Concept of Excitotoxicity via Glutamate Receptors

  • Juan C. Piña-Crespo
  • Sara Sanz-Blasco
  • Stuart A. Lipton
Reference work entry


Since its inception, the concept of glutamate excitotoxicity has provided a foundational framework for understanding the role played by excitatory amino acids in disease states of the brain. At the same time, it has served as a guiding principle in the development and evaluation of new anti-excitotoxic drugs, many of which show promise as neuroprotective therapies in a number of neurological conditions. The discovery that glutamate receptors on the cell surface can engage, through second messengers such as calcium (Ca2+), nitric oxide (NO), and inositol phospholipids, downstream intracellular signaling cascades involved in cell death helped uncover the complexity of the excitotoxic cascade. The identification of numerous intracellular effectors of excitotoxicity has provided a physiological and pharmacological basis for understanding the cellular and molecular mechanisms behind glutamate-mediated nerve cell injury and its role in neuropsychiatric diseases. More recently, knowledge of the molecular biology of glutamate receptors has allowed, for the first time, the identification of differences in the pattern of expression of glutamate receptors in human populations afflicted by neuropsychiatric diseases. This knowledge will be useful in uncovering genes that may confer individual susceptibility to excitotoxic damage and, as a result, predisposition to the development of certain mental and neurological diseases. In this chapter, the role of glutamate receptor overactivation in excitotoxic cell injury as well as potential neuroprotective therapies for limiting glutamate-mediated neurotoxicity in disease states of the central nervous system will be discussed.


NMDA Receptor Glutamate Receptor Reactive Nitrogen Species Domoic Acid Kainate Receptor 
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.

List of Abbreviations


2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid)




Bcl-2-associated death promoter


Bcl-2-associated X protein


B-cell lymphoma 2 protein


B-cell lymphoma – extra large protein




Domoic acid


Delayed calcium deregulation


Deoxyribonucleic acid


Excitatory amino acids


Endoplasmic reticulum


Glyceraldehyde-3-phosphate dehydrogenase




Glutamate receptors


Kainic acid


Mitochondrial calcium uniporter


Mitochondrial Na+/Ca2+ transporter


Mitochondrial permeability transition pore


Na+/Ca2+ exchanger


N-methyl-d-aspartic acid


Nitric oxide


Plasma membrane Ca2+ ATPase


Reactive nitrogen species


Reactive oxygen species


Seven in absentia homolog E3 ubiquitin-protein ligase


Voltage-dependent anion-selective channel


Inner mitochondrial membrane potential


  1. Abramov, A. Y., & Duchen, M. R. (2008). Mechanisms underlying the loss of mitochondrial membrane potential in glutamate excitotoxicity. Biochimica et Biophysica Acta, 1777, 953–964.PubMedGoogle Scholar
  2. Alexander, S. P., Mathie, A., & Peters, J. A. (2011). Guide to Receptors and Channels (GRAC), 5th edition. British Journal of Pharmacology, 164(Suppl 1), S1–S324.PubMedGoogle Scholar
  3. Ankarcrona, M., Dypbukt, J. M., Bonfoco, E., Zhivotovsky, B., Orrenius, S., Lipton, S. A., & Nicotera, P. (1995). Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron, 15, 961–973.PubMedGoogle Scholar
  4. Arundine, M., & Tymianski, M. (2004). Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cellular and Molecular Life Sciences, 61, 657–668.PubMedGoogle Scholar
  5. Bano, D., Young, K. W., Guerin, C. J., Lefeuvre, R., Rothwell, N. J., Naldini, L., Rizzuto, R., Carafoli, E., & Nicotera, P. (2005). Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell, 120, 275–285.PubMedGoogle Scholar
  6. Beal, M. F. (1998). Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis. Annals of Neurology, 44, S110–S114.PubMedGoogle Scholar
  7. Bensimon, G., Lacomblez, L., & Meininger, V. (1994). A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. The New England Journal of Medicine, 330, 585–591.PubMedGoogle Scholar
  8. Benveniste, H., Drejer, J., Schousboe, A., & Diemer, N. H. (1984). Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. Journal of Neurochemistry, 43, 1369–1374.PubMedGoogle Scholar
  9. Bernardi, P. (1999). Mitochondrial transport of cations: Channels, exchangers, and permeability transition. Physiological Reviews, 79, 1127–1155.PubMedGoogle Scholar
  10. Bernardi, P., & Von Stockum, S. (2012). The permeability transition pore as a Ca2+ release channel: New answers to an old question. Cell Calcium, 52, 22–27.PubMedCentralPubMedGoogle Scholar
  11. Besancon, E., Guo, S., Lok, J., Tymianski, M., & Lo, E. H. (2008). Beyond NMDA and AMPA glutamate receptors: Emerging mechanisms for ionic imbalance and cell death in stroke. Trends in Pharmacological Sciences, 29, 268–275.PubMedGoogle Scholar
  12. Bliss, T. V., & Collingridge, G. L. (1993). A synaptic model of memory: Long-term potentiation in the hippocampus. Nature, 361, 31–39.PubMedGoogle Scholar
  13. Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P., & Lipton, S. A. (1995). Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures. Proceedings of the National Academy of Sciences of the United States of America, 92, 7162–7166.PubMedCentralPubMedGoogle Scholar
  14. Boulter, J., Hollmann, M., O’shea-Greenfield, A., Hartley, M., Deneris, E., Maron, C., & Heinemann, S. (1990). Molecular cloning and functional expression of glutamate receptor subunit genes. Science, 249, 1033–1037.PubMedGoogle Scholar
  15. Brorson, J. R., Manzolillo, P. A., & Miller, R. J. (1994). Ca2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells. The Journal of Neuroscience, 14, 187–197.PubMedGoogle Scholar
  16. Brorson, J. R., Marcuccilli, C. J., & Miller, R. J. (1995). Delayed antagonism of calpain reduces excitotoxicity in cultured neurons. Stroke, 26, 1259–1266.PubMedGoogle Scholar
  17. Brouns, R., & De Deyn, P. P. (2009). The complexity of neurobiological processes in acute ischemic stroke. Clinical Neurology and Neurosurgery, 111, 483–495.PubMedGoogle Scholar
  18. Brown, G. C. (2010). Nitric oxide and neuronal death. Nitric Oxide, 23, 153–165.PubMedGoogle Scholar
  19. Buckingham, S. C., Campbell, S. L., Haas, B. R., Montana, V., Robel, S., Ogunrinu, T., & Sontheimer, H. (2011). Glutamate release by primary brain tumors induces epileptic activity. Nature Medicine, 17, 1269–1274.PubMedCentralPubMedGoogle Scholar
  20. Budd, S. L., & Nicholls, D. G. (1996). Mitochondria, calcium regulation, and acute glutamate excitotoxicity in cultured cerebellar granule cells. Journal of Neurochemistry, 67, 2282–2291.PubMedGoogle Scholar
  21. Budd, S. L., Tenneti, L., Lishnak, T., & Lipton, S. A. (2000). Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proceedings of the National Academy of Sciences of the United States of America, 97, 6161–6166.PubMedCentralPubMedGoogle Scholar
  22. Bullock, R., Zauner, A., Woodward, J., & Young, H. F. (1995). Massive persistent release of excitatory amino acids following human occlusive stroke. Stroke, 26, 2187–2189.PubMedGoogle Scholar
  23. Cao, G., Xing, J., Xiao, X., Liou, A. K., Gao, Y., Yin, X. M., Clark, R. S., Graham, S. H., & Chen, J. (2007). Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. The Journal of Neuroscience, 27, 9278–9293.PubMedGoogle Scholar
  24. Chen, H. S., & Lipton, S. A. (2006). The chemical biology of clinically tolerated NMDA receptor antagonists. Journal of Neurochemistry, 97, 1611–1626.PubMedGoogle Scholar
  25. Chen, H. S., Pellegrini, J. W., Aggarwal, S. K., Lei, S. Z., Warach, S., Jensen, F. E., & Lipton, S. A. (1992). Open-channel block of N-methyl-d-aspartate (NMDA) responses by memantine: Therapeutic advantage against NMDA receptor-mediated neurotoxicity. The Journal of Neuroscience, 12, 4427–4436.PubMedGoogle Scholar
  26. Chinopoulos, C., & Adam-Vizi, V. (2006). Calcium, mitochondria and oxidative stress in neuronal pathology. Novel aspects of an enduring theme. The FEBS Journal, 273, 433–450.PubMedGoogle Scholar
  27. Cho, D. H., Nakamura, T., & Lipton, S. A. (2010). Mitochondrial dynamics in cell death and neurodegeneration. Cellular and Molecular Life Sciences, 67, 3435–3447.PubMedGoogle Scholar
  28. Choi, D. W. (1985). Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neuroscience Letters, 58, 293–297.PubMedGoogle Scholar
  29. Choi, D. W. (1987). Ionic dependence of glutamate neurotoxicity. The Journal of Neuroscience, 7, 369–379.PubMedGoogle Scholar
  30. Choi, D. W. (1988). Glutamate neurotoxicity and diseases of the nervous system. Neuron, 1, 623–634.PubMedGoogle Scholar
  31. Choi, D. W. (1990). Ketamine reduces NMDA receptor mediated neurotoxicity in cortical cultures. In E. F. Domino (Ed.), Status of ketamine in anesthesiology (pp. 549–555). Ann Arbor, MI: NPP Books.Google Scholar
  32. Choi, D. W., Viseskul, V., Amirthanayagam, M., & Monyer, H. (1989). Aspartate neurotoxicity on cultured cortical neurons. Journal of Neuroscience Research, 23, 116–121.PubMedGoogle Scholar
  33. Cook, D. J., Teves, L., & Tymianski, M. (2012a). Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature, 483, 213–217.PubMedGoogle Scholar
  34. Cook, D. J., Teves, L., & Tymianski, M. (2012b). A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. Science Translational Medicine, 4, 154ra133.Google Scholar
  35. Cooke, S. F., & Bliss, T. V. (2006). Plasticity in the human central nervous system. Brain, 129, 1659–1673.PubMedGoogle Scholar
  36. Curtis, D. R., Phillis, J. W., & Watkins, J. C. (1959). Chemical excitation of spinal neurones. Nature, 183, 611–612.PubMedGoogle Scholar
  37. Curtis, D. R., Phillis, J. W., & Watkins, J. C. (1960). The chemical excitation of spinal neurones by certain acidic amino acids. The Journal of Physiology, 150, 656–682.PubMedCentralPubMedGoogle Scholar
  38. D’orsi, B., Bonner, H., Tuffy, L. P., Dussmann, H., Woods, I., Courtney, M. J., Ward, M. W., & Prehn, J. H. (2012). Calpains are downstream effectors of bax-dependent excitotoxic apoptosis. The Journal of Neuroscience, 32, 1847–1858.PubMedGoogle Scholar
  39. David, G., Talbot, J., & Barrett, E. F. (2003). Quantitative estimate of mitochondrial [Ca2+] in stimulated motor nerve terminals. Cell Calcium, 33, 197–206.PubMedGoogle Scholar
  40. Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S., & Snyder, S. H. (1991). Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proceedings of the National Academy of Sciences of the United States of America, 88, 6368–6371.PubMedCentralPubMedGoogle Scholar
  41. Dawson, V. L., Kizushi, V. M., Huang, P. L., Snyder, S. H., & Dawson, T. M. (1996). Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. The Journal of Neuroscience, 16, 2479–2487.PubMedGoogle Scholar
  42. Doyle, K. P., Simon, R. P., & Stenzel-Poore, M. P. (2008). Mechanisms of ischemic brain damage. Neuropharmacology, 55, 310–318.PubMedCentralPubMedGoogle Scholar
  43. Duchen, M. R. (2000a). Mitochondria and Ca2+ in cell physiology and pathophysiology. Cell Calcium, 28, 339–348.PubMedGoogle Scholar
  44. Duchen, M. R. (2000b). Mitochondria and calcium: From cell signalling to cell death. The Journal of Physiology, 529(Pt 1), 57–68.PubMedCentralPubMedGoogle Scholar
  45. Duchen, M. R. (2012). Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Archiv: European Journal of Physiology, 464, 111–121.PubMedCentralPubMedGoogle Scholar
  46. Dugan, L. L., Sensi, S. L., Canzoniero, L. M., Handran, S. D., Rothman, S. M., Lin, T. S., Goldberg, M. P., & Choi, D. W. (1995). Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-d-aspartate. The Journal of Neuroscience, 15, 6377–6388.PubMedGoogle Scholar
  47. Dumuis, A., Sebben, M., Haynes, L., Pin, J. P., & Bockaert, J. (1988). NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature, 336, 68–70.PubMedGoogle Scholar
  48. Dykens, J. A. (1994). Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated Ca2+ and Na+: Implications for neurodegeneration. Journal of Neurochemistry, 63, 584–591.PubMedGoogle Scholar
  49. Dykens, J. A., Stern, A., & Trenkner, E. (1987). Mechanism of kainate toxicity to cerebellar neurons in vitro is analogous to reperfusion tissue injury. Journal of Neurochemistry, 49, 1222–1228.PubMedGoogle Scholar
  50. Farooqui, A. A., Ong, W. Y., & Horrocks, L. A. (2008). Neurochemical aspects of excitotoxicity. New York, NY: Springer.Google Scholar
  51. Fleischhacker, W. W., Buchgeher, A., & Schubert, H. (1986). Memantine in the treatment of senile dementia of the Alzheimer type. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 10, 87–93.Google Scholar
  52. Fumagalli, E., Funicello, M., Rauen, T., Gobbi, M., & Mennini, T. (2008). Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. European Journal of Pharmacology, 578, 171–176.PubMedGoogle Scholar
  53. Garthwaite, J., Charles, S. L., & Chess-Williams, R. (1988). Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature, 336, 385–388.PubMedGoogle Scholar
  54. Gereau, R. W., & Swanson, G. (2008). The glutamate receptors. Totowa, NJ: Humana Press.Google Scholar
  55. Gillessen, T., Budd, S. L., & Lipton, S. A. (2002). Excitatory amino acid neurotoxicity. Advances in Experimental Medicine and Biology, 513, 3–40.PubMedGoogle Scholar
  56. Greenamyre, J. T. (1986). The role of glutamate in neurotransmission and in neurologic disease. Archives of Neurology, 43, 1058–1063.PubMedGoogle Scholar
  57. Gunter, K. K., Zuscik, M. J., & Gunter, T. E. (1991). The Na+(-independent Ca2+ efflux mechanism of liver mitochondria is not a passive Ca2+/2H+ exchanger. The Journal of Biological Chemistry, 266, 21640–21648.PubMedGoogle Scholar
  58. Hagberg, H., Lehmann, A., Sandberg, M., Nystrom, B., Jacobson, I., & Hamberger, A. (1985). Ischemia-induced shift of inhibitory and excitatory amino acids from intra- to extracellular compartments. Journal of Cerebral Blood Flow and Metabolism, 5, 413–419.PubMedGoogle Scholar
  59. Hara, M. R., & Snyder, S. H. (2007). Cell signaling and neuronal death. Annual Review of Pharmacology and Toxicology, 47, 117–141.PubMedGoogle Scholar
  60. Hara, M. R., Agrawal, N., Kim, S. F., Cascio, M. B., Fujimuro, M., Ozeki, Y., Takahashi, M., Cheah, J. H., Tankou, S. K., Hester, L. D., Ferris, C. D., Hayward, S. D., Snyder, S. H., & Sawa, A. (2005). S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature Cell Biology, 7, 665–674.PubMedGoogle Scholar
  61. Hayashi, T. (1952). A physiological study of epileptic seizures following cortical stimulation in animals and its application to human clinics. The Japanese Journal of Physiology, 3, 46–64.PubMedGoogle Scholar
  62. Hayashi, T. (1954). Effects of sodium glutamate on the nervous system. The Keio Journal of Medicine, 3, 183–192.Google Scholar
  63. Hollmann, M., & Heinemann, S. (1994). Cloned glutamate receptors. Annual Review of Neuroscience, 17, 31–108.PubMedGoogle Scholar
  64. Hollmann, M., O’shea-Greenfield, A., Rogers, S. W., & Heinemann, S. (1989). Cloning by functional expression of a member of the glutamate receptor family. Nature, 342, 643–648.PubMedGoogle Scholar
  65. Hu, N. W., Ondrejcak, T., & Rowan, M. J. (2012). Glutamate receptors in preclinical research on Alzheimer’s disease: Update on recent advances. Pharmacology, Biochemistry, and Behavior, 100, 855–862.PubMedGoogle Scholar
  66. Ichas, F., Jouaville, L. S., & Mazat, J. P. (1997). Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell, 89, 1145–1153.PubMedGoogle Scholar
  67. Jeffery, B., Barlow, T., Moizer, K., Paul, S., & Boyle, C. (2004). Amnesic shellfish poison. Food and Chemical Toxicology, 42, 545–557.PubMedGoogle Scholar
  68. Jensen, F. E. (2005). Role of glutamate receptors in periventricular leukomalacia. Journal of Child Neurology, 20, 950–959.PubMedGoogle Scholar
  69. Kaul, M., Garden, G. A., & Lipton, S. A. (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature, 410, 988–994.PubMedGoogle Scholar
  70. Keinanen, K., Wisden, W., Sommer, B., Werner, P., Herb, A., Verdoorn, T. A., Sakmann, B., & Seeburg, P. H. (1990). A family of AMPA-selective glutamate receptors. Science, 249, 556–560.PubMedGoogle Scholar
  71. Kim, M. J., Jo, D. G., Hong, G. S., Kim, B. J., Lai, M., Cho, D. H., Kim, K. W., Bandyopadhyay, A., Hong, Y. M., Kim, D. H., Cho, C., Liu, J. O., Snyder, S. H., & Jung, Y. K. (2002). Calpain-dependent cleavage of cain/cabin1 activates calcineurin to mediate calcium-triggered cell death. Proceedings of the National Academy of Sciences of the United States of America, 99, 9870–9875.PubMedCentralPubMedGoogle Scholar
  72. Kirichok, Y., Krapivinsky, G., & Clapham, D. E. (2004). The mitochondrial calcium uniporter is a highly selective ion channel. Nature, 427, 360–364.PubMedGoogle Scholar
  73. Koumura, A., Nonaka, Y., Hyakkoku, K., Oka, T., Shimazawa, M., Hozumi, I., Inuzuka, T., & Hara, H. (2008). A novel calpain inhibitor, ((1S)-1((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl) carbamic acid 5-methoxy-3-oxapentyl ester, protects neuronal cells from cerebral ischemia-induced damage in mice. Neuroscience, 157, 309–318.PubMedGoogle Scholar
  74. Kroemer, G., Galluzzi, L., & Brenner, C. (2007). Mitochondrial membrane permeabilization in cell death. Physiological Reviews, 87, 99–163.PubMedGoogle Scholar
  75. Kumar, J., & Mayer, M. L. (2012). Functional insights from glutamate receptor ion channel structures. Annual Review of Physiology, 75, 313–337.PubMedGoogle Scholar
  76. Kupina, N. C., Nath, R., Bernath, E. E., Inoue, J., Mitsuyoshi, A., Yuen, P. W., Wang, K. K., & Hall, E. D. (2001). The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury. Journal of Neurotrauma, 18, 1229–1240.PubMedGoogle Scholar
  77. Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P., & Meininger, V. (1996). Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet, 347, 1425–1431.PubMedGoogle Scholar
  78. Lafon-Cazal, M., Pietri, S., Culcasi, M., & Bockaert, J. (1993). NMDA-dependent superoxide production and neurotoxicity. Nature, 364, 535–537.PubMedGoogle Scholar
  79. Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S., & Snyder, S. H. (1998). Cain, a novel physiologic protein inhibitor of calcineurin. The Journal of Biological Chemistry, 273, 18325–18331.PubMedGoogle Scholar
  80. Landshamer, S., Hoehn, M., Barth, N., Duvezin-Caubet, S., Schwake, G., Tobaben, S., Kazhdan, I., Becattini, B., Zahler, S., Vollmar, A., Pellecchia, M., Reichert, A., Plesnila, N., Wagner, E., & Culmsee, C. (2008). Bid-induced release of AIF from mitochondria causes immediate neuronal cell death. Cell Death and Differentiation, 15, 1553–1563.PubMedCentralPubMedGoogle Scholar
  81. Latremoliere, A., & Woolf, C. J. (2009). Central sensitization: A generator of pain hypersensitivity by central neural plasticity. The Journal of Pain, 10, 895–926.PubMedCentralPubMedGoogle Scholar
  82. Lau, A., & Tymianski, M. (2010). Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Archiv: European Journal of Physiology, 460, 525–542.PubMedGoogle Scholar
  83. Lazarewicz, J. W., Wroblewski, J. T., Palmer, M. E., & Costa, E. (1988). Activation of N-methyl-d-aspartate-sensitive glutamate receptors stimulates arachidonic acid release in primary cultures of cerebellar granule cells. Neuropharmacology, 27, 765–769.PubMedGoogle Scholar
  84. Lefebvre, K. A., & Robertson, A. (2010). Domoic acid and human exposure risks: A review. Toxicon, 56, 218–230.PubMedGoogle Scholar
  85. Lipton, S. A. (2004). Turning down, but not off. Nature, 428, 473.PubMedGoogle Scholar
  86. Lipton, S. A. (2007). Pathologically activated therapeutics for neuroprotection. Nature Reviews Neuroscience, 8, 803–808.PubMedGoogle Scholar
  87. Lipton, S. A., & Rosenberg, P. A. (1994). Excitatory amino acids as a final common pathway for neurologic disorders. The New England Journal of Medicine, 330, 613–622.PubMedGoogle Scholar
  88. Lipton, S. A., Choi, Y. B., Pan, Z. H., Lei, S. Z., Chen, H. S., Sucher, N. J., Loscalzo, J., Singel, D. J., & Stamler, J. S. (1993). A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature, 364, 626–632.PubMedGoogle Scholar
  89. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., & Wang, X. (1996). Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell, 86, 147–157.PubMedGoogle Scholar
  90. Liu, J., Liu, M. C., & Wang, K. K. (2008). Calpain in the CNS: From synaptic function to neurotoxicity. Science Signaling, 1, re1.PubMedGoogle Scholar
  91. Lodge, D. (2009). The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology, 56, 6–21.PubMedGoogle Scholar
  92. Lu, Y. M., Yin, H. Z., Chiang, J., & Weiss, J. H. (1996). Ca2+-permeable AMPA/kainate and NMDA channels: High rate of Ca2+ influx underlies potent induction of injury. The Journal of Neuroscience, 16, 5457–5465.PubMedGoogle Scholar
  93. Lubisch, W., Beckenbach, E., Bopp, S., Hofmann, H. P., Kartal, A., Kastel, C., Lindner, T., Metz-Garrecht, M., Reeb, J., Regner, F., Vierling, M., & Moller, A. (2003). Benzoylalanine-derived ketoamides carrying vinylbenzyl amino residues: Discovery of potent water-soluble calpain inhibitors with oral bioavailability. Journal of Medicinal Chemistry, 46, 2404–2412.PubMedGoogle Scholar
  94. Lucas, D. R., & Newhouse, J. P. (1957). The toxic effect of sodium l-glutamate on the inner layers of the retina. Archives of Ophthalmology, 58, 193–201.PubMedGoogle Scholar
  95. Majewska, M. D., & Bell, J. A. (1990). Ascorbic acid protects neurons from injury induced by glutamate and NMDA. Neuroreport, 1, 194–196.PubMedGoogle Scholar
  96. Martinez-Ruiz, A., Cadenas, S., & Lamas, S. (2011). Nitric oxide signaling: Classical, less classical, and nonclassical mechanisms. Free Radical Biology & Medicine, 51, 17–29.Google Scholar
  97. Mattson, M. P. (2003). Excitotoxic and excitoprotective mechanisms: Abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Medicine, 3, 65–94.PubMedGoogle Scholar
  98. Mattson, M. P., Haughey, N. J., & Nath, A. (2005). Cell death in HIV dementia. Cell Death and Differentiation, 12(Suppl. 1), 893–904.PubMedGoogle Scholar
  99. Mcshane, R., Areosa Sastre, A., & Minakaran, N. (2006). Memantine for dementia. Cochrane Database of Systematic Reviews, 2, CD003154.Google Scholar
  100. Mehta, A., Prabhakar, M., Kumar, P., Deshmukh, R., & Sharma, P. L. (2013). Excitotoxicity: Bridge to various triggers in neurodegenerative disorders. European Journal of Pharmacology, 698, 6–18.PubMedGoogle Scholar
  101. Meldrum, B. S. (1993). Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathology, 3, 405–412.PubMedGoogle Scholar
  102. Miller, R. G., Mitchell, J. D., & Moore, D. H. (2012). Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database of Systematic Reviews, 3, CD001447.PubMedGoogle Scholar
  103. Mucke, L., & Selkoe, D. J. (2012). Neurotoxicity of amyloid beta-protein: Synaptic and network dysfunction. Cold Spring Harbor Perspectives in Medicine, 2, a006338.PubMedCentralPubMedGoogle Scholar
  104. Nakamura, T., & Lipton, S. A. (2010). Preventing Ca2+-mediated nitrosative stress in neurodegenerative diseases: Possible pharmacological strategies. Cell Calcium, 47, 190–197.PubMedCentralPubMedGoogle Scholar
  105. Nakamura, T., & Lipton, S. A. (2011). Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death and Differentiation, 18, 1478–1486.PubMedCentralPubMedGoogle Scholar
  106. Nakanishi, S. (1992). Molecular diversity of glutamate receptors and implications for brain function. Science, 258, 597–603.PubMedGoogle Scholar
  107. Nicholls, J. G., Martin, A. R., Fuchs, P. A., Brown, D. A., Diamond, M. E., & Weisblat, D. (2012). From neuron to brain (5th ed.). Sunderland, MA: Sinauer Associates.Google Scholar
  108. Nicoletti, F., Bockaert, J., Collingridge, G. L., Conn, P. J., Ferraguti, F., Schoepp, D. D., Wroblewski, J. T., & Pin, J. P. (2011). Metabotropic glutamate receptors: From the workbench to the bedside. Neuropharmacology, 60, 1017–1041.PubMedCentralPubMedGoogle Scholar
  109. Nimmrich, V., Reymann, K. G., Strassburger, M., Schoder, U. H., Gross, G., Hahn, A., Schoemaker, H., Wicke, K., & Moller, A. (2010). Inhibition of calpain prevents NMDA-induced cell death and beta-amyloid-induced synaptic dysfunction in hippocampal slice cultures. British Journal of Pharmacology, 159, 1523–1531.PubMedCentralPubMedGoogle Scholar
  110. Niswender, C. M., & Conn, P. J. (2010). Metabotropic glutamate receptors: Physiology, pharmacology, and disease. Annual Review of Pharmacology and Toxicology, 50, 295–322.PubMedCentralPubMedGoogle Scholar
  111. O’collins, V. E., Macleod, M. R., Donnan, G. A., Horky, L. L., Van Der Worp, B. H., & Howells, D. W. (2006). 1,026 experimental treatments in acute stroke. Annals of Neurology, 59, 467–477.PubMedGoogle Scholar
  112. Okamoto, S. (1951). Epileptogenic action of glutamate directly applied into the brains of animals and inhibitory effects of protein and tissue emulsions on its action. Journal of the Physiological Society, Japan, 13, 555–562.Google Scholar
  113. Olney, J. W. (1969). Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science, 164, 719–721.PubMedGoogle Scholar
  114. Olney, J. W. (1978). Neurotoxicity of excitatory amino acids. In E. G. McGeer, J. W. Olney, & P. L. McGeer (Eds.), Kainic acid as a tool in neurobiology (pp. 95–121). New York, NY: Raven Press.Google Scholar
  115. Olney, J. W. (2003). Excitotoxicity, apoptosis and neuropsychiatric disorders. Current Opinion in Pharmacology, 3, 101–109.PubMedGoogle Scholar
  116. Olney, J. W., & Ho, O. L. (1970). Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine. Nature, 227, 609–611.PubMedGoogle Scholar
  117. Olney, J. W., & Sharpe, L. G. (1969). Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science, 166, 386–388.PubMedGoogle Scholar
  118. Olney, J. W., Price, M. T., Labruyere, J., Salles, K. S., Frierdich, G., Mueller, M., & Silverman, E. (1987). Anti-parkinsonian agents are phencyclidine agonists and N-methyl-d-aspartate antagonists. European Journal of Pharmacology, 142, 319–320.PubMedGoogle Scholar
  119. Orrenius, S., Zhivotovsky, B., & Nicotera, P. (2003). Regulation of cell death: The calcium-apoptosis link. Nature Reviews. Molecular Cell Biology, 4, 552–565.PubMedGoogle Scholar
  120. Ow, Y. P., Green, D. R., Hao, Z., & Mak, T. W. (2008). Cytochrome c: Functions beyond respiration. Nature Reviews. Molecular Cell Biology, 9, 532–542.PubMedGoogle Scholar
  121. Perez-Pinzon, M. A., Stetler, R. A., & Fiskum, G. (2012). Novel mitochondrial targets for neuroprotection. Journal of Cerebral Blood Flow and Metabolism, 32, 1362–1376.PubMedCentralPubMedGoogle Scholar
  122. Perl, T. M., Bedard, L., Kosatsky, T., Hockin, J. C., Todd, E. C., & Remis, R. S. (1990). An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. The New England Journal of Medicine, 322, 1775–1780.PubMedGoogle Scholar
  123. Pivovarova, N. B., Hongpaisan, J., Andrews, S. B., & Friel, D. D. (1999). Depolarization-induced mitochondrial Ca accumulation in sympathetic neurons: Spatial and temporal characteristics. The Journal of Neuroscience, 19, 6372–6384.PubMedGoogle Scholar
  124. Polster, B. M., Basanez, G., Etxebarria, A., Hardwick, J. M., & Nicholls, D. G. (2005). Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. The Journal of Biological Chemistry, 280, 6447–6454.PubMedGoogle Scholar
  125. Puttfarcken, P. S., Lyons, W. E., & Coyle, J. T. (1992). Dissociation of nitric oxide generation and kainate-mediated neuronal degeneration in primary cultures of rat cerebellar granule cells. Neuropharmacology, 31, 565–575.PubMedGoogle Scholar
  126. Rabey, J. M., Nissipeanu, P., & Korczyn, A. D. (1992). Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson’s disease. Journal of Neural Transmission. Parkinson’s Disease and Dementia Section, 4, 277–282.PubMedGoogle Scholar
  127. Randall, R. D., & Thayer, S. A. (1992). Glutamate-induced calcium transient triggers delayed calcium overload and neurotoxicity in rat hippocampal neurons. The Journal of Neuroscience, 12, 1882–1895.PubMedGoogle Scholar
  128. Raymond, L. A., Andre, V. M., Cepeda, C., Gladding, C. M., Milnerwood, A. J., & Levine, M. S. (2011). Pathophysiology of Huntington’s disease: Time-dependent alterations in synaptic and receptor function. Neuroscience, 198, 252–273.PubMedCentralPubMedGoogle Scholar
  129. Rego, A. C., Santos, M. S., & Oliveira, C. R. (2000). Glutamate-mediated inhibition of oxidative phosphorylation in cultured retinal cells. Neurochemistry International, 36, 159–166.PubMedGoogle Scholar
  130. Reisberg, B., Doody, R., Stoffler, A., Schmitt, F., Ferris, S., & Mobius, H. J. (2003). Memantine in moderate-to-severe Alzheimer’s disease. The New England Journal of Medicine, 348, 1333–1341.PubMedGoogle Scholar
  131. Reynolds, I. J., & Hastings, T. G. (1995). Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. The Journal of Neuroscience, 15, 3318–3327.PubMedGoogle Scholar
  132. Rigoulet, M., Yoboue, E. D., & Devin, A. (2011). Mitochondrial ROS generation and its regulation: Mechanisms involved in H2O2 signaling. Antioxidants & Redox Signaling, 14, 459–468.Google Scholar
  133. Rizzuto, R., De Stefani, D., Raffaello, A., & Mammucari, C. (2012). Mitochondria as sensors and regulators of calcium signalling. Nature Reviews. Molecular Cell Biology, 13, 566–578.PubMedGoogle Scholar
  134. Rothman, S. (1984). Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. The Journal of Neuroscience, 4, 1884–1891.PubMedGoogle Scholar
  135. Rothman, S. M., & Olney, J. W. (1986). Glutamate and the pathophysiology of hypoxic – ischemic brain damage. Annals of Neurology, 19, 105–111.PubMedGoogle Scholar
  136. Rothstein, J. D. (1996). Therapeutic horizons for amyotrophic lateral sclerosis. Current Opinion in Neurobiology, 6, 679–687.PubMedGoogle Scholar
  137. Sabbagh, M. N., Hake, A. M., Ahmed, S., & Farlow, M. R. (2005). The use of memantine in dementia with Lewy bodies. Journal of Alzheimer’s Disease, 7, 285–289.PubMedGoogle Scholar
  138. Sanz-Blasco, S., Valero, R. A., Rodriguez-Crespo, I., Villalobos, C., & Nunez, L. (2008). Mitochondrial Ca2+ overload underlies Aβ oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS One, 3, e2718.PubMedCentralPubMedGoogle Scholar
  139. Sattler, R., Xiong, Z., Lu, W. Y., Hafner, M., Macdonald, J. F., & Tymianski, M. (1999). Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science, 284, 1845–1848.PubMedGoogle Scholar
  140. Savitz, S. I., & Fisher, M. (2007). Future of neuroprotection for acute stroke: In the aftermath of the SAINT trials. Annals of Neurology, 61, 396–402.PubMedGoogle Scholar
  141. Siman, R., Noszek, J. C., & Kegerise, C. (1989). Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage. The Journal of Neuroscience, 9, 1579–1590.PubMedGoogle Scholar
  142. Simon, R. P., Swan, J. H., Griffiths, T., & Meldrum, B. S. (1984). Blockade of N-methyl-d-aspartate receptors may protect against ischemic damage in the brain. Science, 226, 850–852.PubMedGoogle Scholar
  143. Skolnick, P., Popik, P., & Trullas, R. (2009). Glutamate-based antidepressants: 20 years on. Trends in Pharmacological Sciences, 30, 563–569.PubMedGoogle Scholar
  144. Sladeczek, F., Pin, J. P., Recasens, M., Bockaert, J., & Weiss, S. (1985). Glutamate stimulates inositol phosphate formation in striatal neurones. Nature, 317, 717–719.PubMedGoogle Scholar
  145. Sugiyama, H., Ito, I., & Hirono, C. (1987). A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature, 325, 531–533.PubMedGoogle Scholar
  146. Surmeier, D. J., Guzman, J. N., Sanchez-Padilla, J., & Goldberg, J. A. (2011). The origins of oxidant stress in Parkinson’s disease and therapeutic strategies. Antioxidants & Redox Signaling, 14, 1289–1301.Google Scholar
  147. Susin, S. A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, E., Geuskens, M., & Kroemer, G. (1996). Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. The Journal of Experimental Medicine, 184, 1331–1341.PubMedGoogle Scholar
  148. Sutherland, B. A., Minnerup, J., Balami, J. S., Arba, F., Buchan, A. M., & Kleinschnitz, C. (2012). Neuroprotection for ischaemic stroke: Translation from the bench to the bedside. International Journal of Stroke, 7, 407–418.PubMedGoogle Scholar
  149. Syntichaki, P., & Tavernarakis, N. (2003). The biochemistry of neuronal necrosis: Rogue biology? Nature Reviews Neuroscience, 4, 672–684.PubMedGoogle Scholar
  150. Takano, T., Lin, J. H., Arcuino, G., Gao, Q., Yang, J., & Nedergaard, M. (2001). Glutamate release promotes growth of malignant gliomas. Nature Medicine, 7, 1010–1015.PubMedGoogle Scholar
  151. Teitelbaum, J. S., Zatorre, R. J., Carpenter, S., Gendron, D., Evans, A. C., Gjedde, A., & Cashman, N. R. (1990). Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. The New England Journal of Medicine, 322, 1781–1787.PubMedGoogle Scholar
  152. Tenneti, L., & Lipton, S. A. (2000). Involvement of activated caspase-3-like proteases in N-methyl-d-aspartate-induced apoptosis in cerebrocortical neurons. Journal of Neurochemistry, 74, 134–142.PubMedGoogle Scholar
  153. Tenneti, L., D’emilia, D. M., Troy, C. M., & Lipton, S. A. (1998). Role of caspases in N-methyl-d-aspartate-induced apoptosis in cerebrocortical neurons. Journal of Neurochemistry, 71, 946–959.PubMedGoogle Scholar
  154. Thayer, S. A., & Wang, G. J. (1995). Glutamate-induced calcium loads: Effects on energy metabolism and neuronal viability. Clinical and Experimental Pharmacology & Physiology, 22, 303–304.Google Scholar
  155. Trapp, B. D., & Stys, P. K. (2009). Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurology, 8, 280–291.PubMedGoogle Scholar
  156. Traynelis, S. F., Wollmuth, L. P., Mcbain, C. J., Menniti, F. S., Vance, K. M., Ogden, K. K., Hansen, K. B., Yuan, H., Myers, S. J., & Dingledine, R. (2010). Glutamate receptor ion channels: Structure, regulation, and function. Pharmacological Reviews, 62, 405–496.PubMedCentralPubMedGoogle Scholar
  157. Troy, C. M., Akpan, N., & Jean, Y. Y. (2011). Regulation of caspases in the nervous system implications for functions in health and disease. Progress in Molecular Biology and Translational Science, 99, 265–305.PubMedGoogle Scholar
  158. Tymianski, M. (2010). Can molecular and cellular neuroprotection be translated into therapies for patients?: Yes, but not the way we tried it before. Stroke, 41, S87–S90.PubMedGoogle Scholar
  159. Van Houten, B., Woshner, V., & Santos, J. H. (2006). Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair, 5, 145–152.PubMedGoogle Scholar
  160. Vandenabeele, P., Orrenius, S., & Zhivotovsky, B. (2005). Serine proteases and calpains fulfill important supporting roles in the apoptotic tragedy of the cellular opera. Cell Death and Differentiation, 12, 1219–1224.PubMedGoogle Scholar
  161. Vandongen, A. M. (2009). Biology of the NMDA receptor. Boca Raton, FL: CRC Press.Google Scholar
  162. Volterra, A., Trotti, D., Cassutti, P., Tromba, C., Salvaggio, A., Melcangi, R. C., & Racagni, G. (1992). High sensitivity of glutamate uptake to extracellular free arachidonic acid levels in rat cortical synaptosomes and astrocytes. Journal of Neurochemistry, 59, 600–606.PubMedGoogle Scholar
  163. Vosler, P. S., Brennan, C. S., & Chen, J. (2008). Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Molecular Neurobiology, 38, 78–100.PubMedCentralPubMedGoogle Scholar
  164. Wang, K. K., Nath, R., Posner, A., Raser, K. J., Buroker-Kilgore, M., Hajimohammadreza, I., Probert, A. W., Jr., Marcoux, F. W., Ye, Q., Takano, E., Hatanaka, M., Maki, M., Caner, H., Collins, J. L., Fergus, A., Lee, K. S., Lunney, E. A., Hays, S. J., & Yuen, P. (1996). An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective. Proceedings of the National Academy of Sciences of the United States of America, 93, 6687–6692.PubMedCentralPubMedGoogle Scholar
  165. Wang, H. G., Pathan, N., Ethell, I. M., Krajewski, S., Yamaguchi, Y., Shibasaki, F., Mckeon, F., Bobo, T., Franke, T. F., & Reed, J. C. (1999). Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science, 284, 339–343.PubMedGoogle Scholar
  166. Ward, M. W., Rego, A. C., Frenguelli, B. G., & Nicholls, D. G. (2000). Mitochondrial membrane potential and glutamate excitotoxicity in cultured cerebellar granule cells. The Journal of Neuroscience, 20, 7208–7219.PubMedGoogle Scholar
  167. Watkins, J. C. (1962). The synthesis of some acidic amino acids possessing neuropharmacological activity. Journal of Medicinal and Pharmaceutical Chemistry, 91, 1187–1199.PubMedGoogle Scholar
  168. Watkins, J. C. (2000). l-Glutamate as a central neurotransmitter: Looking back. Biochemical Society Transactions, 28, 297–309.PubMedGoogle Scholar
  169. Watkins, J. C., & Evans, R. H. (1981). Excitatory amino acid transmitters. Annual Review of Pharmacology and Toxicology, 21, 165–204.PubMedGoogle Scholar
  170. Watkins, S., & Sontheimer, H. (2012). Unique biology of gliomas: Challenges and opportunities. Trends in Neurosciences, 35, 546–556.PubMedCentralPubMedGoogle Scholar
  171. Weil-Malherbe, H. (1950). Significance of glutamic acid for the metabolism of nervous tissue. Physiological Reviews, 30, 549–568.PubMedGoogle Scholar
  172. Wu, H. Y., Tomizawa, K., & Matsui, H. (2007). Calpain-calcineurin signaling in the pathogenesis of calcium-dependent disorder. Acta Medica Okayama, 61, 123–137.PubMedGoogle Scholar
  173. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T. I., Jones, D. P., & Wang, X. (1997). Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science, 275, 1129–1132.PubMedGoogle Scholar
  174. Ye, Z. C., & Sontheimer, H. (1999). Glioma cells release excitotoxic concentrations of glutamate. Cancer Research, 59, 4383–4391.PubMedGoogle Scholar
  175. Yi, J. H., & Hazell, A. S. (2006). Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochemistry International, 48, 394–403.PubMedGoogle Scholar
  176. Yu, S. W., Wang, H., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., & Dawson, V. L. (2002). Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science, 297, 259–263.PubMedGoogle Scholar
  177. Zoratti, M., & Szabo, I. (1995). The mitochondrial permeability transition. Biochimica et Biophysica Acta, 1241, 139–176.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Juan C. Piña-Crespo
    • 1
  • Sara Sanz-Blasco
    • 1
  • Stuart A. Lipton
    • 1
  1. 1.Del E. Webb Center for Neuroscience, Aging, and Stem Cell ResearchSanford-Burnham Medical Research InstituteLa JollaUSA

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