Glutamate excitotoxicity — a mechanism for axonal damage and oligodendrocyte death in Multiple Sclerosis?

  • P. Werner
  • D. Pitt
  • C. S. Raine
Conference paper


Glutamate excitotoxicity mediated by the AMPA/kainate-type of glutamate receptors is known not only to damage neurons but also the myelin-producing cell of the central nervous system (CNS), the oligodendro­cyte. In Multiple Sclerosis (MS), myelin, oligodendrocytes and axons are lost or damaged as a result of an inflammatory attack on the CNS. Activated immune cells produce glutamate in large quantities by deamidating glutamine via glutaminase. Thus, we hypothesized that during inflammation in MS, glutamate excitotoxicity may contribute to the lesion. This was addressed by treating mice sensitized to develop acute experimental autoimmune encepha­lomyelitis (EAE) with an AMPA/kainate antagonist, NBQX. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced axonal damage, as indicated by the levels of dephospho­rylated neurofilament-H. Despite the clinical differences, NB QX-treatment had no effect on lesion size and did not reduce the degree of CNS inflammation. In addition, NBQX did not alter the proliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect at the level of the immune system. In separate studies, infiltrating immune cells present in perivascular cuffs, commonly the site of entry for invading immune cells, were found to express glutaminase in abundance, supporting the production of glutamate in inflammatory lesions. Thus, glutamate excitotoxicity appears to be an important mechanism in autoimmune demyelination and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for MS.


Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Myelin Basic Protein Lymph Node Cell Experimental Allergic Encephalomyelitis 
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  1. Adams RD, Kubik CS (1952) The morbid anatomy of the demyelinative diseases. Am J Med 12: 510-518PubMedCrossRefGoogle Scholar
  2. Buryakova AV, Sytinsky IA (1975) Amino acid composition of cerebrospinal fluid in acute neuroinfections in children. Arch Neurol 32: 28-31PubMedCrossRefGoogle Scholar
  3. Cannella B, et al (1988) The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for Multiple Sclerosis. Proc Natl Acad Sci U S A 95: 10100-10105CrossRefGoogle Scholar
  4. Carlton SM, Coggeshall RE (1999) Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res 820: 63-70PubMedCrossRefGoogle Scholar
  5. Collins RC, Dobkin BH, Choi DW (1989) Selective vulnerability of the brain: new insights into the pathophysiology of stroke. Ann Intern Med 110: 992-1000PubMedGoogle Scholar
  6. Ding M, et al (1998) Antisense knockdown of inducible nitric oxide synthase inhibits induction of experimental autoimmune encephalomyelitis in SJL/J mice. J Immunol 160: 2560-2564PubMedGoogle Scholar
  7. Genain CP, Cannella B, Hauser SL, Raine CS (1999) Identification of autoantibodies associated with myelin damage in Multiple Sclerosis. Nat Med 5: 170-175PubMedCrossRefGoogle Scholar
  8. Gijbels K, Galardy RE, Steinman L (1994) Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. J Clin Invest 94: 2177-2182PubMedCrossRefGoogle Scholar
  9. Hardin-Pouzet, et al (1997) Glutamate metabolism is down-regulated in astrocytes during experimental allergic encephalomyelitis. Glia 20: 79-85CrossRefGoogle Scholar
  10. Matute C, Sanchez-Gomez MV, Martinez-Millan L, Miledi R (1997) Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci USA 94(16): 8830-8835PubMedCrossRefGoogle Scholar
  11. McDonald JW, Althomsons SP, Hyrc KL, Choi D, Goldberg MP (1998) Oligoden­drocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med 4: 291-297PubMedCrossRefGoogle Scholar
  12. O’Neill MJ, et al (1998) Decahydroisoquinolines: novel competitive AMPA/kainate antagonists with neuroprotective effects in global cerebral ischaemia. Neurophar­macology 37: 1211-1222CrossRefGoogle Scholar
  13. Piani D, Frei K, Do KQ, Cuénod M, Fontana A (1991) Murine brain macrophages induce NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci Lett 133: 159-162PubMedCrossRefGoogle Scholar
  14. Pitt D, Werner P, Raine CS (2000) Glutamate excitotoxicity in a model of Multiple Sclerosis. Nat Med 6: 67-70PubMedCrossRefGoogle Scholar
  15. Prineas JW, McDonald I (1997) Demyelinating diseases. In: Graham DI, Lantos PL (eds) Greenfield’s neuropathology. Arnold, New York, pp 813-881Google Scholar
  16. Raine CS (1997) The lesion in Multiple Sclerosis and chronic relapsing experimental allergic encephalomyelitis: a structural comparison. In: Raine CS, McFarland HF, Tourtellotte WW (eds) Multiple Sclerosis clinical and pathogenetic basis. Chapman& Hall, London, pp 243-286Google Scholar
  17. Rodriguez-Moreno A, Herreras O, Lerma J (1997) Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus. Neuron 19: 893­-901PubMedCrossRefGoogle Scholar
  18. Rosenberg LJ, Teng YD, Wrathall J (1999) 2,3-Dihydroxy-6-nitro-7-sulfamoyl­benzo(f)quinoxaline reduces glial loss and acute white matter pathology after experimental spinal cord contusion. J Neurosci 19: 464-475PubMedGoogle Scholar
  19. Rothman SM, Olney JW (1987) Excitotoxicity and the NMDA receptor. TINS 10: 299-­302Google Scholar
  20. Selmaj KW, Raine CS (1988) Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 23: 339-346PubMedCrossRefGoogle Scholar
  21. Smith T, Groom A, Zhu B, Turski L (2000) Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6: 62-66PubMedCrossRefGoogle Scholar
  22. Stover JF, et al (1997) Neurotransmitters in cerebrospinal fluid reflect pathological activ­ity. Eur J Clin Invest 27: 1038-1043PubMedCrossRefGoogle Scholar
  23. Szaro BG, Whitnall MH, Gainer H (1990) Phosphorylation-dependent epitopes on neurofilament proteins and neurofilament densities differ in axons in the corti­cospinal and primary sensory dorsal column tracts in the rat spinal cord. J Comp Neurol 302: 220-235PubMedCrossRefGoogle Scholar
  24. Trapp BD, et al (1998) Axonal transection in the lesions of Multiple Sclerosis. N Engl J Med 338: 278-285PubMedCrossRefGoogle Scholar
  25. Yoshioka A, Bacskai B, Pleasure D (1996) Pathophysiology of oligodendroglial excito-toxicity. J Neurosci Res 46: 427-437PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • P. Werner
    • 1
    • 2
    • 3
  • D. Pitt
    • 1
  • C. S. Raine
    • 1
    • 2
    • 4
  1. 1.Department of NeurologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of Pathology (Neuropathology)Albert Einstein College of MedicineBronxUSA
  3. 3.Department of NeuroscienceAlbert Einstein College of MedicineBronxUSA
  4. 4.Department of NeurologyBeth Israel Medical CenterNew YorkUSA

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