Glycogen synthase kinase 3 is part of the molecular machinery regulating the adaptive response to LPS stimulation in microglial cells

Ajmone‐Cat, Maria Antonietta; D’Urso, Maria Cristina; Blasio, Giorgia di; Brignone, Maria Stefania; Simone, Roberta De; Minghetti, Luisa

doi:10.1016/j.bbi.2015.11.012

Cited by 55 publications

(41 citation statements)

References 47 publications

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“…Therefore, in our study, we administered TWS119 at 3.5 h after MCAO and found that it reduced the permeability of the BBB. This finding suggests that TWS119 has a protective effect on the BBB after ischemic stroke, and GSK-3β could be a potential target for brain protection, which was consistent with other studies33, 34.…”

Section: Discussionsupporting

confidence: 92%

GSK-3β as a target for protection against transient cerebral ischemia

Wang¹,

Li²,

Wang³

et al. 2017

Int. J. Med. Sci.

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Stroke remains the leading cause of death and disability worldwide. This fact highlights the need to search for potential drug targets that can reduce stroke-related brain damage. We showed recently that a glycogen synthase kinase-3β (GSK-3β) inhibitor attenuates tissue plasminogen activator-induced hemorrhagic transformation after permanent focal cerebral ischemia. Here, we examined whether GSK-3β inhibition mitigates early ischemia-reperfusion stroke injury and investigated its potential mechanism of action. We used the rat middle cerebral artery occlusion (MCAO) model to mimic transient cerebral ischemia. At 3.5 h after MCAO, cerebral blood flow was restored, and rats were administered DMSO (vehicle, 1% in saline) or GSK-3β inhibitor TWS119 (30 mg/kg) by intraperitoneal injection. Animals were sacrificed 24 h after MCAO. TWS119 treatment reduced neurologic deficits, brain edema, infarct volume, and blood-brain barrier permeability compared with those in the vehicle group. TWS119 treatment also increased the protein expression of β-catenin and zonula occludens-1 but decreased β-catenin phosphorylation while suppressing the expression of GSK-3β. These results indicate that GSK-3β inhibition protects the blood-brain barrier and attenuates early ischemia-reperfusion stroke injury. This protection may be related to early activation of the Wnt/β-catenin signaling pathway.

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Section: Discussionsupporting

confidence: 92%

GSK-3β as a target for protection against transient cerebral ischemia

Wang¹,

Li²,

Wang³

et al. 2017

Int. J. Med. Sci.

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“…Activation of the signalling cascade mediated by glycogen synthase kinase (GSK)-3 functions as an endogenous mechanism to inhibit IL-10 production, whilst enhancing the production of pro-inflammatory cytokines, by microglial cells upon TLR4 activation [127]. In line with this, abrogation of GSK-3, through chemical inhibitors or siRNA, was shown to restore TLR4-induced IL-10 production in microglia with a concomitant reduction in the levels of pro-inflammatory mediators [82, 128]. Furthermore, blockade of GSK-3 was shown to induce p38 and ERK, thus confirming the role for these MAPKs in enhancing IL-10 production [82].…”

Section: Molecular Mechanisms Regulating Il-10 Production In the Cnsmentioning

confidence: 99%

Balancing the immune response in the brain: IL-10 and its regulation

Lobo-Silva

Carriche

Castro

et al. 2016

J Neuroinflammation

296

185

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BackgroundThe inflammatory response is critical to fight insults, such as pathogen invasion or tissue damage, but if not resolved often becomes detrimental to the host. A growing body of evidence places non-resolved inflammation at the core of various pathologies, from cancer to neurodegenerative diseases. It is therefore not surprising that the immune system has evolved several regulatory mechanisms to achieve maximum protection in the absence of pathology.Main bodyThe production of the anti-inflammatory cytokine interleukin (IL)-10 is one of the most important mechanisms evolved by many immune cells to counteract damage driven by excessive inflammation. Innate immune cells of the central nervous system, notably microglia, are no exception and produce IL-10 downstream of pattern recognition receptors activation. However, whereas the molecular mechanisms regulating IL-10 expression by innate and acquired immune cells of the periphery have been extensively addressed, our knowledge on the modulation of IL-10 expression by central nervous cells is much scattered. This review addresses the current understanding on the molecular mechanisms regulating IL-10 expression by innate immune cells of the brain and the implications of IL-10 modulation in neurodegenerative disorders.ConclusionThe regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain.

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“…Inflammatory mediators are being increasingly incriminated in mood disorders; in this regard the current evidence suggests that a constant low-grade inflammatory state persists that causes neuro-progression and also underlies the many comorbidities associated with these conditions 28). GSK3 is thought to increase the phosphorylation of nuclear factor kappa B and signal transducer and activator of transcription 3, which are the main regulators of the production of pro-inflammatory cytokines, at the same time inhibiting cAMP response element-binding protein and activator protein 1 which effect expression of anti-inflammatory cytokine, interleukin (IL)-10. mTOR pathway has been shown to decrease inflammatory cytokine production by inactivating GSK3, while inhibitors of this enzyme rescue mice from an otherwise lethal dose of lipopolysacchride 29). To sum up, in BD increased activity of GSK3 may underpin enhanced expression of key inflammatory mediators like IL-6 and tumor necrosis factor α during affective exacerbations, and inhibition of this enzyme by mood stabilizers leads to the resolution of the inflammatory state.…”

Section: Main Subjectsmentioning

confidence: 99%

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Muneer

2017

Clin Psychopharmacol Neurosci

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The neurobiology of bipolar disorder, a chronic and systemic ailment is not completely understood. The bipolar phenotype manifests in myriad ways, and psychopharmacological agents like lithium have long term beneficial effects. The enzyme glycogen synthase kinase 3 (GSK3) has come into focus, as lithium and several other mood stabilizing medications inhibit its activity. This kinase and its key upstream modulator, Wnt are dysregulated in mood disorders and there is a growing impetus to delineate the chief substrates involved in the development of these illnesses. In May 2016, a comprehensive literature search was undertaken which revealed that there is over activity of GSK3 in bipolar disorder with deleterious downstream effects like proinflammatory status, increased oxidative stress, and circadian dysregulation leading to declining neurotrophic support and enhanced apoptosis of neural elements. By developing specific GSK3 inhibitors the progressive worsening in bipolar disorder can be forestalled with improved prospects for the sufferers.

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Glycogen synthase kinase 3 is part of the molecular machinery regulating the adaptive response to LPS stimulation in microglial cells

Cited by 55 publications

References 47 publications

GSK-3β as a target for protection against transient cerebral ischemia

GSK-3β as a target for protection against transient cerebral ischemia

Balancing the immune response in the brain: IL-10 and its regulation

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

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