title: Methylthioadenosine reverses brain autoimmune disease.
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-kappaB 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 (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10).
  
  
  CONCLUSIONS
  MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases.
authors.affiliation: Neuroscience and Gene Therapy Division, Center for Applied Medical Research, University of Navarra, Navarra, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Moreno
authors.forename: Henar
authors.initials: H
authors.lastname: Hevia
authors.forename: Monica
authors.initials: M
authors.lastname: Santamaria
authors.forename: Jorge
authors.initials: J
authors.lastname: Sepulcre
authors.forename: Javier
authors.initials: J
authors.lastname: Muñoz
authors.forename: Elena R
authors.initials: ER
authors.lastname: García-Trevijano
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
authors.forename: Matias A
authors.initials: MA
authors.lastname: Avila
authors.forename: Pablo
authors.initials: P
authors.lastname: Villoslada
mesh_terms: D000328:Adult; D017668:Age of Onset; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D013872:Thionucleosides / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D007155:Immunologic Factors; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D013872:Thionucleosides; D052247:Nitric Oxide Synthase Type II