Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition

Francois Renault-Mihara, Hiroyuki Katoh, Takeshi Ikegami, Akio Iwanami, Masahiko Mukaino, Akimasa Yasuda, Satoshi Nori, Yo Mabuchi, Hirobumi Tada, Shinsuke Shibata, Ken Saito, Masayuki Matsushita, Kozo Kaibuchi, Seiji Okada, Yoshiaki Toyama, Masaya Nakamura, Hideyuki Okano

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39 Citations (Scopus)

Abstract

The migratory response of astrocytes is essential for restricting inflammation and preserving tissue function after spinal cord injury (SCI), but the mechanisms involved are poorly understood. Here, we observed stimulation of in vitro astrocyte migration by the new potent glycogen synthase kinase-3 (GSK-3) inhibitor Ro3303544 and investigated the effect of Ro3303544 administration for 5 days following SCI in mice. This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibres and significantly promoted functional recovery. Moreover, the decreased extent of chondroitin sulphate proteoglycans and collagen IV demonstrated that scarring was reduced in Ro3303544-treated mice. 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.

Original languageEnglish
Pages (from-to)682-696
Number of pages15
JournalEMBO Molecular Medicine
Volume3
Issue number11
DOIs
Publication statusPublished - 11-2011

All Science Journal Classification (ASJC) codes

  • Molecular Medicine

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    Renault-Mihara, F., Katoh, H., Ikegami, T., Iwanami, A., Mukaino, M., Yasuda, A., Nori, S., Mabuchi, Y., Tada, H., Shibata, S., Saito, K., Matsushita, M., Kaibuchi, K., Okada, S., Toyama, Y., Nakamura, M., & Okano, H. (2011). Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition. EMBO Molecular Medicine, 3(11), 682-696. https://doi.org/10.1002/emmm.201100179