical mechanisms of the excitotoxicity of kainic acid. Free radical formation. Mol Chem Neuropathol 1992, 17:51–63PubMedCrossRefGoogle Scholar
  50. Tymianski M., Charlton M.P., Carlen P. L. et al. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J. Neurosci 1993, 13:2085–2104PubMedGoogle Scholar
  51. Tymianski M., Wallace M.C., Spigelman I., et al. Cell-permanent Ca2+ chelators reduce early excitotoxic and ischemic neuronal injury in vitro and in vivo. Neuron 1993, 11:221–235PubMedCrossRefGoogle Scholar
  52. Wang G.J., Randall R.D., and Thaymer S. A. Glutamate-induced intracellular acidification of cultured hippocampal neurons demonstrates altered energy metabolism resulting from Ca2+ loads. J Neurophysiol 1994, 72:2563–2569PubMedGoogle Scholar
  53. White R. J. and Reynolds I. J. Mitochondria and Na+/Ca2+ exchange buffer glutamateinduced calcium loads in cultured cortical neurons. J Neurosci 1995, 15:1318–1328PubMedGoogle Scholar
  54. Yoshida T., Limmroth Y., Irikura K., et al. The NOS inhibitor, 7-nitroindazole, decreases focal infarct volume but not the response to topical acetylcholine in pial vessels. J Cereb Blood Flow Metab 1994, 14:924–929PubMedCrossRefGoogle Scholar
  55. Zeevalk G.D. and Nicklas W.J. Chemically induced hypoglycemia and anoxia: relationship to glutamate receptor-mediated toxicity in retina. J Pharmacol Exp Ther 1990, 253:1285–1292PubMedGoogle Scholar
  56. Zeevalk G.D. and Nicklas W.J. Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition. J Pharmacol Exp Ther 1991, 257:870–878PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • M. Flint Beal
    • 1
  1. 1.Department of Neurology and NeuroscienceWeill Medical College of Cornell University, New York Presbyterian HospitalNew YorkUSA

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