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Autoimmune encephalomyelitis ameliorated by AMPA antagonists

Abstract

Multiple sclerosis is an immune-mediated disorder of the central nervous system leading to progressive decline of motor and sensory functions and permanent disability1,2. The therapy of multiple sclerosis is only partially effective, despite anti-inflammatory, immunosuppresive and immunomodulatory measures3. White matter inflammation and loss of myelin, the pathological hallmarks of multiple sclerosis, are thought to determine disease severity4,5. Experimental autoimmune encephalomyelitis reproduces the features of multiple sclerosis in rodents and in nonhuman primates6,7. The dominant early clinical symptom of acute autoimmune encephalomyelitis is progressive ascending muscle weakness6. However, demyelination may not be profound and its extent may not correlate with severity of neurological decline8, indicating that targets unrelated to myelin or oligodendrocytes may contribute to the pathogenesis of acute autoimmune encephalomyelitis. Here we report that within the spinal cord in the course of autoimmune encephalomyelitis not only myelin but also neurons are subject to lymphocyte attack and may degenerate. Blockade of glutamate AMPA receptors ameliorated the neurological sequelae of autoimmune encephalomyelitis, indicating the potential for AMPA antagonists in the therapy of multiple sclerosis.

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Figure 1: Dose–response relationship of AMPA/kainate antagonists on motor disability induced by autoimmune encephalomyelitis in rats.
Figure 2: Electron micrographs of the ventral horn of the lumbar spinal cord from Lewis rats immunized with myelin basic protein, at the peak of the disease course, showing different stages of degeneration of motoneurons associated with lymphocyte entry.
Figure 3: Light immunomicrographs showing that T lymphocytes but not macrophages/microglia or astrocytes invade motoneurons.
Figure 4: Effect of AMPA/kainate antagonist NBQX on chronic relapsing EAE in mice.

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Acknowledgements

The assistance of M. Turmaine (University College London, UK) and L. Rivers is acknowledged. We thank C. Ikonomidou (Humboldt University, Berlin) for criticism and advice on electron microscopy and stereology. We also thank Y. Machida and Y. Yamanishi for advice and support.

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Correspondence to Terence Smith or Lechoslaw Turski.

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Smith, T., Groom, A., Zhu, B. et al. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6, 62–66 (2000). https://doi.org/10.1038/71548

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