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

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 - EMBO Mol Med (2011)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.

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In vivo administration of Ro3303544 for the first 5 days after SCI in mice is effectiveExperimental design.Immunoblot of spinal cord lysates at 5 DPI revealed that intraperitoneal injections of Ro3303544 potently increased the levels of a phosphorylated active form of β-catenin in vivo. Histogram displays the mean ± SEM of one experiment (four mice per group) (*p < 0.05, Wilcoxon rank-sum test).At 4 DPI, confocal analysis showed that while active β-catenin is weakly expressed and localized exclusively to the cytoplasm of neurons in the spinal cords of control mice (arrows), injections of Ro3303544 resulted in drastic upregulation and nuclear accumulation of β-catenin in neurons (arrowheads). Note that the relative upregulation of active β-catenin is even more pronounced in reactive astrocytes (asterisks).
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fig03: In vivo administration of Ro3303544 for the first 5 days after SCI in mice is effectiveExperimental design.Immunoblot of spinal cord lysates at 5 DPI revealed that intraperitoneal injections of Ro3303544 potently increased the levels of a phosphorylated active form of β-catenin in vivo. Histogram displays the mean ± SEM of one experiment (four mice per group) (*p < 0.05, Wilcoxon rank-sum test).At 4 DPI, confocal analysis showed that while active β-catenin is weakly expressed and localized exclusively to the cytoplasm of neurons in the spinal cords of control mice (arrows), injections of Ro3303544 resulted in drastic upregulation and nuclear accumulation of β-catenin in neurons (arrowheads). Note that the relative upregulation of active β-catenin is even more pronounced in reactive astrocytes (asterisks).

Mentions: Next, the in vivo effects of Ro3303544 after SCI were examined. To focus on the compaction of inflammatory cells by reactive astrocytes, the protocol consisted of intraperitoneal administration of Ro3303544 for only the first 5 days after thoracic contusive SCI in mice (Fig 3A). This is in contrast to a previous report in which Dill et al (2008) administered SB415286 for 3–4 weeks after SCI and reported increased axonal growth and improved functional recovery. Axonal growth is a delayed event that commences after the inflammatory reaction has subsided, while the compaction of inflammatory cells by reactive astrocytes occurs during the sub-acute phase of SCI, namely the first 2 weeks after injury in mice (Okada et al, 2006).


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

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 - EMBO Mol Med (2011)

In vivo administration of Ro3303544 for the first 5 days after SCI in mice is effectiveExperimental design.Immunoblot of spinal cord lysates at 5 DPI revealed that intraperitoneal injections of Ro3303544 potently increased the levels of a phosphorylated active form of β-catenin in vivo. Histogram displays the mean ± SEM of one experiment (four mice per group) (*p < 0.05, Wilcoxon rank-sum test).At 4 DPI, confocal analysis showed that while active β-catenin is weakly expressed and localized exclusively to the cytoplasm of neurons in the spinal cords of control mice (arrows), injections of Ro3303544 resulted in drastic upregulation and nuclear accumulation of β-catenin in neurons (arrowheads). Note that the relative upregulation of active β-catenin is even more pronounced in reactive astrocytes (asterisks).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3377108&req=5

fig03: In vivo administration of Ro3303544 for the first 5 days after SCI in mice is effectiveExperimental design.Immunoblot of spinal cord lysates at 5 DPI revealed that intraperitoneal injections of Ro3303544 potently increased the levels of a phosphorylated active form of β-catenin in vivo. Histogram displays the mean ± SEM of one experiment (four mice per group) (*p < 0.05, Wilcoxon rank-sum test).At 4 DPI, confocal analysis showed that while active β-catenin is weakly expressed and localized exclusively to the cytoplasm of neurons in the spinal cords of control mice (arrows), injections of Ro3303544 resulted in drastic upregulation and nuclear accumulation of β-catenin in neurons (arrowheads). Note that the relative upregulation of active β-catenin is even more pronounced in reactive astrocytes (asterisks).
Mentions: Next, the in vivo effects of Ro3303544 after SCI were examined. To focus on the compaction of inflammatory cells by reactive astrocytes, the protocol consisted of intraperitoneal administration of Ro3303544 for only the first 5 days after thoracic contusive SCI in mice (Fig 3A). This is in contrast to a previous report in which Dill et al (2008) administered SB415286 for 3–4 weeks after SCI and reported increased axonal growth and improved functional recovery. Axonal growth is a delayed event that commences after the inflammatory reaction has subsided, while the compaction of inflammatory cells by reactive astrocytes occurs during the sub-acute phase of SCI, namely the first 2 weeks after injury in mice (Okada et al, 2006).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus