Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition.
Bottom Line: This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibres and significantly promoted functional recovery.A variety of in vitro and in vivo experiments further suggested that GSK-3 inhibition stimulated astrocyte migration by decreasing adhesive activity via reduced surface expression of β1-integrin.Our results reveal a novel benefit of GSK-3 inhibition for SCI and suggest that the stimulation of astrocyte migration is a feasible therapeutic strategy for traumatic injury in the central nervous system.
Affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.Show MeSH
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Mentions: Although the potency and specificity of Ro3303544 have been evaluated in kinase assays (Adachi et al, 2007), its potency was evaluated in more detail in primary cultures of hippocampal neurons, which are recognized as very sensitive to any toxicity. In the absence of Wnt-induced signalling, cytoplasmic β-catenin is constitutively phosphorylated by GSK-3 and degraded by the ubiquitin-proteasome system (Inestrosa & Arenas, 2010). Upon initiation of the Wnt signal and subsequent inhibition of GSK-3 activity, β-catenin accumulates in the cytoplasm, translocates into the nucleus and promotes the transactivation of various genes. Treatment of E17.5 hippocampal neurons with 1 µM Ro3303544 for 48 h resulted in a strong nuclear and peri-nuclear accumulation of β-catenin as expected (Fig 1A).
Affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.