title: Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition.
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.
authors: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
authors: Francois
authors: F
authors: Renault-Mihara
authors: Hiroyuki
authors: H
authors: Katoh
authors: Takeshi
authors: T
authors: Ikegami
authors: Akio
authors: A
authors: Iwanami
authors: Masahiko
authors: M
authors: Mukaino
authors: Akimasa
authors: A
authors: Yasuda
authors: Satoshi
authors: S
authors: Nori
authors: Yo
authors: Y
authors: Mabuchi
authors: Hirobumi
authors: H
authors: Tada
authors: Shinsuke
authors: S
authors: Shibata
authors: Ken
authors: K
authors: Saito
authors: Masayuki
authors: M
authors: Matsushita
authors: Kozo
authors: K
authors: Kaibuchi
authors: Seiji
authors: S
authors: Okada
authors: Yoshiaki
authors: Y
authors: Toyama
authors: Masaya
authors: M
authors: Nakamura
authors: Hideyuki
authors: H
authors: Okano
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*
chemical_list: D004791:Enzyme Inhibitors; D039641:Integrin beta Chains; D038362:Glycogen Synthase Kinase 3