Original Article

Methylthioadenosine reverses brain autoimmune disease

  1. Beatriz Moreno PhD1,†,
  2. Henar Hevia PhD2,†,
  3. Monica Santamaria PhD2,
  4. Jorge Sepulcre MD1,
  5. Javier Muñoz BSc2,
  6. Elena R. García-Trevijano PhD2,
  7. Carmen Berasain PhD2,
  8. Fernando J. Corrales PhD2,†,
  9. Matias A. Avila PhD2,†,
  10. Pablo Villoslada MD1,†,*

Article first published online: 19 JUN 2006

DOI: 10.1002/ana.20895

Issue

Annals of Neurology

Annals of Neurology

Volume 60, Issue 3, pages 323–334, September 2006

Additional Information

How to Cite

Moreno, B., Hevia, H., Santamaria, M., Sepulcre, J., Muñoz, J., García-Trevijano, E. R., Berasain, C., Corrales, F. J., Avila, M. A. and Villoslada, P. (2006), Methylthioadenosine reverses brain autoimmune disease. Ann Neurol., 60: 323–334. doi: 10.1002/ana.20895

Author Information

  1. 1

    Neuroscience and Gene Therapy Division, Center for Applied Medical Research, University of Navarra, Navarra, Spain

  2. 2

    Hepathology and Gene Therapy Division, Center for Applied Medical Research, University of Navarra, Navarra, Spain

  1. †

    B.M. and H.H. made equal contribution to this work. F.J.C., M.A.A., and P.V. share senior authorship.

*Neuroimmunology Lab 2.05, Division of Neuroscience, Center for Applied Medical Research (CIMA), Pio XII 55, 31008 Pamplona, Spain

Publication History

  1. Issue published online: 18 SEP 2006
  2. Article first published online: 19 JUN 2006
  3. Manuscript Accepted: 22 APR 2006
  4. Manuscript Revised: 31 MAR 2006
  5. Manuscript Received: 26 OCT 2005

Funded by

  • FIMA and the “UTE project CIMA,”
  • Fundación Ramon Areces
  • PIUNA program at the University of Navarra
  • Instituto de Salud Carlos III. Grant Numbers: C03/02, G03/015, PI051098
  • Ministerio de Sanidad y Consumo. Grant Numbers: FIS PI020369, PI040819, CP04/00123
  • Gobierno de Navarra (Ortiz de Landazuri)
  • Ministerio de Educación y Ciencia. Grant Numbers: SAF 2004-03538, SAF 2004-01855
  • Fundación Ramón Areces

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Abstract

Objective

To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis.

Methods

We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-κB modulation by Western blot.

Results

We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IκB-α) degradation and in the impaired activation transcription factor nuclear factor-κB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-γ, tumor necrosis factor-α, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10).

Interpretation

MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases. Ann Neurol 2006

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