Abstract
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).
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References
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, 298:846–850
Abele A.E. and Miller R.I. Potassium channel activators abolish excitotoxicity in cultured hippocampal pyramidal neurons. Neurosci Lett 1990, 115:195–200
Albin R.L. and Greenamyre J.T. Alternative excitotoxic hypotheses. Neurology 1992, 42:733–738
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, 64:2004–2012
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, 15:961–973
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, 225–228
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, 14:537–544
Beal M. F. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 1992, 31:119–130
Bondy S.C. and Lee D. K. Oxidative stress induced by glutamate receptor agonists. Brain Res 1993, 610:229–233
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, 192:199–200
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.
Chan P.H., Chu L., Chen S.F., et al. Reduced neurotoxicity in transgenic mice overexpressing human copper-zinc superoxide dismutase. Stroke 1990, 21:III80
Choi D.W. Ionic dependence of glutamate neurotoxicity. J Neurosci 1987, 7: 369–379
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.
Dawson V.L., Dawson T.M., Bartley D.A. et al. Mechanisms of nitric oxide mediated neurotoxicity in primary brain cultures. J Neurosci 1993, 13:2651–2661
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, 88:6368–6371
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, 15:6377–6388
Dykens J.A. Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated Ca2+ and Na+: implications for neurodegeneration. J Neurochem 1994, 63:584–591
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, 49:1222–1228
Eimerl S. and Schramm M. The quantity of calcium that appears to induce neuronal death. J Neurochem., 1994, 62:1223–1226
Favit A., Nicoletti F., Scapagnini U. et al. Ubiquinone protects cultured neurons agonist spontaneous and excitotoxin-induced degeneration. J Cereb Blood Flow Metab 1992, 12:638–645
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.
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.
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, 122:265–269
Hong S-C, Goto Y, Lanzino G., et al., Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke 1994, 25, 663–669
Huang Z., Huang P.L., Panahian N., et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994, 265:1883–1885
Lafon-Cazal M., Pietri S., Culcasi M., et al. NMDA-dependent superoxide production and neurotoxicity. Nature 1993, 364:535–537
Lee K.S., Frank S., Vanderklish P., et al. Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci USA 1991, 88:7233–7237
Lees G.T. and Leong W. The sodium-potassium ATPase inhibitor ouabain is neurotoxic in the rat substantia nigra and striatum. Neurosci Lett 1995, 188:113–116
Lei S.Z., Zhang D., Abele A.E. et al. Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+ prevents neurotoxicity. Brain Res 1992, 598:196–202
Lerner-Natoli M., Rondouin G., de Block F., et al. Chronic NO synthase inhibition fails to protect hippocampal neurons against NMDA toxicity. Neuroreport 1992, 3:1109–1112
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.
Majewska M.D. and Bell J.A. Ascorbic acid protects neurons from injury induced by glutamate and NMDA. NeuroReport 1990, 1:194–196
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: 1288–1295
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, 64:2262–2272
Moncada C., Lekieffre D., Arvin B., et al. Effect of NO synthase inhibition on NMDA-and ischaemia-induced hippocampal lesions. Neuroreport 1992, 3:530–532
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, 110:219–224
Nicholls D.G. and Budd S.L. Mitochondria and neuronal survival. Physiol Rev 2000, 80:315–360
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, 451:205–212
Olney J.W. Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science, 1969, 164: 719–721.
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: 1882–1895
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, 15:3318–3327
Rothman S.R. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 1984, 4: 1884–1891
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, 284:1845–1848
Schulz J.B., Henshaw D.R., Siwek D. et al. Involvement of free radicals in excitotoxicity in vivo. J Neurochem 1995, 64:2239–2247
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, 20:1661
Siman R. and Noszek J. C. Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron 1988, 1:279–287
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, 1:366–373
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, 17:51–63
Tymianski M., Charlton M.P., Carlen P. L. et al. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J. Neurosci 1993, 13:2085–2104
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, 11:221–235
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, 72:2563–2569
White R. J. and Reynolds I. J. Mitochondria and Na+/Ca2+ exchange buffer glutamateinduced calcium loads in cultured cortical neurons. J Neurosci 1995, 15:1318–1328
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, 14:924–929
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, 253:1285–1292
Zeevalk G.D. and Nicklas W.J. Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition. J Pharmacol Exp Ther 1991, 257:870–878
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Beal, M.F. (2004). Introduction and Historical Notes. In: Ferrarese, C., Beal, M.F. (eds) Excitotoxicity in Neurological Diseases. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8959-8_1
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DOI: https://doi.org/10.1007/978-1-4419-8959-8_1
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