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Antiglutamate therapy of ALS — which is the next step?

  • A. C. Ludolph
  • T. Meyer
  • M. W. Riepe
Conference paper
Part of the 6th International Winter Conference on N eurodegeneration book series (NEURAL SUPPL, volume 55)

Summary

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which was thought to be untreatable for a long time. However, recent evidence in men indicates that antiglutamatergic strategies are the first to have an influence on its pathogenesis and slow down the disease process. Since the effect of the drugs is still small, this progress cannot only be seen as a success of the present but most also be acknowledged as a starting point for the future. How will these future studies look like? They will have to take into account that ALS presumably has a long preclinical period and they will use a number of novel compounds and treatment strategies which have recently been shown to be effective in a transgenic animal model. This also implies that we are likely to use combination therapies and have to try to treat patients early. The latter will be necessarily connected with the demand for a novel clinical attitude to the diagnosis of the disease.

Keywords

Amyotrophic Lateral Sclerosis Motor Neuron Excitatory Amino Acid Motor Neuron Disease Hereditary Spastic Paraplegia 
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.

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References

  1. Ankercrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P (1995) Apoptosis and mitochondria. Neuron 15: 961–973.CrossRefGoogle Scholar
  2. Aoki M, Lin CL, Rothstein JD, Geller BA, Hosier BA, Munsat TL, Horvitz HR, Brown RH Jr (1998) Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis. Ann Neurol 43: 645–653.PubMedCrossRefGoogle Scholar
  3. Azzouz M, Leclerc N, Gurney M, Warter JM, Poindron P, Borg J (1997) Progressive motor neuron impairment in an animal model of familial amyotrophic lateral sclerosis. Muscle Nerve 20: 45–51.PubMedCrossRefGoogle Scholar
  4. Beal MF (1992) Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 31: 119–130.PubMedCrossRefGoogle Scholar
  5. Benazzouz A, Boraud T, Dubédat P, Boireau A, Stutzmann JM, Gross C (1995) Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey: a pilot study. Eur J Pharmacol 284: 299–307.PubMedCrossRefGoogle Scholar
  6. Benoit E, Escande D (1991) Riluzole specifically blocks inactivated Na+ channels in myelinated nerve fibers. Pflügers Arch 419: 603–609.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. Block W, Karitzky J, Traber F, Pohl C, Keller E, Mundegar RR, Lamerichs R, Rink H, Ries F, Schild HH, Jerusalem F (1998) Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease. Sub-group analysis and follow-up measurements. Arch Neurol 55: 931–936.PubMedCrossRefGoogle Scholar
  9. Boireau A, Dubédat P, Bordier F, Peny C, Miquet JM, Durand G, Meunier M, Doble A (1994) Riluzole and experimental parkinsonism: antagonism of MPTP-induced decrease in central dopamine levels in mice. Neuroreport 5: 2657–2660.PubMedCrossRefGoogle Scholar
  10. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18: 327–338.PubMedCrossRefGoogle Scholar
  11. Burright EN, Clark HB, Servadlo A, Matilla T, Feddersen RM, Yunis WS, Duvick LA, Zoghbi HY, Orr HAT (1995) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82: 937–948.PubMedCrossRefGoogle Scholar
  12. Charcot JM (1974) Lecons sur les maladies du systéme nerveux faites à la Salpetrière. Paris. Progrès Medical 213-242.Google Scholar
  13. Cheramy A, Barbeito L, Godeheu G, Glowinsky J (1992) Riluzole inhibits the release of glutamate in the caudate nucleus of the cat in vivo. Neurosci Lett 147: 209–212.PubMedCrossRefGoogle Scholar
  14. Chiu AY, Zhai P, Dal Canto MC, Peters TM, Kwon YW, Prattis TM, Gurney ME (1995) Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. Mol Cell Neurosci 6: 349–362.PubMedCrossRefGoogle Scholar
  15. Choi DW (1998) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634.CrossRefGoogle Scholar
  16. Couratier P, Hugon J, Sindou P, Vallat JM, Dumas M (1993) Cell culture evidence for neuronal degeneration in amyotrophic lateral sclerosis being linked to glutamate AMPA/kainate receptors. Lancet 341: 265–268.PubMedCrossRefGoogle Scholar
  17. Couratier P, Sindou P, Esclaire F, Louvel E, Hugon J (1994) Neuroprotective effects of riluzole in ALS CSF toxicity. Neuroreport 5: 1012–1014.PubMedCrossRefGoogle Scholar
  18. Dal Canto MC, Gurney ME (1994) Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol 145: 1271–1279.Google Scholar
  19. Doble A (1996) The pharmacology and mechanism of action of riluzole. Neurology 47 [Suppl 4]: 233–241.Google Scholar
  20. Doble A (1997) Effects of riluzole on glutamatergic neurotransmission in the mammalian central nervous system, and other pharmacological effects. Rev Contemp Pharmacother 8: 213–225.Google Scholar
  21. Dugan LL, Turetsky DM, Du C, Lobner D, Wheeler M, Almli CR, Shen CK, Luh TY, Choi DW (1997) Carboxyfullerenes as neuroprotective agents. Proc Natl Acad Sci USA 94: 9434–9439.PubMedCrossRefGoogle Scholar
  22. Friedländer RM, Brown RH, Gagliardini V, Wang J, Yuan J (1997) Inhibition of ICE slows ALS in mice. Science 388: 31.Google Scholar
  23. Gravel C, Götz R, Lorrain A, Sendtner M (1997) Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons. Nat Med 3: 765–770.PubMedCrossRefGoogle Scholar
  24. Gurney M, Pu H, Chiu A, Dal Canto M, Polchow C, Alexander D, Caliendo J, Hantati A, Kwon Y, Deng H, Chen W, Zhai P, Sifit R, Siddique T (1994) Motor neuron degeneration in mice that express a human Cu, Zn Superoxide dismutase mutation. Science 264: 1773–1775.CrossRefGoogle Scholar
  25. Gurney M, Cutting FB, Zhai P, Doble A, Taylor C, Andrus PK, Hall ED (1996) Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol 39: 147–157.PubMedCrossRefGoogle Scholar
  26. Guyot MC, Palfi S, Stutzmann JM, Maziere M, Hantraye P, Brouillet E (1997) Riluzole protects from motor deficits and striatal degeneration produced by systemic 3-nitropropionic acid intoxication in rats. Neuroscience 81: 141–149.PubMedCrossRefGoogle Scholar
  27. Haase G, Kennel P, Pettmann B, Vigne E, Akli S, Revah F, Schmalbruch H, Kahn A (1997) Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors. Nat Med 3: 429–436.PubMedCrossRefGoogle Scholar
  28. Hengartner MO (1998) Death cycle and Swiss army knives. Nature 391: 441–442.PubMedCrossRefGoogle Scholar
  29. Henneberry RC, Novelli A, Cox JA, Lysko PG (1989) Neurotoxicity at the N-methyl-D-aspartate receptor in energy-compromised neurons: an hypothesis for cell death in aging and disease. Ann NY Acad Sci 568: 225–233.PubMedCrossRefGoogle Scholar
  30. Hottinger AF, Fine EG, Gurney ME, Zum AD, Aebischer P (1997). The copper chelator d-penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis. Eur J Neurosci 9: 1548–1551.PubMedCrossRefGoogle Scholar
  31. Hubert JP, Delumeau JC, Prémont J, Glowinski 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 mecahnism of action. Br J Pharmacol 113: 261–267.PubMedGoogle Scholar
  32. Ikonomidou C, Qin YQ, Labruyere J, Olney JW (1996) Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 55: 211–224.PubMedCrossRefGoogle Scholar
  33. Jain RK (1998) The next frontier of molecular medicine: Delivery of therapeutics. Nature Med 4: 655–657.PubMedCrossRefGoogle Scholar
  34. Kong J, Xu Z (1998) Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci 18: 3241–3250.PubMedGoogle Scholar
  35. Kostic V, Jackson-Lewis V, de Bilbao F, Dubois-Dauphin M, Przedborski S (1997) Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science 277: 559–562.PubMedCrossRefGoogle Scholar
  36. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V (1996) Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 347: 1425–1431.PubMedGoogle Scholar
  37. Leist M, Nicotera P (1998) Apotosis, excitoxicity, and neuropathology. Exp Cell Res 239: 183–201.PubMedCrossRefGoogle Scholar
  38. Lin CLG, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD (1998) Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20: 589–602.PubMedCrossRefGoogle Scholar
  39. Löscher W, Hönack D, Taylor CP (1991) Gabapentin increases aminooxyacetic acidinduced GABA accumulation in regions of rat brain. Neurosci Lett 128: 150–154.PubMedCrossRefGoogle Scholar
  40. Louvel E, Hugon J, Doble A (1997) Therapeutic advances in amyotrophic lateral sclerosis. TIPS 18: 196–203.PubMedGoogle Scholar
  41. Lucas DR, Newhouse JP (1957) The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch Ophtalmol 58: 193–204.CrossRefGoogle Scholar
  42. 5Ludolph AC, Riepe MW (1999) Do the benefits of currently available treatments justify early diagnosis and treatment of amyotrophic laterals sclerosis? Against, in press.Google Scholar
  43. Ludolph AC, Riepe M, Ullrich K (1993) Excitotoxicity, energy metabolism and neuronal degeneration. J Inher Metab Dis 16: 716–723.PubMedCrossRefGoogle Scholar
  44. Malessa S, Leigh PN, Bertel O, Sluga E, Hornykiewicz O (1991) Amyotrophic lateral sclerosis: glutamate dehydrogenase and transmitter amino acids in the spinal cord. J Neurol Neurosurg Psychiatry 54: 984–988.PubMedCrossRefGoogle Scholar
  45. Malgouris C, Bardot F, Daniel M, Pellis F, Rataud J, Uzan A, Blanchard C, Laduron RM (1989) Riluzole, a novel antiglutamate, prevents memory loss and hippocampal neuronal damage in ischémic gerbils. J Neurosci 9: 3720–3727.PubMedGoogle Scholar
  46. Martin D, Thompson MA, Nadler JV (1993) The neuroprotective agent riluzole inhibits release of glutamate and asparatate from slices of hippocampal area CA1. Eur J Pharmacol 250: 473–476.PubMedCrossRefGoogle Scholar
  47. Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 40: 759–766.PubMedCrossRefGoogle Scholar
  48. Masliah E, Raber J, Alford M, Mallory M, Mattson MP, Yang D, Wong D, Mucke L (1998) Amyloid protein precursor stimulates excitatory amino acid transport. Implications for roles in neuroprotection and pathogenesis. J Biol Chem 273:12548–12554.PubMedCrossRefGoogle Scholar
  49. Meyer T, Lenk U, Küther GL, Speer A, Weindl A, Ludolph AC (1995) Studies of the coding region of the neuronal glutamate transporter (EAAC1) gene in ALS. Ann Neurol 37: 817–819.PubMedCrossRefGoogle Scholar
  50. Meyer T, Meyer B, Münch C, Sitte W, Küther G, Speer A, Ludolph AC (1996) The glial glutamate transporter cDNA in patients with amyotrophic lateral sclerosis. Ann Neurol 40: 456–459.PubMedCrossRefGoogle Scholar
  51. Meyer T, Ludolph AC, Morkel M, Hagemeier C, Speer A (1997) Genomic organization of the human excitatory amino acid transporter gene GLT-1. Neuroreport 8: 775–777.PubMedCrossRefGoogle Scholar
  52. Meyer T, Münch C, Knappenberger B, Liebau S, Völkel H, Ludolph AC (1998a) Alternative splicing of the glutamate transporter EAAT2. Neurosci Lett 241: 1–3.CrossRefGoogle Scholar
  53. Meyer T, Münch C, Völkel H, Booms P, Ludolph AC (1998b) The EAAT 2 (GLT-1) gene in motor neuron disease: Absence of mutations in amyotrophic lateral sclerosis and a point mutation in individuals with hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry, in press.Google Scholar
  54. Miller RG, Moore D, Young LA, Armon C, Barohn RJ, Bromberg MB, Bryan WW, Gelinas DF, Mendoza MC, Neville HE, Parry GJ, Petajan JH, Ravits JM, Ringel SP, Ross MA, the WALS Study Group (1996) Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 47: 1383–1388.PubMedGoogle Scholar
  55. Mizoule J, Meldrum D, Mazadier M, Croucher M, Ollat C, Uzan A, Legrand J, Gueremy C, Le Fur G (1985) 2-amino-6-trifluoromethoxybenzothiazole, a possible antagonist of excitatory amino acid transmission. 1. Anticonvulsant properties. Neuropharmacol 24: 767–773.CrossRefGoogle Scholar
  56. Münch C, Schwalenstöcker B, Liebau S, Völkel H, Ludolph AC, Meyer T (1998) 5′-Heterogeneity of the human glutamate transporter cDNA EAAT2 (GLT-1). Neuroreport 9: 1295–1297.PubMedCrossRefGoogle Scholar
  57. Nagai M, Abe K, Okamoto K, Itoyama Y (1998) Identification of alternative splicing forms of GLT-1 mRNA in the spinal cord of amyotrophic lateral sclerosis patients. Neurosci Lett 244: 165–168.PubMedCrossRefGoogle Scholar
  58. Ochs G, Penn RD, Beck M, Giess R, Magnus T, Sims T, Sendtner M, Toyka KV (1998) Intrathecal infusion of recombinant human-brain-derived neurotrophic factor (rhBDNF) is well tolerated in patients with ALS. Abstract, 9th International Symposium on ALS/MND.Google Scholar
  59. Olney JW (1969a) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164: 719–721.PubMedCrossRefGoogle Scholar
  60. Olney JW (1969b) Glutamate-induced retinal degeneration in neonatal mice. Electron microscopy of the acutely evolving lesion. J Neuropathol Exp Neurol 28: 455–474.PubMedCrossRefGoogle Scholar
  61. Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL (1998) Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Gen 19: 171–174.CrossRefGoogle Scholar
  62. Penn RD, Kroin JS, York MM, Cedarbaum JM (1997) Intrathecal ciliary neurotrophic factor delivery for treatment of amyotrophic lateral sclerosis (phase I trial). Neurosurgery 40: 94–99.PubMedGoogle Scholar
  63. Perry TL, Hansen S, Jones K (1987) Brain glutamate deficiency in amyotrophic lateral sclerosis. Neurology 37: 1845–1848.PubMedGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. Riepe M, Hori N, Ludolph AC, Carpenter DO, Spencer PS, Allen CA (1992) Inhibition of energy metabolism by 3-nitropropionic acid activates ATP-sensitive potassium channels. Brain Res 586: 61–66.PubMedCrossRefGoogle Scholar
  66. Riepe M, Ludolph A, Seelig M, Spencer PS, Ludolph AC (1994) Increase of ATP levels by glutamate antagonists is unrelated to neuroprotection. Neuroreport 5: 2130–2132.PubMedCrossRefGoogle Scholar
  67. Riepe HW, Hori 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.PubMedCrossRefGoogle Scholar
  68. Riviere M, Meininger V, Zeisser P, Munsat T (1998) An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole. Arch Neurol 55:526–528.PubMedCrossRefGoogle Scholar
  69. Rosen DR, Siddique T, Pattersson D, Figlewicz DA, Sapp P, Hentati A et al. (1993) Mutations in Cu/Zn Superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59–62.PubMedCrossRefGoogle Scholar
  70. Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased brain and spinal cord glutamate transport in amyotrophic lateral sclerosis. N Engl J Med 326: 1464–1468.PubMedCrossRefGoogle Scholar
  71. Rothstein JD, Van Kammen M, Levey AI, Martin L, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38: 73–84.PubMedCrossRefGoogle Scholar
  72. Sendtner M (1997) Gene therapy for motor neuron disease. Nat Med 3: 380–381.PubMedCrossRefGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. Stefani A, Spadoni F, Bernardi G (1997) Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neurons: implications for neuroprotective strategies. Exp Neurol 147: 115–122.PubMedCrossRefGoogle Scholar
  75. Taylor CP (1995) Gabapentin — mechanisms of action. In: Levy RH, Mattson RH, Meldrum BNM (eds) Antiepileptic drugs, 4th ed. Raven Press, New York, pp 829–841.Google Scholar
  76. Terro F, Lasort M, Vlader F, Ludolph A, Hugon J (1996) Antioxidant drugs block in vitro the neurotoxicity of CSF from patients with amyotrophic lateral sclerosis. Neuroreport 7: 1970–1972.PubMedCrossRefGoogle Scholar
  77. Torp R, Lekieffre D, Levy LM, Haug FM, Danbolt NC, Meldrum BS, Ottersen OP (1995) Reduced postischemic expression of a glial glutamate transporter, GLT1, in the rat hippocampus. Exp Brain Res 103: 51–58.PubMedCrossRefGoogle Scholar
  78. Tsai G, Stauch-Slusher B, Sim L et al. (1990) Reductions in acidic amino acids and N-acetyl-aspartyl-glutamate (NAAG) in amyotrophic lateral sclerosis CSF. Brain Res 556: 151–156.CrossRefGoogle Scholar
  79. Wiedemann FR, Winkler K, Kuznetsov AV, Bartels C, Vielhaber S, Feistner H, Kunz WS (1998) Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci 156: 65–72.PubMedCrossRefGoogle Scholar
  80. Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14: 1105–1116.PubMedCrossRefGoogle Scholar
  81. World Federation of Neurology Research Group on Neuromuscular Diseases (1994) El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 124(Suppl.): 96–107.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1999

Authors and Affiliations

  • A. C. Ludolph
    • 1
  • T. Meyer
    • 1
  • M. W. Riepe
    • 1
  1. 1.Department of NeurologyUniversity of UlmUlmFederal Republic of Germany

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