Skip to main content
SpringerLink
Log in

Glutamate, excitotoxicity and amyotrophic lateral sclerosis

  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

The “glutamate hypothesis” is one of three major pathophysiological mechanisms of motor neurone injury towards which current research effort into amyotrophic lateral sclerosis (ALS) is directed. There is great structural and functional diversity in the glutamate receptor family which results from combinations of 14 known gene products and their splice variants, with or without additional RNA editing. It is possible that motor neurones express a unique molecular profile of glutamate receptors. Abnormal activation of glutamate receptors is one of five main candidates as a final common pathway to neuronal death. In classical acute excitotoxicity, there is influx of Na+ and Cl−, and destabilisation of intracellular Ca2+ homeostasis, which activates a cascade of harmful biochemical events. The concept of secondary excitotoxicity, where cellular injury by glutamate is triggered by disturbances in neuronal energy status, may be particularly relevant to a chronic neurodegenerative disease such as ALS. Data are now beginning to emerge on the fine molecular structure of the glutamate receptors present on human motor neurones, which have a distinct profile of AMPA receptors. Two important molecular features of motor neurones have been identified that may contribute to their vulnerability to neurodegeneration. The low expression of calcium binding proteins and the low expression of the GluR2 AMPA receptor subunit by vulnerable motor neurone groups may render them unduly susceptible to calcium-mediated toxic events following glutamate receptor activation. Eight lines of evidence that indicate a disturbance of glutamatergic neurotransmission in ALS patients are reviewed. The links between abnormal activation of glutamate receptors and other potential mechanisms of neuronal injury, including activation of calcium-mediated second messenger systems and free radical mechanisms, are emphasised. Riluzole, which modulates the glutamate neurotransmitter system, has been shown to prolong survival in patients with ALS. Further research may allow the development of subunit-specific therapeutic targeting of glutamate receptors and modulation of “downstream” events within motor neurones, aimed at protecting vulnerable molecular targets in specific populations of ALS patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Shaw PJ (1994) Excitotoxicity and motor neurone disease: a review of the evidence. J Neurol Sci 124 [Suppl]: 6–13

    PubMed  Google Scholar 

  2. Rothstein JD (1995) Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis. Adv Neurol 68: 7–20

    PubMed  CAS  Google Scholar 

  3. Zeman S, Lloyd C, Meldrum B, Leigh PN (1994) Excitatory amino acids, free radicals and the pathogenesis of motor neuron disease. Neuropathol Appl Neurobiol 20: 219–231

    PubMed  CAS  Google Scholar 

  4. Brown RH (1995) Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice. Cell 80: 687–692

    PubMed  CAS  Google Scholar 

  5. Olanow CW (1993) A radical hypothesis for neurodegeneration. Trends Neurosci 16: 439–444

    PubMed  CAS  Google Scholar 

  6. Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate and neurodegenerative disorders. Science 262: 689–695

    PubMed  CAS  Google Scholar 

  7. Smith RG, Hamilton S, Hofmann F, et al (1992) Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis. N Engl J Med 327: 1721–1728

    PubMed  CAS  Google Scholar 

  8. Appel SH, Smith RG, Engelhardt JI, Stefani E (1993) Evidence for autoimmunity in amyotrophic lateral sclerosis. J Neurol Sci 118: 169–174

    PubMed  CAS  Google Scholar 

  9. Young AB, Penney JB, Dauth GW, Bromberg MB, Gilman S (1983) Glutamate or aspartate as a possible neurotransmitter of the cerebral corticofugal fibres in the monkey. Neurology 33: 1513–1516

    PubMed  CAS  Google Scholar 

  10. O’Brien RJ, Fischbach GD (1986) Modulation of embryonic chick motor neuron glutamate sensitivity by interneurones and agonists. J Neurosci 6: 3290–3296

    PubMed  Google Scholar 

  11. Storm-Mathisen J, Otterson OP (1988) Localisation of excitatory amino acid transmitters. In: Lodge D (ed) Excitatory amino acids in health and disease. Wiley, Chichester, pp 107–143

    Google Scholar 

  12. Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17: 31–108

    PubMed  CAS  Google Scholar 

  13. Boulter J, Hollmann M, O’Shea-Greenfield A, et al (1990) Molecular cloning and functional expression of glutamate receptor subunit genes. Science 249: 1033–1037

    PubMed  CAS  Google Scholar 

  14. Keinanen K, Wisden W, Sommer B, et al (1990) A family of AMPA-selective glutamate receptors. Science 249: 556–560

    PubMed  CAS  Google Scholar 

  15. Nakanishi N, Shneider NA, Axel R (1990) A family of glutamate receptor genes: evidence for the formation of heteromultimeric receptors with distinct channel properties. Neuron 5: 569–581

    PubMed  CAS  Google Scholar 

  16. Egebjerg J, Bettler B, Hermans-Borgmeyer I, Heinemann S (1991) Cloning of a cDNA for a glutamate receptor subunit activated by kainate but not AMPA. Nature 351: 745–748

    PubMed  CAS  Google Scholar 

  17. Bettler B, Egebjerg J, Sharma G, et al (1992) Cloning of a putative glutamate receptor: a low-affinity kainate binding subunit. Neuron 8: 257–265

    PubMed  CAS  Google Scholar 

  18. Werner P, Voigt M, Keinanen K, et al (1991) Cloning of a putative high affinity kainate receptor expressed predominantly in hippocampal CA3 cells. Nature 351: 742–744

    PubMed  CAS  Google Scholar 

  19. Herb A, Burnashev N, Werner P, et al (1992) The KA-2 subunit of excitatory amino acid receptors shows widespread expression in brain and forms ion channels with distantly related subunits. Neuron 8: 775–785

    PubMed  CAS  Google Scholar 

  20. Yamazaki M, Mori H, Araki K, et al (1992) Cloning expression and modulation of a mouse NMDA receptor subunit. FEBS Lett 300: 39–45

    PubMed  CAS  Google Scholar 

  21. Meguro H, Mori H, Araki K et al (1992) Functional characterisation of a heteromeric NMDA receptor channel expressed from cloned cDNAs. Nature 357: 70–74

    PubMed  CAS  Google Scholar 

  22. Kutsuwada T, Kashiwabuchi N, Mori H, et al (1992) Molecular diversity of the NMDA receptor channel. Nature 358: 36–41

    PubMed  CAS  Google Scholar 

  23. Sommer B, Seeburg PH (1992) Glutamate receptor channels: novel properties and new clones. Trends Pharmacol Sci 13: 291–296

    PubMed  CAS  Google Scholar 

  24. Sommer B, Keinanen K, Verdoorn T, et al (1990) Flip and flop: a cell-specific functional switch in glutamate-operated channels in the CNS. Science 249: 1580–1585

    PubMed  CAS  Google Scholar 

  25. Burnashev N, Schoepfer R, Monyer H, et al (1992) Control by asparagine residues of calcium permeability and magnesium blockade of the NMDA receptor. Science 257: 1415–1419

    PubMed  CAS  Google Scholar 

  26. Hume RI, Dingledine R, Heinemann SF (1991) Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 253: 1028–1031

    PubMed  CAS  Google Scholar 

  27. Pines G, Danbolt NC, Bjoras M, et al (1992) Cloning and expression of a rat brainl-glutamate transporter. Nature 360: 464–467

    PubMed  CAS  Google Scholar 

  28. Kanai Y, Hediger MA (1992) Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360: 467–471

    PubMed  CAS  Google Scholar 

  29. Storck T, Schulte S, Hofmann K, Stoffel W (1992) Structure, expression and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci USA 89: 10955–10959

    PubMed  CAS  Google Scholar 

  30. Rothstein JD, Martin L, Levey AI, et al (1994) Localization of neuronal and glial glutamate transporters. Neuron 13: 713–725

    PubMed  CAS  Google Scholar 

  31. Danbolt NC, Storm-Mathisen J, Kanner BI (1992) An [Na+−K+] coupledl-glutamate transporter purified from rat brain is localized in glial cell processes. Neuroscience 51: 295–310

    PubMed  CAS  Google Scholar 

  32. Fairman WA, Vandenberg RJ, Arriza JL, Kavanaugh MP, Amara SG (1995) An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375: 599–602

    PubMed  CAS  Google Scholar 

  33. Laake JH, Slyngstad TA, Haug F-MS, Ottersen OP (1995) Glutamine from glial cells is essential for the maintenance of the nerve terminal pool of glutamate: immunogold evidence from hippocampal slice cultures. J Neurochem 65: 871–881

    PubMed  CAS  Google Scholar 

  34. Lucas DR, Newhouse JP (1957) The toxic effect of sodiuml-glutamate on the inner layers of the retina. Arch Ophthalmol 58: 193–204

    CAS  Google Scholar 

  35. Olney JW (1978) Neurotoxicity of excitatory amino acids. In: McGeer EG, Olney JW, McGeer P (eds) Kainic acid as a tool in neurobiology. Raven, New York, pp 95–121

    Google Scholar 

  36. Choi DW (1987) Tonic dependence of glutamate neurotoxicity in cortical cell culture. J Neurosci 7: 369–379

    PubMed  CAS  Google Scholar 

  37. Miller RJ, Murphy SN, Glaum SR (1989) Neuronal Ca2+ channels and their regulation by excitatory amino acids. Ann NY Acad Sci 568: 149–158

    PubMed  CAS  Google Scholar 

  38. Siesjö BK (1988) Historical overview. Calcium, ischemia and death of brain cells. Ann NY Acad Sci 522: 638–661

    PubMed  Google Scholar 

  39. Meldrum B, Garthwaite J (1990) Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci 11: 379–387

    PubMed  CAS  Google Scholar 

  40. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634

    PubMed  CAS  Google Scholar 

  41. Prehn JHM, Lippert K, Krieglstein J (1995) Are NMDA or AMPA/kainate receptor antagonists more efficacious in the delayed treatment of excitotoxic neuronal injury. Eur J Pharmacol 292: 179–189

    PubMed  CAS  Google Scholar 

  42. Novelli A, Reilly JA, Lysko PG, Henneberry RC (1988) Glutamate becomes neurotoxic via theN-methyl-d-aspartate receptor when intracellular energy levels are reduced. Brain Res 451: 205–212

    PubMed  CAS  Google Scholar 

  43. Riepe MW, Hor N, Ludolph AC, Carpenter DO (1995) Failure of neuronal ion exchange, not potentiated excitation, causes excitotoxicity after inhibition of oxidative phosphorylation. Neuroscience 64: 91–97

    PubMed  CAS  Google Scholar 

  44. Beal MF (1993) Role of excitotoxicity in human neurological disease. Curr Opin Neurobiol 2: 657–662

    Google Scholar 

  45. Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT (1989) Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2: 1547–1558

    PubMed  CAS  Google Scholar 

  46. Meister A, Anderson ME (1983) Glutathione. Annu Rev Biochem 52: 711–760

    PubMed  CAS  Google Scholar 

  47. Lees GJ (1993) Contributory mechanisms in the causation of neurodegenerative disorders. Neuroscience 54: 287–322

    PubMed  CAS  Google Scholar 

  48. Pellegrini-Giampietro DE (1994) Free radicals and the pathogenesis of neuronal death: co-operative role of excitatory amino acids. In: Armstrong D (ed) Free radicals in diagnostic medicine. Plenum, New York, pp 59–71

    Google Scholar 

  49. Whetsell WO, Schwartz R (1989) Prolonged exposure to submicromolar concentrations of quinolinic acid causes excitotoxic damage in organotypic cultures of rat corticostriatal system. Neurosci Lett 97: 271–275

    PubMed  CAS  Google Scholar 

  50. Susel Z, Engber TM, Kuo S, Chase TN (1991) Prolonged infusion of quinolinic acid into rat striatum as an excitotoxic model of neurodegenerative disease. Neurosci Lett 121: 234–238

    PubMed  CAS  Google Scholar 

  51. Rothstein JD, Lin L, Dykes-Hoberg M, Kuncl RW (1993) Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc Natl Acad Sci USA 90: 6591–6595

    PubMed  CAS  Google Scholar 

  52. Monaghan DT, Bridge RJ, Cotman CW (1989) The excitatory amino acid receptors: their classes, pharmacology and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol 29: 365–402

    PubMed  CAS  Google Scholar 

  53. Jakoi ER, Sombati S, Gerwin C, De-Lorenzo RJ (1992) Excitatory amino acid receptor activation produces a selective and long-lasting modulation of gene expression in hippocampal neurons. Brain Res 582: 282–290

    PubMed  CAS  Google Scholar 

  54. Reiter RJ (1995) Oxidative processes and antioxidative defense mechanisms in the aging brain. FASEB J 9: 526–533

    PubMed  CAS  Google Scholar 

  55. Shaw PJ, Ince PG, Johnson M, Perry EK, Candy JM (1991) The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human spinal cord. Brain Res 539: 164–168

    PubMed  CAS  Google Scholar 

  56. Williams TL, Ince PG, Oakley AE, Shaw PJ (1996) An immunocytochemical study of the distribution of AMPA selective glutamate receptor subunits in the normal human motor system. Neuroscience 74: 185–198

    PubMed  CAS  Google Scholar 

  57. Stewart GR, Olney JW, Pathikonda M, Snider WD (1991) Excitotoxicity in the embryonic chick spinal cord. Ann Neurol 30: 758–766

    PubMed  CAS  Google Scholar 

  58. Estevez AG, Stutzmann J-M, Barbeito L (1995) Protective effect of riluzole on excitatory amino acid-mediated neurotoxicity in motorneuron-enriched cultures. Eur J Pharmacol 280: 47–53

    PubMed  CAS  Google Scholar 

  59. Shaw PJ, Chinnery RM, Ince PG (1994) [3H]d-aspartate binding sites in the normal human spinal cord and changes in motor neuron disease: a quantitative autoradiographic study. Brain Res 655: 195–201

    PubMed  CAS  Google Scholar 

  60. Chinnery RM, Shaw PJ, Ince PG, Johnson M (1993) Autoradiographic distribution of binding sites for the non-NMDA receptor antagonist [3H]CNQX in the human motor cortex, brainstem and spinal cord. Brain Res 630: 75–81

    PubMed  CAS  Google Scholar 

  61. Shaw PJ, Ince PG, Matthews JNS, Johnson M, Candy JM (1994)N-Methyl-d-aspartate (NMDA) receptors in the spinal cord and motor cortex in motor neurone disease: a quantitative autoradiographic study using [3H]MK-801. Brain Res 637: 297–302

    PubMed  CAS  Google Scholar 

  62. Shaw PJ, Chinnery RM, Ince PG (1994) Non-NMDA receptors in motor neuron disease (MND): a quantitative autoradiographic study in spinal cord and motor cortex using [3H]CNQX and [3H]kainate. Brain Res 655: 186–194

    PubMed  CAS  Google Scholar 

  63. Williams TL, Day NC, Ince PG, et al (1997) Calcium permeable AMPA receptors: a molecular basis for selective vulnerability in motor neurone disease. Ann Neurol (in press)

  64. Burnashev N, Monyer H, Seeberg PH, Sakmann B (1992) Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8: 189–198

    PubMed  CAS  Google Scholar 

  65. Bettler B, Mulle C (1995) Review: neurotransmitter receptors II. AMPA and kainate receptors. Neuropharmacology 34: 123–139

    PubMed  CAS  Google Scholar 

  66. Westbrook GL (1994) Glutamate receptor update. Curr Opin Neurobiol 4: 337–346

    PubMed  CAS  Google Scholar 

  67. Brorson JR, Manzolillo PA, Gibbons SJ, Miller RJ (1995) AMPA receptor desensitisation predicts the selective vulnerability of cerebellar Purkinje cells to excitotoxicity. J Neurosci 15: 4515–4524

    PubMed  CAS  Google Scholar 

  68. Ballerini L, Bracci E, Nistri A (1995) Desensitisation of AMPA receptors limits the amplitude of EPSP’s and the excitability of motoneurons of the rat isolated spinal cord. Eur J Neurosci 7: 1229–1234

    PubMed  CAS  Google Scholar 

  69. Traynelis SF, Hartley M, Heinemann SF (1995) Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines. Science 268: 873–876

    PubMed  CAS  Google Scholar 

  70. McIlwain DL (1991) Nuclear and cell body size in spinal motor neurons. In: Rowland LP (ed) Advances in neurology, vol 56. Raven, New York, pp 67–74

    Google Scholar 

  71. Lee MK, Cleveland DW (1996) Neuronal intermediate filaments. Annu Rev Neurosci 19: 187–217

    PubMed  CAS  Google Scholar 

  72. Shaw PJ, Chinnery RM, Thageson H, Borthwick G, Ince PG (1997) Immunocytochemical study of the distribution of the free radical scavenging enzymes Cu/Zn superoxide dismutase (SOD1), Mn superoxide dismutase (MnSOD) and catalase in the normal human spinal cord and in motor neuron disease. J Neurol Sci (in press)

  73. Ince PG, Stout N, Shaw PJ, et al (1993) Parvalbumin and calbindin D-28k in the human motor system and in motor neuron disease. Neuropathol Appl Neurobiol 19: 291–299

    PubMed  CAS  Google Scholar 

  74. Mattson MP, Guthrie PB, Kater SB (1989) A role for Na+-dependent Ca++ extrusion in protection against neuronal excitototixicity. FASEB J 3: 2519–2526

    PubMed  CAS  Google Scholar 

  75. Plaitakis A, Constantakakis E, Smith J (1988) The neuroexcitotoxic amino acids glutamate and aspartate are altered in the spinal cord and brain in amyotrophic lateral sclerosis. Ann Neurol 24: 446–449

    PubMed  CAS  Google Scholar 

  76. Perry TL, Hansen S, Jones K (1987) Brain glutamate deficiency in amyotrophic lateral sclerosis. Neurology 37: 1845–1848

    PubMed  CAS  Google Scholar 

  77. Tsai G, Stauch-Slusher B, Sim L, et al (1991) Reductions in acidic amino acids andN-acetyl-aspartyl-glutamate (NAAG) in amyotrophic lateral sclerosis CNS. Brain Res 556: 151–156

    PubMed  CAS  Google Scholar 

  78. Rothstein JD, Tsai G, Kuncl RW, et al (1990) Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 28: 18–25

    PubMed  CAS  Google Scholar 

  79. Shaw PJ, Forrest V, Ince PG, Richardson JP, Wastell HJ (1995) CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration 4: 209–216

    PubMed  CAS  Google Scholar 

  80. Perry TL, Krieger C, Hansen S, Eisen A (1990) Amyotrophic lateral sclerosis: amino acid levels in plasma and cerebrospinal fluid. Ann Neurol 28: 12–17

    PubMed  CAS  Google Scholar 

  81. Ferrarese L, Pecora N, Frigo M, Appollonio I, Frattola L (1993) Assessment of reliability and biological significance of glutamate levels in cerebrospinal fluid. Ann Neurol 33: 316–319

    PubMed  CAS  Google Scholar 

  82. Couratier P, Hugon J, Sindou P, Vallat JM, Dumas M (1993) Cell culture evidence for neuronal degeneration in amyotrophic lateral sclerosis being linked to AMPA/kainate receptors. Lancet 341: 265–268

    PubMed  CAS  Google Scholar 

  83. Plaitakis A, Caroscio JT (1987) Abnormal glutamate metabolism in amyotrophic lateral sclerosis. Ann Neurol 22: 575–579

    PubMed  CAS  Google Scholar 

  84. Iwasaki Y, Ikeda K, Kinoshita M (1992) Plasma amino acid levels in patients with amyotrophic lateral sclerosis. J Neurol Sci 107: 219–222

    PubMed  CAS  Google Scholar 

  85. Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326: 1464–1468

    PubMed  CAS  Google Scholar 

  86. Rothstein JD, Dykes-Hoberg M, Pardo CA, et al (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16: 675–686

    PubMed  CAS  Google Scholar 

  87. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38: 73–84

    PubMed  CAS  Google Scholar 

  88. Bristol LA, Rothstein JD (1996) Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Ann Neurol 39: 676–679

    PubMed  CAS  Google Scholar 

  89. Volterra A, Trotti D, Tromba C, Floridi S, Racagni G (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J Neurosci 14: 2924–2932

    PubMed  CAS  Google Scholar 

  90. Hugon J, Vallat JM (1990) Abnormal distribution of phosphorylated neurofilaments in neuronal degeneration induced by kainic acid. Neurosci Lett 119: 45–48

    PubMed  CAS  Google Scholar 

  91. Rothstein JD, Kuncl RW (1995) Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity. J Neurochem 65: 643–651

    PubMed  CAS  Google Scholar 

  92. Spencer PS, Ludolph A, Dwivedi MP, Roy DN, Hugon J, Schaumburg HH (1986) Lathyrism: evidence for role of the neuroexcitatory amino acid BOAA. Lancet II: 1066–1070

    Google Scholar 

  93. Striefler M, Cohn DF, Hirano A, Schujman E (1997) The central nervous system in a case of neurolathyrism. Neurology 27: 1176–1178

    Google Scholar 

  94. Cohn DF, Streifler M (1981) Human neurolathyrism, a follow-up study of 200 patients. Arch Suisse Neurol Neurochir Psychiatr 128: 151–156.

    CAS  Google Scholar 

  95. Hirano A, Llena JF, Streifler M, Cohn DF (1976) Anterior horn cell changes in a case neurolathyrism. Acta Neuropathol (Berl) 35: 277–283

    CAS  Google Scholar 

  96. Spencer PS, Nunn PB, Hugon J, et al (1987) Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin. Science 237: 517–522

    PubMed  CAS  Google Scholar 

  97. Duncan MW, Steele JC, Kopin IJ, Markey SP (1990) 2-Amino-3-(methylamino)-propanoic acid (BMAA) in cycad flour: an unlikely cause of amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Neurology 40: 767–772

    PubMed  CAS  Google Scholar 

  98. Spencer PS, Allen CN, Kisby CE, Ludolph AL, Ross SM, Roy DW (1991) Lathyrism and Western Pacific amyotrophic lateral sclerosis; etiology of short- and long-latency motor system disorders. In: Rowland LP (ed) Advances in neurology, vol 56. Raven, New York, pp 287–299

    Google Scholar 

  99. Perl TM, Bedard L, Kosatsky T, Hockin JC, Todd ECD, Remis RS (1990) An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. N Engl J Med 322: 1775–1780

    PubMed  CAS  Google Scholar 

  100. Teitelbaum JS, Zatorre RJ, Carpenter S, et al (1990) Neurotoxic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. J Engl J Med 322: 1781–1787

    Article  CAS  Google Scholar 

  101. Kew JJM, Leigh PN, Playford ED, et al (1993) Cortical function in amyotrophic lateral sclerosis. A positron emission tomography study. Brain 116: 655–680

    PubMed  Google Scholar 

  102. Eisen A, Pant B, Stewart H (1993) Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. Can J Neurol Sci 20: 11–16

    PubMed  CAS  Google Scholar 

  103. Mills KR (1995) Motor neurone disease: studies of the corticospinal excitation of single motoneurons by magnetic brain stimulation. Brain 118: 971–982

    PubMed  Google Scholar 

  104. Bensimon G, Lacomblez L, Meininger V and the ALS/Riluzole study group (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 330: 585–591

    PubMed  CAS  Google Scholar 

  105. Lacomblez L, Bensimon G, Leigh PN, et al (1996) Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 347: 1425–1432

    PubMed  CAS  Google Scholar 

  106. Hubert JP, Delumeau JC, Glowinski J, Prémont J, Doble A (1994) Antagonism by riluzole of entry of calcium evoked by NMDA and veratridine in rat cultured granule cells: evidence for a dual mechanism of action. Br J Pharmacol 113: 261–267

    PubMed  CAS  Google Scholar 

  107. Malgouris C, Daniel M, Doble A (1994) Neuroprotective effects of riluzole onN-methyl-d-aspartate or veratridine-induced neurotoxicity in rat hippocampal slices. Neurosci Lett 177: 95–99

    PubMed  CAS  Google Scholar 

  108. Benoît E, Escande D (1991) Riluzole specifically blocks inactive Na+ channels in myelinated nerve fibers. Pflügers Arch 419: 603–607

    PubMed  Google Scholar 

  109. Debono MW, Canton T, Pradier L, Doble A, Blanchard JC (1993) Effects of riluzole on electrophysiological responses mediated by rat kainate and NMDA receptors expressed in xenopus oocytes. Eur J Pharmacol 235: 283–287

    PubMed  CAS  Google Scholar 

  110. Doble A, Hubert JP, Blanchard JC (1992) Pertussis toxin pretreatment abolishes the inhibitory effect of riluzole and carbachol ond-[3H] aspartate release from cultured cerebellar granule cells. Neurosci Lett 140: 251–254

    PubMed  CAS  Google Scholar 

  111. Girdlestone DA, Dupuy A, Roy-Contancin L, Escande D (1989) Riluzole antagonises excitatory amino acid evoked firing in rat facial motoneurons. Br J Pharmacol 97: 583P

  112. Malgouris C, Bardot F, Daniel M, et al (1989) Riluzole, a novel antiglutamate prevents memory loss and hoppocampal neuronal damage in ischaemic gerbils. J Neurosci 9: 3720–3727

    PubMed  CAS  Google Scholar 

  113. Stutzmann J-M, Doble A (1994) Blockade of glutamatergic transmission and neuroprotection: the strange case of riluzole. In: Jolles G, Stutzmann JM (eds) Neurodegenerative diseases. Academic Press, New York, p 205

    Google Scholar 

  114. Hebert T, Drapeau P, Pradier L, Dunn RJ (1994) Block of the rat brain 1A sodium channel α subunit by the neuroprotective drug riluzole. Mol Pharmacol 45: 1055–1060

    PubMed  CAS  Google Scholar 

  115. Rosen DR, Siddique T, Patterson D, et al (1993) Mutations in Cu/Zn superoxide dismutase are associated with familial amyotrophic lateral sclerosis. Nature 362: 59–62

    PubMed  CAS  Google Scholar 

  116. McCord JM, Fridovich I (1969) Superoxide dismutase. J Biol Chem 244: 6049–6055

    PubMed  CAS  Google Scholar 

  117. Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59: 1609–1623

    PubMed  CAS  Google Scholar 

  118. Gurney ME, Pu H, Chiu AY, et al (1994) Motor neuron degeneration in mice that express a human Cu/Zn superoxide dismutase mutation. Science 264: 1772–1775

    PubMed  CAS  Google Scholar 

  119. Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW (1995) Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 92: 659–693

    Google Scholar 

  120. Ikonomidou C, Qin Y, Labruyere J, Olney JW (1996) Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD transgenic mouse model of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 55: 211–224

    PubMed  CAS  Google Scholar 

  121. Gurney ME, Cutting FB, Zhai P, et al (1996) Benefit of vitamin E, riluzole and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol 39: 147–158

    PubMed  CAS  Google Scholar 

  122. Shaw PJ, Ince PG, Falkous G, Mantle D (1995) Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol 38: 691–695

    PubMed  CAS  Google Scholar 

  123. Bowling AL, Schultz JB, Brown RH, Beal MF (1993) Superoxide dismutase activity, oxidative damage and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 61: 2322–2325

    PubMed  CAS  Google Scholar 

  124. Ince PG, Shaw PJ, Candy JM, et al (1994) Iron, selenium and glutathione peroxidase activity are elevated in sporadic motor neuron disease. Neurosci Lett 182: 87–90

    PubMed  CAS  Google Scholar 

  125. Bergeron C, Muntasser S, Somerville MJ, Weyer L, Percy ME (1994) Copper zinc superoxide dismutase mRNA levels are increased in sporadic amyotrophic lateral sclerosis motor neurons. Brain Res 659: 272–276

    PubMed  CAS  Google Scholar 

  126. Markesbery WR, Ehmann WD, Candy JM, et al (1995) Neutron activation analysis of trace elements in motor neuron disease spinal cord. Neurodegeneration 4: 383–390

    PubMed  CAS  Google Scholar 

  127. Kurlander HM, Patten BM (1979) Metals in spinal cord tissue of patients dying of motor neuron disease. Ann Neurol 6: 21–24

    PubMed  CAS  Google Scholar 

  128. Sillevis-Smitt PAE, Mulder TPJ, Verspaget HW, Blaauwgeers HGT, Troost D, De Jong JMBV (1994) Metallothionein in amyotrophic lateral sclerosis. Biol Signals 3: 193–197

    PubMed  CAS  Google Scholar 

  129. Louwerse ES, Weverling GJ, Bussuyt PMM, Posthumus Meyjes FE, De Jong JMBV (1995) Randomized double-blind controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol 52: 559–564

    PubMed  CAS  Google Scholar 

  130. Schor NF (1988) Inactivation of mammalian brain glutamine synthetase by oxygen radicals. Brain Res 456: 17–21

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Royal Victoria Infirmary, University Department of Neurology, NE1 4LP, Newcastle upon Tyne, UK

    P. J. Shaw

  2. Department of Neuropathology and the MRC Neurochemical Pathology Unit, University of Newcastle upon Tyne, NE1 4LP, Newcastle upon Tyne, UK

    P. G. Ince

Authors
  1. P. J. Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. G. Ince
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shaw, P.J., Ince, P.G. Glutamate, excitotoxicity and amyotrophic lateral sclerosis. J Neurol 244 (Suppl 2), S3–S14 (1997). https://doi.org/10.1007/BF03160574

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03160574

Key words

Search

Navigation