Cell cycle inhibition attenuates microglial proliferation and production of IL‐1β, MIP‐1α, and NO after focal cerebral ischemia in the rat

Zhang, Qiang; Chen, Chen; Lu, Junlin; Xie, Mingxing; Pan, Dengji; Luo, Xiang; Yu, Zhiyuan; Dong, Qiang; Wang, Wei

doi:10.1002/glia.20816

Cited by 43 publications

(45 citation statements)

References 57 publications

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“…In our previous study, we found that high glucose induced cyclin B1 expression in neurons [11]. It has been reported that the expression of cyclin A, cyclin B, and cyclin E was increased in glial cells in ischemia brain [36]. In the present study, we found that cyclin B1 was upregulated in OGD/R treated neurons, which means that the increased expression of cyclin B1 plays an important role in mediating neuronal cells re-entering cell cycle.…”

Section: Discussionsupporting

confidence: 63%

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

Meng

Chu

Yang

et al. 2016

Cell Physiol Biochem

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Background/Aims: Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. Methods: Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. Results: Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. Conclusion: Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R.

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Section: Discussionsupporting

confidence: 63%

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

Meng

Chu

Yang

et al. 2016

Cell Physiol Biochem

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“…20,21 Microglia activation manifests morphology change into an amoeboid shape, increased phagocytosis, and release of cytokines. 22,23 Our in vivo study exhibited that ICV injection of lentiviral-overexpressed miR-424 prominently decreased ramified Iba-1-positive microglia and Iba-1 protein levels, and, meanwhile, reduced the TNF-α level in the cortex after 8-hour ischemia. Moreover, in vitro study showed that miR-424 mimics reduced the activation of BV2 microglial cells and decreased mRNA level and release of TNF-α.…”

Section: Discussionmentioning

confidence: 79%

MiRNA-424 Protects Against Permanent Focal Cerebral Ischemia Injury in Mice Involving Suppressing Microglia Activation

Zhao

Wang²,

Gao³

et al. 2013

Stroke

171

109

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MiR-424 is a member of the miR-16 family. The genomic organization of miR-424 and miR-503 suggested that they are part of the same transcriptional unit .2 Increasing evidence indicates the crucial role of miR-424 in regulation of cell differentiation. A study in human cord blood CD34+ cells showed that miR-424 is highly expressed during monocyte/ macrophage differentiation , 3 and miR-424 overexpression promotes the maturation of monoblastic cell . 4 Two transcriptional start sites for the pri-miR-424 have been identified at upstream of the pre-miRNA 5′end. The PU.1 factor was shown to interact with the miR-424 promoter and to be responsible for its activation . 3,5,6 In addition, miR-322/424 is induced during muscle differentiation through cdk2 inhibition . 7 MiR-424 expression in human bone marrow-derived mesenchymal stem cells was reported to be higher than in osteoblasts and chondrocytes.8 However, miR-424 was found to negatively regulate the adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells, 9 suggestingBackground and Purpose-We observed that microRNA-424 (miR-424) significantly decreased in an miRNA profile of circulating lymphocytes of patients with ischemic stroke. The present study focused on the potential and mechanism of miR-424 in protecting ischemic brain injury in mice. Methods-Cerebral ischemia was induced by middle cerebral artery occlusion in C57/BL6 mice. Cerebral infarction volume, neuronal apoptosis, and microglia activation were determined by 2,3,5-triphenyltetrazolium chloride staining, immunofluorescence, and Western blot. BV2 microglial cell activity, cell cycle, mRNA, and protein levels of miR-424 targets were accessed by enzyme-linked immunosorbent assay, flow cytometry, real-time polymerase chain reaction, and Western blot, respectively. Results-MiR-424 levels were decreased in the plasma of patients with acute ischemic stroke, as well as in mouse plasma and ipsilateral brain tissue at 4, 8, and 24 hours after ischemia, likewise, in the cortex, hippocampus, and basal ganglia, respectively, after 8-hour ischemia. Interestingly, pre-and post-treatment with overexpression of miR-424 both decreased cerebral infarction size and brain edema after middle cerebral artery occlusion. Meanwhile, lentiviral overexpression of miR-424 inhibited neuronal apoptosis and microglia activation, including suppressing ionized calcium binding adaptor molecule-1 immunoreactivity and protein level, and reduced tumor necrosis factor-α production. In vitro study demonstrated that miR-424 mimics caused G1 phase cell-cycle arrest, inhibited BV2 microglia activity, and reduced the mRNA and protein levels of CDC25A, cyclin D1, and CDK6 in BV2 microglial cells, which were upregulated in brain of middle cerebral artery occlusion mice. Conclusions-MiR-424 overexpression lessened the ischemic brain injury through suppressing microglia activation by translational depression of key activators of G1/S transition, suggesting a novel miR-based intervention strategy for stroke. (Stroke. 2013;44...

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“…According to existing studies, inflammatory mediators synthesized in microglia upon activation contribute largely to ischemic brain injury, promoting neuronal death in the penumbra and the progression of penumbra into ischemic infarction [42,43] . The phosphorylation and activation of p38 is of particular importance in regulating the production of inflammatory mediators induced by hypoxia [44,45] .…”

Section: Discussionmentioning

confidence: 99%

T33, a novel peroxisome proliferator-activated receptor γ/α agonist, exerts neuroprotective action via its anti-inflammatory activities

et al. 2011

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Aim: To examine the neuroprotective effects of T33, a peroxisome proliferator-activated receptor gamma/alpha (PPARγ/α) agonist, in acute ischemic models in vitro and in vivo. Methods: Primary astrocytes subjected to oxygen-glucose deprivation/reperfusion (O/R) and BV-2 cells subjected to hypoxia were used as a model simulating the ischemic core and penumbra, respectively. The mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured using qPCR. The levels of TNF-α secreted by BV-2 cells were measured using ELISA. Protein levels of cyclooxygenase-2 (COX-2), p65, phosphorylated I-κBα/I-κBα, phosphorylated I-κB kinase (pIKK), phosphorylated eukaryote initiation factor 2α (p-eIF-2α)/eIF-2α and p-p38/p38 were detected using Western blot. PPARγ activity was measured using EMSA. The neuroprotection in vivo was examined in rat middle cerebral artery occlusion (MCAO) model with neurological scoring and TTC staining. Results: Addition of T33 (0.5 µmol/L) increased the level of I-κBα protein in primary astrocytes subjected to O/R, which was due to promoting protein synthesis without affecting degradation. In primary astrocytes subjected to O/R, addition of T33 amplified I-κBα gene transcription and mRNA translation, thus suppressing the nuclear factor-kappa B (NF-κB) pathway and reducing inflammatory mediators (TNF-α, IL-1β, and COX-2). In BV-2 cells subjected to hypoxia, T33 (0.5 µmol/L) reduced TNF-α, COX-2, and p-P38 production, which was antagonized by pre-administration of the specific PPARγ antagonist GW9662 (30 µmol/L). T33 (2 mg/kg, ip) attenuated MCAO-induced inflammatory responses and brain infarction, which was antagonized by pre-administered GW9662 (4 mg/kg, ip). Conclusion: T33 exerted anti-inflammatory effects in the ischemic core and penumbra via PPARγ activation, which contributed to its neuroprotective action.

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Cell cycle inhibition attenuates microglial proliferation and production of IL‐1β, MIP‐1α, and NO after focal cerebral ischemia in the rat

Cited by 43 publications

References 57 publications

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

MiRNA-424 Protects Against Permanent Focal Cerebral Ischemia Injury in Mice Involving Suppressing Microglia Activation

T33, a novel peroxisome proliferator-activated receptor γ/α agonist, exerts neuroprotective action via its anti-inflammatory activities

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