Stroke Literature Synopses: Basic Science.

Sozmen et al (Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice. Proc Natl Acad Sci USA. 2016;113:E8453–E8462. doi: 10.1073/ pnas.1615322113) investigated the roles of Nogo/ NgR1 signaling in remyelination after white matter stroke. This study used a mouse model of white matter stroke by injecting L-Nio into the corpus callosum region. L-Nio is a nonselective inhibitor of all nitric oxide synthase isoforms, and L-Nio injection induces focal ischemia by vasoconstriction. With this model, the authors first demonstrated that oligodendrocyte precursor cells proliferated in the damaged white matter region. However, those oligodendrocyte precursor cells failed to mature into oligodendrocytes but instead differentiated toward astrocytes. Because Nogo/NgR1 signaling regulates oligodendrocyte precursor cell differentiation, the authors then examined the expression levels of NgR1-binding molecules after white matter stroke in both young (>2.5 months old) and aged (24 months old) mice by assessing their mRNA levels in subcortical white matter region. In both young and aged mice, white matter stroke increased the levels of NgR1 ligands and decreased the ones of endogenous NgR1 inhibitors, but those changes were more significant in aged mice. Finally, to study the roles of NgR1 ligands in white matter repair, the authors used NgR(OMNI)-Fc, an engineered soluble hybrid of NgR1/NgR2 that binds and neutralizes several NgR1 ligands. Even in aged mice, animals that receive NgR(OMNI)-Fc exhibited a greater number of mature oligodendrocytes along with enhanced motor recovery under the conditions of white matter stroke. These data demonstrated the negative effects of NgR1 ligands in white matter repair after injury, but the NgR1 actions can be neutralized by clinically relevant engineered compounds.