Delayed administration of a potent cyclin dependent kinase and glycogen synthase kinase 3 β inhibitor produces long-term neuroprotection in a hypoxia-ischemia model of brain injury

Cowper-Smith, Christopher D.; Anger, G; Magal, Ella; Norman, Mark H.; Robertson, George S.

doi:10.1016/j.neuroscience.2008.05.051

Cited by 21 publications

(18 citation statements)

References 53 publications

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“…The MPTP-triggered cell death was closely associated with IRI development (15). Along the same lines of cytoprotection, Gsk3 inhibition was also shown to protect kidneys and brains from IRI pathology (29–31), as well as livers from drug-induced toxicity (32). Our in vitro hepatocyte culture data are consistent with the positive regulatory role of Gsk3 in stress-induced cell death pathway (data not shown).…”

Section: Discussionmentioning

confidence: 98%

Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism

et al. 2011

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The ubiquitous serine/threnine kinase glycogen synthase kinase 3β (Gsk3β) differentially regulates macrophage TLR-triggered pro- and anti-inflammatory cytokine programs. This study was designed to determine in vivo role and therapeutic potential of Gsk3β modulation in tissue inflammation and injury in a murine model of liver partial warm ischemia/reperfusion (IRI). As a constitutively activated liver kinase, Gsk3β became quickly inactivated (phosphorylated) following IR. The active Gsk3β, however, was essential for the development of IRI pathology, as administration of its specific inhibitor SB216763, ameliorated the hepatocellular damage, evidenced by reduced sALT levels and well-preserved liver architecture, compared with controls. The liver protective effect of Gsk3β inhibition was dependent on an immune regulatory mechanism, rather than direct cytoprotection via mitochondria permeability transition pores (MPTP). Indeed: (a) co-administration of SB216763 and atractyloside (MPTP opener) failed to abrogate local cytoprotective Gsk3β inhibition effect; (b) SB216763 selectively inhibited IR-triggered liver pro-inflammatory, but spared IL-10, gene induction program; and (c) IL-10 neutralization restored liver inflammation and IRI in SB216763-treated mice. Gsk3β inactivation by IR was a self-regulatory mechanism in liver homeostasis, critically dependent on phosphoinositide 3 (PI3)-kinase activation, as administration of PI3 kinase inhibitor, wortmannin, reduced Gsk3 phosphorylation and augmented liver damage. In vitro, IL-10 was critical for the suppression of pro-inflammatory gene programs by Gsk3 inhibition in bone marrow-derived macrophages in response to TLR4 stimulation. Our novel findings document the key immune regulatory function of Gsk3β signaling in the pathophysiology of liver IRI, and provide the rationale to target Gsk3β as a refined therapeutic strategy to ameliorate liver IRI.

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Section: Discussionmentioning

confidence: 98%

Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism

et al. 2011

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“…This was accompanied by suppression of ischemia-induced oxidative stress, apoptosis, and neuroinflammation. Delayed treatment with Compound I, a GSK-3β and Cdk inhibitor, decreased TUNEL-positive cells in the ipsilateral hippocampus and striatum of adult (but not juvenile) mice subjected to hypoxic–ischemic injury (Cowper-Smith et al, 2008). These neuroprotective effects of Compound I were associated with long-lasting functional recovery.…”

Section: Neuroprotective Effects Of Lithium In Preclinical Models Of mentioning

confidence: 99%

GSK-3 as a Target for Lithium-Induced Neuroprotection Against Excitotoxicity in Neuronal Cultures and Animal Models of Ischemic Stroke

Chuang¹,

Wang²,

Chiu³

2011

Front. Mol. Neurosci.

143

114

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The mood stabilizer lithium inhibits glycogen synthase kinase-3 (GSK-3) directly or indirectly by enhancing serine phosphorylation of both α and β isoforms. Lithium robustly protected primary brain neurons from glutamate-induced excitotoxicity; these actions were mimicked by other GSK-3 inhibitors or silencing/inhibiting GSK-3α and/or β isoforms. Lithium rapidly activated Akt to enhance GSK-3 serine phosphorylation and to block glutamate-induced Akt inactivation. Lithium also up-regulated Bcl-2 and suppressed glutamate-induced p53 and Bax. Induction of brain-derived neurotrophic factor (BDNF) was required for lithium’s neuroprotection to occur. BDNF promoter IV was activated by GSK-3 inhibition using lithium or other drugs, or through gene silencing/inactivation of either isoform. Further, lithium’s neuroprotective effects were associated with inhibition of NMDA receptor-mediated calcium influx and down-stream signaling. In rodent ischemic models, post-insult treatment with lithium decreased infarct volume, ameliorated neurological deficits, and improved functional recovery. Up-regulation of heat-shock protein 70 and Bcl-2 as well as down-regulation of p53 likely contributed to lithium’s protective effects. Delayed treatment with lithium improved functional MRI responses, which was accompanied by enhanced angiogenesis. Two GSK-3-regulated pro-angiogenic factors, matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor were induced by lithium. Finally, lithium promoted migration of mesenchymal stem cells (MSCs) by up-regulation of MMP-9 through GSK-3β inhibition. Notably, transplantation of lithium-primed MSCs into ischemic rats enhanced MSC migration to the injured brain regions and improved the neurological performance. Several other GSK-3 inhibitors have also been reported to be beneficial in rodent ischemic models. Together, GSK-3 inhibition is a rational strategy to combat ischemic stroke and other excitotoxicity-related brain disorders.

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“…Changes in GSK-3b activity that depend on the region, the injury severity, and ischemia model occur after cerebral ischemia; for example, increased expression of GSK-3b by cortical and striatal neurons following global ischemia (Bhat et al, 2000;Sasaki et al, 2001;Cowper-Smith et al, 2008), decreases in GSK-3b expression in the hippocampal CA1, but not CA3 region following global ischemia Fig. 6.…”

Section: Discussionmentioning

confidence: 99%

Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus

et al. 2015

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Delayed administration of a potent cyclin dependent kinase and glycogen synthase kinase 3 β inhibitor produces long-term neuroprotection in a hypoxia-ischemia model of brain injury

Cited by 21 publications

References 53 publications

Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism

Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism

GSK-3 as a Target for Lithium-Induced Neuroprotection Against Excitotoxicity in Neuronal Cultures and Animal Models of Ischemic Stroke

Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus

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