Abstract
BackgroundMethylthioadenosine is a metabolite of the polyamine pathway that modulates methyltransferase activity, thereby influencing DNA and protein methylation. Since methylthioadenosine produces neuroprotection in models of inflammation, ischemia and epilepsy, we set out to evaluate the role of methylthioadenosine in promoting remyelination, a process that will protect axons in demyelinating diseases and that will aid functional recovery.MethodsThe effect of methylthioadenosine in promoting remyelination was tested in mouse cerebellum organotypic cultures that were exposed to lipopolysaccharide to induce neuroinflammation, or lysolecithin to induce chemical demyelination. In addition methylthioadenosine administration was also tested in vivo, using the cuprizone model of demyelination. The molecular pathways involved in this methylthioadenosine activity were evaluated in primary cortical mouse astrocytes.ResultsIn models of neuroinflammation or chemical demyelination, methylthioadenosine prevented the loss of myelin and promoted remyelination in vitro by increasing the number of mature myelinating oligodendrocytes. Methylthioadenosine enhanced myelin production in the cuprizone model, in conjunction with a clinical improvement. Methylthioadenosine enhanced STAT-3 phosphorylation in astrocytes in vitro, and the production of ciliary neurotrophic factor (CNTF), a trophic factor known to promote oligodendrocyte maturation and differentiation, as well as remyelination.ConclusionsThe remyelination promoted by methylthioadenosine suggests a role for the polyamine pathway in oligodendrocyte maturation and survival, paving the way for new therapeutic strategies to promote regeneration in Multiple Sclerosis and other demyelinating diseases.
Highlights
Methylthioadenosine is a metabolite of the polyamine pathway that modulates methyltransferase activity, thereby influencing DNA and protein methylation
Methylthioadenosine promotes remyelination in organotypic cerebellar cultures Neuroinflammation is a common process in several neurological diseases, including Multiple Sclerosis (MS) where it leads to demyelination and axonal damage
We observed a significant decrease in interleukin 1β (IL-1β), TNF-α and inducible nitric oxide synthase (iNOS) expression in methylthioadenosine pretreated cultures (Fig. 1B), as described previously [16], as well as the persistence of cyclic-nucleotide ́-phosphodiesterase (CNPase) detected in Western blots (Fig. 1B)
Summary
Methylthioadenosine is a metabolite of the polyamine pathway that modulates methyltransferase activity, thereby influencing DNA and protein methylation. Since methylthioadenosine produces neuroprotection in models of inflammation, ischemia and epilepsy, we set out to evaluate the role of methylthioadenosine in promoting remyelination, a process that will protect axons in demyelinating diseases and that will aid functional recovery. Methylthioadenosine exhibits immunomodulatory activity by suppressing the production of pro-inflammatory cytokines and enhancing the production of antiinflammatory cytokines through an interaction with the nuclear factor kappa B (NFkB) pathway. Such activity produces benefits in models of autoimmune diseases like MS [13, 14]. Methylthioadenosine displays neuroprotective activity, preventing neuronal damage in models of ischemia, epilepsy and Parkinson’s disease [15]
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