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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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Ro3303544 is more potent than a previously utilized GSK-3 inhibitorTreatment of E17 rat hippocampal neurons in vitro with 1 µM Ro3303544 for 48 h resulted in dramatic nuclear and perinuclear accumulation of β-catenin. Scale bars: 20 µm.Complete abrogation of Thr514-CRMP2 phosphorylation with Ro3303544 under the same conditions as in A confirmed the higher potency of Ro33034544 compared to SB415286. Data represent mean ± SEM of three independent experiments. ***p < 0.001; *p < 0.05.Treatment of E17 rat hippocampal neurons in vitro with Ro3303544 for 72 h significantly promoted neurite outgrowth. Green: βIII-tubulin, blue: Hoechst. Scale bar: 50 µm. Data represent mean ± SD of three independent experiments performed in triplicate. ***p < 0.001.
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fig01: Ro3303544 is more potent than a previously utilized GSK-3 inhibitorTreatment of E17 rat hippocampal neurons in vitro with 1 µM Ro3303544 for 48 h resulted in dramatic nuclear and perinuclear accumulation of β-catenin. Scale bars: 20 µm.Complete abrogation of Thr514-CRMP2 phosphorylation with Ro3303544 under the same conditions as in A confirmed the higher potency of Ro33034544 compared to SB415286. Data represent mean ± SEM of three independent experiments. ***p < 0.001; *p < 0.05.Treatment of E17 rat hippocampal neurons in vitro with Ro3303544 for 72 h significantly promoted neurite outgrowth. Green: βIII-tubulin, blue: Hoechst. Scale bar: 50 µm. Data represent mean ± SD of three independent experiments performed in triplicate. ***p < 0.001.

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).


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)

Ro3303544 is more potent than a previously utilized GSK-3 inhibitorTreatment of E17 rat hippocampal neurons in vitro with 1 µM Ro3303544 for 48 h resulted in dramatic nuclear and perinuclear accumulation of β-catenin. Scale bars: 20 µm.Complete abrogation of Thr514-CRMP2 phosphorylation with Ro3303544 under the same conditions as in A confirmed the higher potency of Ro33034544 compared to SB415286. Data represent mean ± SEM of three independent experiments. ***p < 0.001; *p < 0.05.Treatment of E17 rat hippocampal neurons in vitro with Ro3303544 for 72 h significantly promoted neurite outgrowth. Green: βIII-tubulin, blue: Hoechst. Scale bar: 50 µm. Data represent mean ± SD of three independent experiments performed in triplicate. ***p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

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

fig01: Ro3303544 is more potent than a previously utilized GSK-3 inhibitorTreatment of E17 rat hippocampal neurons in vitro with 1 µM Ro3303544 for 48 h resulted in dramatic nuclear and perinuclear accumulation of β-catenin. Scale bars: 20 µm.Complete abrogation of Thr514-CRMP2 phosphorylation with Ro3303544 under the same conditions as in A confirmed the higher potency of Ro33034544 compared to SB415286. Data represent mean ± SEM of three independent experiments. ***p < 0.001; *p < 0.05.Treatment of E17 rat hippocampal neurons in vitro with Ro3303544 for 72 h significantly promoted neurite outgrowth. Green: βIII-tubulin, blue: Hoechst. Scale bar: 50 µm. Data represent mean ± SD of three independent experiments performed in triplicate. ***p < 0.001.
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).

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