Moreno B et al. (2006) Methylthioadenosine reverses brain autoimmune disease. Ann Neurol [doi: 10.1002/ana.20895]

Multiple sclerosis (MS) can be diagnosed when only minor CNS damage has occurred. Approximately 40% of patients, however, fail to respond to current immunomodulatory treatments and progress to major brain damage and disability. Early results indicated that the nucleoside methylthioadenosine, which has a strong inhibitory effect on polyamine biosynthesis and has been demonstrated to have pharmacological effects on cellular function, could be an effective treatment in MS.

Moreno and colleagues at the University of Navarra, Spain, carried out a series of tests in rats and humans. They found that methylthioadenosine prevented the acute phase, and reversed the chronic relapsing phase, of experimental autoimmune encephalomyelitis, an animal model of autoimmune CNS inflammation. Administration of the drug to rats inhibited brain inflammation and reduced brain damage. Methylthioadenosine suppressed T-cell activation in vivo and in vitro, probably by blocking T-cell signaling, leading to prevention of degradation of IκB (inhibitor of kappa B) and impaired activation of NFκB (nuclear factor kappa B). The drug downregulated expression of proinflammatory genes and cytokines and enhanced interleukin-10 production. These mechanisms suggest an important immunomodulatory role for methylthioadenosine, which might also have a role in the CNS innate immune system through modulation of microglial activity.

Unlike current treatments for MS, methylthioadenosine might be suitable for oral administration and is not associated with treatment-limiting side effects. Moreno et al. suggest that this drug could be effectively combined with other immunomodulatory agents to halt progression not just of MS, but possibly also other autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, in which T-cell activation has a critical role. Research is ongoing, and clinical trials in humans are planned for the near future.