Methylthioadenosine Reverses Brain Autoimmune Disease Beatriz Moreno, PhD, 1 Henar Hevia, PhD, 2 Monica Santamaria, PhD, 2 Jorge Sepulcre, MD, 1 Javier Mun ˜oz, BSc, 2 Elena R. Garcı ´a-Trevijano, PhD, 2 Carmen Berasain, PhD, 2 Fernando J. Corrales, PhD, 2 Matias A. Avila, PhD, 2 and Pablo Villoslada, MD 1 Objective: To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune en- cephalomyelitis (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-B 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 (IB-) degra- dation and in the impaired activation transcription factor nuclear factor-B. Indeed, MTA suppressed the production of proin- flammatory genes and cytokines (interferon-, tumor necrosis factor-, 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;60:323–334 Methylthioadenosine (MTA) is a lipophilic sulfur- containing adenine nucleoside produced from S-adenosylmethionine, during the synthesis of the polyamines spermine and spermidine. 1 Besides its strong inhibitory effect on the polyamine biosynthesis, MTA has been shown to exert other potent and spe- cific pharmacological effects on cellular function, such as control of hepatocellular proliferation, inhibition of the development of neoplastic liver lesions, protection from toxic liver injury, and modulation of the inflam- matory response. 2 Indeed, we have recently reported that MTA prevented bacterial lipopolysaccharide (LPS)-induced lethality in mice, likely through the suppression of tumor necrosis factor- (TNF-) pro- duction and inducible nitric oxide synthase (iNOS) gene expression and by enhancing the expression of interleukin-10 (IL-10). 3 Multiple sclerosis (MS) is an autoimmune disease af- fecting two million people around the world, mainly in well-developed countries. 4 MS represents a significant health and social burden because it affects young adults, many of whom suffer a significant disability, and because the cost of years with the disease is high. MS is diagnosed when only minor central nervous sys- tem (CNS) damage has already occurred, which sug- gests that if we stop the inflammatory process at the early phase of the disease, we can prevent most of the brain damage and future disability. Although in recent years it has been stressed that the progressive phase of MS can be considered a neurodegenerative process, even during this chronic phase, the major cause of ax- onal damage appears to be related to the immunopa- thology secondary to the autoimmune process. 5 Thus, controlling the autoimmune response into the brain From the 1 Neuroscience and 2 Hepathology and Gene Therapy Di- visions, Center for Applied Medical Research, University of Na- varra, Navarra, Spain. Received Oct 26, 2005, and in revised form Mar 31, 2006. Ac- cepted for publication Apr 22, 2006. B.M. and H.H. made equal contribution to this work. F.J.C., M.A.A., and P.V. share senior authorship. This article includes supplementary materials available via the Internet at http://www.interscience.wiley.com/jpages/0364-5134/suppmat Published online Jun 19, 2006, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.20895 Address correspondence to Dr Villoslada, Neuroimmunology Lab 2.05, Division of Neuroscience, Center for Applied Medical Re- search (CIMA), Pio XII 55, 31008 Pamplona, Spain. E-mail: pvilloslada@unav.es © 2006 American Neurological Association 323 Published by Wiley-Liss, Inc., through Wiley Subscription Services